Case#: Haider_2000_Proband_2, sex, age, and origin not reported

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband is part of a cohort in which all patients had a diagnosis of enhanced S-cone syndrome, based on electroretinogram and/or psychophysics, as well as optical coherence tomography. Other phenotypes within the cohort members (but not tracked individually) included increased sensitivity to blue light; visual loss, night blindness occurring from early in life, varying degrees of L-cone and M-cone vision, and retinal degeneration.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.

CaseMethod1: Sanger sequencing of NR2E3

CaseMethod2: SSCP analysis of PCR products from NR2E3

CaseGenotypingMethod: Genotyping was performed by Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.

Variant: The individual harbors the NM_014249.4(NR2E3):c.200_208del (p.Cys67_Gly69del) variant in the homozygous state.

ClinVarID: 5531

gnomAD: The variant was not found in gnomAD version 4.1.0.

VariantEvidence: NM_014249.4(NR2E3):c.200_208del (p.Cys67_Gly69del) is a short in-frame deletion variant within the zinc finger / DNA-binding domain of NR2E3.

CaseAddInfo: It is not clear whether the proband came from a consanguineous family.

CasePMIDs: N/A

Case#: Haider_2000_Proband_4, sex, age, and origin not reported

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband is part of a cohort in which all patients had a diagnosis of enhanced S-cone syndrome, based on electroretinogram and/or psychophysics, as well as optical coherence tomography. Other phenotypes within the cohort members (but not tracked individually) included increased sensitivity to blue light; visual loss, night blindness occurring from early in life, varying degrees of L-cone and M-cone vision, and retinal degeneration.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.

CaseMethod1: Sanger sequencing of NR2E3

CaseMethod2: SSCP analysis of PCR products from NR2E3

CaseGenotypingMethod: Genotyping was performed by Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.

Variant: The individual harbors the NM_014249.4(NR2E3):c.227G>A (p.Arg76Gln) variant in the homozygous state.

ClinVarID: 5530

gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.0004046 in the South Asian population (36 alleles / 88,984 total alleles, with 1 homozygote) https://gnomad.broadinstitute.org/variant/chr15-71811591-G-A?dataset=gnomad_r4

VariantEvidence: NM_014249.4(NR2E3):c.227G>A (p.Arg76Gln) is a missense variant within the zinc finger / DNA-binding domain of NR2E3, and occurs at the same amino acid position as another missense substitution reported in the same article.

CaseAddInfo: It is not clear whether the proband came from a consanguineous family.

CasePMIDs: N/A

FamilyLabel: van_Huet_2014_Family_A, national origin reported as Dutch

Family#PresentingHPOs: HP:0410280 (Pediatric onset), HP:0007663 (Reduced visual acuity), HP:0007787 (Posterior subcapsular cataract), HP:0011504 (Bull's eye maculopathy), HP:0500087 (Peripapillary atrophy), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007722 (Retinal pigment epithelial atrophy), HP:0007737 (Bone spicule pigmentation of the retina)

FamilyHPOFreeText: The patient and family members have been diagnosed with retinitis pigmentosa, with macular abnormalities present in all cases.

Family#PresentingNotHPOs: N/A

CountryOrigin: Netherlands

Ethnicity: Reported as Dutch

Race: Not mentioned

Family#PreviousTesting: Previous genotyping outside of the IMPG2 locus has not been described for this family.

Family#Method1: Sanger sequencing of the 19 exons of the IMPG2 gene

Family#Method2: N/A

Family#GenotypingMethod: Genotyping may have been limited to Sanger sequencing of the 19 exons of the IMPG2 gene, as previous genotyping of other loci has not been described for this family.

Affected: 3

Unaffected: 3

Segregations: Two segregations are reported in the family, with none inconsistent. The family is apparently not consanguineous. The pedigree is shown in Figure 1.

PublishedLOD: N/A

eLOD: 1.50

AddSegregationInfo: N/A

ProbandLabel: van_Huet_2014_Patient_A-II:1

Variant: The affected family members harbor the NM_016247.4(IMPG2):c.887+430_908+274del variant in the homozygous state.

ClinVar: 3547

gnomAD: This variant was not found in gnomAD v2.1.1.

FamilyAddInfo: Despite the homozygous state of the variant, the family is reportedly not consanguineous.

FamilyPMIDs: N/A

Case#: van_Huet_2014_Patient_F-II:2, female, age 10 years at time of onset, age 32 at the time of report, national origin reported as from Pakistan

CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0000662 (Nyctalopia), HP:0000545 (Myopia), HP:0007663 (Reduced visual acuity), HP:0011504 (Bull's eye maculopathy), HP:0100014 (Epiretinal membrane), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0000546 (Retinal degeneration), HP:0007737 (Bone spicule pigmentation of the retina)

CaseHPOFreeText: The patient and her family members have been diagnosed with retinitis pigmentosa, with macular abnormalities present in all cases.

CaseNotHPOs: HP:0000517 (Abnormal lens morphology, such as cataract)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping outside of the IMPG2 locus has not been described for this family.

CaseMethod1: Sanger sequencing of the 19 exons of the IMPG2 gene

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping may have been limited to Sanger sequencing of the 19 exons of the IMPG2 gene, as previous genotyping of other loci has not been described for this family.

Variant: The affected family members harbor the NM_016247.4(IMPG2):c.1680T>A (p.Tyr560Ter) variant in the homozygous state.

ClinVar: 437938

gnomAD: This variant was not found in gnomAD v2.1.1.

VariantEvidence: The NM_016247.4(IMPG2):c.1680T>A (p.Tyr560Ter) variant is a nonsense variant in exon 13 of 19 that is predicted to lead to nonsense mediated decay or at least to C-terminal truncation of 55% of the protein product.

CaseAddInfo: The family is reportedly consanguineous, with the parents being first cousins. The proband has an affected brother and an affected mother who have the same genotype, as well as a heterozygous carrier father.

CasePMIDs: PMID: 20673862

Case#: van_Huet_2014_Patient_H-II:6, female, age 17 years at time of onset, age 46 years at the time of report, national origin reported as Dutch

CasePresentingHPOs: Nyctalopia HP:0000662, HP:0011462 (Young adult onset), HP:0000545 (Myopia), HP:0007663 (Reduced visual acuity), HP:0000518 (Cataract), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000550 (Undetectable electroretinogram), HP:0011510 (Drusen)

CaseHPOFreeText: The patient and her family members have been diagnosed with retinitis pigmentosa, with macular abnormalities present in all cases.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of autozygosity mapping (PMID: 20673862).

CaseMethod1: Homozygosity mapping

CaseMethod2: Sanger sequencing of the 19 exons of the IMPG2 gene

CaseGenotypingMethod: Genotyping consisted of autozygosity mapping (PMID: 20673862) followed by Sanger sequencing of the 19 exons of the IMPG2 gene.

Variant: The affected family members harbor the NM_016247.4(IMPG2):c.513T>G (p.Tyr171Ter) and NM_016247.4(IMPG2):c.2716C>T (p.Arg906Ter) variants in the compound heterozygous state.

ClinVar: 191181, 3548

gnomAD: These two variants were not found in gnomAD v2.1.1.

VariantEvidence: The NM_016247.4(IMPG2):c.513T>G (p.Tyr171Ter) variant is a nonsense variant in exon 4 of 19 that is predicted to lead to nonsense mediated decay or at least to C-terminal truncation of 86% of the protein product. The NM_016247.4(IMPG2):c.2716C>T (p.Arg906Ter) variant is a nonsense variant in exon 13 of 19 that is predicted to lead to nonsense mediated decay or at least to C-terminal truncation of 27% of the protein product.

CaseAddInfo: The family is reportedly non-consanguineous, and the patient has a similarly affected sister with the same genotype. Segregation of the two variants has been demonstrated within the family.

CasePMIDs: PMID: 20673862

Case#: van_Huet_2014_Patient_B-II:1, female, in childhood at time of onset, age 66 at the time of report, national origin reported as Iraqi Jewish

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0011003 (High myopia), HP:0007663 (Reduced visual acuity), HP:0007787 (Posterior subcapsular cataract), HP:0100018 (Nuclear cataract), HP:0030856 (Posterior staphyloma), HP:0007401 (Macular atrophy), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007722 (Retinal pigment epithelial atrophy), HP:0007737 (Bone spicule pigmentation of the retina), HP:0007688 (Undetectable light- and dark-adapted electroretinogram)

CaseHPOFreeText: The patient and her family members have been diagnosed with retinitis pigmentosa, with macular abnormalities present in all cases.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping outside of the IMPG2 locus has not been described for this family.

CaseMethod1: Sanger sequencing of the 19 exons of the IMPG2 gene

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping may have been limited to Sanger sequencing of the 19 exons of the IMPG2 gene, as previous genotyping of other loci has not been described for this family.

Variant: The affected family members harbor the NM_016247.4(IMPG2):c.635C>G (p.Ser212Ter) variant in the homozygous state.

ClinVar: 3546

gnomAD: This variant was not found in gnomAD v2.1.1.

VariantEvidence: The NM_016247.4(IMPG2):c.635C>G (p.Ser212Ter) variant is a nonsense variant in exon 6 of 19 that is predicted to lead to nonsense mediated decay or at least to C-terminal truncation of 83% of the protein product.

CaseAddInfo: The family is reportedly consanguineous, with the parents being first cousins. The proband has two affected sisters who share the same genotype, and each parent is a heterozygous carrier.

CasePMIDs: PMID: 20673862

Case#: Huang_1995_Family_#3397_Patient_AR76, male, age and ethnic origin note mentioned

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000662 (Nyctalopia), HP:0007994 (Peripheral visual field loss), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude), HP:0007984 (Electronegative electroretinogram)

CaseHPOFreeText: The proband and his affected family members have been diagnosed with autosomal retinitis pigmentosa.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Sanger sequencing of PDE6A has been performed in the patient and her affected family members.

CaseMethod1: SSCP

CaseMethod2: Sanger sequencing of PDE6A

CaseGenotypingMethod: The patient and his affected sibling were subjected to SSCP of PDE6A PCR products followed by Sanger sequencing to identify the variant.

Variant: The proband harbors the NM_000440.3(PDE6A):c.1032C>A (p.Ser344Arg) and NM_000440.3(PDE6A):c.1683G>A (p.Trp561Ter) variants in the compound heterozygous state.

ClinVar: 13111, 13112

gnomAD: NM_000440.3(PDE6A):c.1032C>A (p.Ser344Arg) was not found in gnomAD v2.1.1, while NM_000440.3(PDE6A):c.1683G>A (p.Trp561Ter) was found at a frequency of 0.000008792 (1/113736) in the European non-Finnish population. https://gnomad.broadinstitute.org/variant/5-149274791-C-T

VariantEvidence: NM_000440.3(PDE6A):c.1032C>A (p.Ser344Arg) is a missense variant in exon 7 of 22 total, and does not have evidence of a functional effect on the protein product. NM_000440.3(PDE6A):c.1683G>A (p.Trp561Ter) is a nonsense variant in exon 13 of 22 total, and is predicted to trigger NMD or to at least disrupt the C-terminal 35% of the protein product.

CaseAddInfo: The proband is from a family with an affected sibling and unaffected parents.

CasePMIDs: N/A

Case#: Huang_1995_Family_#3526_Patient_AR23, female, age and ethnic origin note mentioned

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000662 (Nyctalopia), HP:0007994 (Peripheral visual field loss), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude), HP:0007984 (Electronegative electroretinogram)

CaseHPOFreeText: The proband and her affected family members have been diagnosed with autosomal retinitis pigmentosa.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Sanger sequencing of PDE6A has been performed in the patient and her affected family members.

CaseMethod1: SSCP

CaseMethod2: Sanger sequencing of PDE6A

CaseGenotypingMethod: The patient and her affected family members were subjected to SSCP of PDE6A PCR products followed by Sanger sequencing to identify the variant.

Variant: The proband harbors the NM_000440.3(PDE6A):c.1749C>G (p.Tyr583Ter) variant in the homozygous state.

ClinVar: 13110

gnomAD: This variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_000440.3(PDE6A):c.1749C>G (p.Tyr583Ter) is a nonsense variant in exon 14 of 22 total, and is predicted to trigger NMD or to at least truncate ~32% of the protein product.

CaseAddInfo: The proband is from a family with two affected siblings, two unaffected siblings, and unaffected parents.

CasePMIDs: N/A

FamilyLabel: Bowne_2011_Family_TCD-G

Family#PresentingHPOs: HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0007994 (Peripheral visual field loss), HP:0000533 (Chorioretinal atrophy), HP:0000546 (Retinal degeneration)

Family#PresentingHPOFreeText: Onset was in the 2nd to 5th decade of life, typically with impaired dark adaptation. Genotype-positive members of the family exhibited a wide range of phenotypes.

FamilyNotHPOs: HP:0003593 (Infantile onset), HP:0011463 (Childhood onset)

CountryOrigin: Ireland

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: SNP-based linkage analysis was performed on all family members, mapping the phenotype of autosomal dominant retinitis pigmentosa to an 8.8-Mb genomic region located at chr1 p31. Whole exome sequencing of 3 affected an 1 unaffected family members then identified candidate variants of interest.

Family#Method1: SNP-based linkage analysis and whole exome sequencing of a subset of family members

Family#Method2: Candidate gene sequencing

Family#GenotypingMethod: Sanger sequencing of 11 candidate genes among the 50 known genes from the mapped region, including RPE65 and PDE4B.

Affected: 20

Unaffected: N/A

Segregations: 21 segregations were reported. 4 genotype-positive individuals were unaffected (reflecting reduced penetrance), with one of them having an affected child. The pedigree can be found in Figure 1a. Consanguinity of the family was not mentioned.

PublishedLOD: 3.6

eLOD: 6.32

AddSegregationInfo: 4 genotype-positive individuals were unaffected, with one of them having an affected child. Another non-genotyped but unaffected individual had an affected child as well. In combination with the 20 genotype-positive and phenotype-positive individuals, this reflects incomplete penetrance of approximately 80%.

ProbandLabel: Bowne_2011_Family_TCD-G_Patient_53

Variant: Affected individuals harbor the NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant in one allele of RPE65.

ClinVar: 750796

gnomAD: The NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant was not found in gnomAD.

FamilyAddInfo: N/A

FamilyPMIDs: PMID: 20861475

Case#: Bowne_2011_Family_TCD-H_Patient_01, male, unspecified age, family origin in Ireland

CasePresentingHPOs: N/A

CaseHPOFreeText: The patient was provisionally diagnosed with choroideremia prior to genotyping that excluded the presence of a variant in the CHM locus.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Candidate gene sequencing of the CHM locus to exclude the initial diagnosis of choroideremia

CaseMethod1: Two-point linkage analysis of the RPE65 locus, as well as haplotype analysis using STR genotypes surrounding the variant of interest

CaseMethod2: Candidate gene sequencing

CaseGenotypingMethod: Sanger sequencing of the RPE65 locus

Variant: The patient harbors the NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant in one allele of RPE65.

ClinVar: 750796

gnomAD: The NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant was not found in gnomAD.

VariantEvidence: Exogenous expression of the variant reveals protein expression levels, cellular localization and retinoid isomerase activity comparable to the wild-type (PMID: 29659842). However, knock-in mouse models exhibit retinyl ester accumulation (PMID: 29659842), abnormally slow regeneration of 11-cis-retinal after light exposure, and ERG results indicative of delayed dark adaptation (PMID: 28041994). Mice with CRISPR-mediated knock-in of the variant also exhibit a splicing defect in RPE65 due to the introduction of a cryptic splice site, which likely triggers a frameshift, exclusion of exons 13 and 14 from the transcript, and premature truncation of the protein product (PMID: 30628748).

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Zeitz_2006_Family_A_II-5, male, onset in early childhood, family ancestry reported as Swiss

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000639 (Nystagmus), HP:0007663 (Reduced visual acuity), HP:0000613 (Photophobia)

CaseHPOFreeText: The proband and his sibling have diagnosis of congenital stationary night blindness, in the absence of family history of the disease. BCVA was 20/100 at age 15 years. Disease course was stationary for 30 years but later included a decrease in visual acuity and development of moderate photophobia.

CaseNotHPOs: HP:0000662 (Nyctalopia)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of PCR products from the CACNA1F gene. The authors also implied that similarly screening was performed all other known genes associated CSNB, which at the time included RHO, GNAT1, PDE6B, GRK1, SAG, NYX, and GRM6.

CaseMethod1: Sanger sequencing of CABP4

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping was limited to Sanger sequencing of PCR products from the CACNA1F and CABP4 genes, with possible sequencing of other known CSNB-associated genes RHO, GNAT1, PDE6B, GRK1, SAG, NYX, and GRM6.

Variant: The individual harbors the NM_145200.3(CABP4):c.800_801delAG variant in the homozygous state.

ClinVar ID: 1952

gnomAD: The variant is found in gnomAD version 4.1.1 at a frequency of 0.00007043 in the European (non-Finnish) population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/11-67226099-CAG-C?dataset=gnomad_r2_1

VariantEvidence: NM_145200.3(CABP4):c.800_801delAG is a frameshift variant within exon 6 of 6 that is predicted not to trigger nonsense-mediated decay but rather to disrupt the C-terminal 9 amino acids (3%) of the protein product and to extend the remaining protein by 91 additional amino acids. Analysis of patient mRNA indicates that splicing occurs normally but that expression at the mRNA level is decreased by more than 50% relative to the unaffected family member control.

CaseAddInfo: The proband's family is reportedly non-consanguineous, and includes a similarly affected brother who is also homozygous for the variant, as well as unaffected parents and 4 unaffected siblings who are heterozygous or lacking the variant (Figure 2A). Family history was negative for CSNB.

CasePMIDs: N/A

FamilyLabel: Jacobson_1995_Family_1

Family#PresentingHPOs: HP:0000662 (Nyctalopia), HP:0011510 (Drusen), HP:0200056 (Macular scar), HP:0000608 (Macular degeneration), HP:0000603 (Central scotoma), HP:0025243 (Subretinal hemorrhage)

FamilyHPOFreeText: Onset in the 4th or early 5th decade of life with drusen appearing first and progression to macular scarring and degeneration.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: United States (mentioned in PMID:8981947)

Family#PreviousTesting: SSCP using PCR-amplified exon 5 from TIMP3, followed by Sanger sequencing of the exon 5 PCR product.

Family#GenotypingMethod: PCR amplification of exon 5 in samples from each family member, followed by enzyme digestion with the Bbv1 restriction endonuclease.

Affected: 6

Unaffected: 2

Segregations: 5

PublishedLOD: N/A

eLOD: 1.5

AddSegregationInfo: N/A

ProbandLabel: Jacobson_1995_Family_1_Patient_III-5

Variant: Patients harbor the NM_000362.5(TIMP3):c.568G>T (p.Gly190Cys) missense variant.

CAID: CA411540415

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: N/A

FamilyPMIDs: N/A

Case: Jacobson_1995_Family_1_Patient_III-5, male, country of origin United States (PMID:8981947), onset in 4th or early 5th decade of life

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo: The variant was inherited by the proband rather than acquired de novo.

CasePresentingHPOs: HP:0011510 (Drusen), HP:0200056 (Macular scar), HP:0000608 (Macular degeneration), HP:0000603 (Central scotoma), HP:0025243 (Subretinal hemorrhage), HP:0000662 (Nyctalopia)

CaseHPOFreeText: Onset in the 4th or early 5th decade of life with drusen appearing first and progression to macular scarring (secondary to subretinal hemorrhage) and degeneration.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: N/A

CasePreviousTesting: SSCP using PCR-amplified exon 5 from TIMP3, followed by Sanger sequencing of the exon 5 PCR product.

GenotypingMethod: PCR amplification of exon 5, followed by enzyme digestion with the Bbv1 restriction endonuclease.

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Patients harbor the NM_000362.5(TIMP3):c.568G>T (p.Gly190Cys) missense variant.

CAID: CA411540415

gnomAD: Variant is absent from gnomAD.

VariantEvidence: This missense variant within exon 5 of TIMP3 results in an unpaired Cys residue.

Case#: Gong_2001_Proband_5, no reported gender, age or national origin

CasePresentingHPOs: HP:0004349 (Reduced bone mineral density)

CaseHPOFreeText: The proband has been diagnosed with osteoporosis-pseudoglioma syndrome segregating with an autosomal recessive mode of inheritance. This implies a combination of ophthalmologic and radiographic features, but these have not been described in detail.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genome-wide linkage mapping with 160 SSRP markers was performed on three different consanguineous kindreds (from Finland, South Africa, and Italy) (fig. 1), but it is not clear whether this proband was a member of one of these kindreds.

CaseMethod1: Linkage analysis with additional markers around a strong candidate marker

CaseMethod2: Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus

CaseGenotypingMethod: Genotyping appears to have been limited to Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus.

Variant: The patient harbors the NM_002335.4(LRP5):c.2557C>T (p.Gln853Ter) variant in the homozygous state.

ClinVar: 6272

gnomAD: The NM_002335.4(LRP5):c.2557C>T (p.Gln853Ter) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LRP5):c.2557C>T (p.Gln853Ter) is a nonsense variant in exon 12 out of 23 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal ~47% of the protein product. It appears to be stable at the protein level but is not secreted in the exogenous expression system, consistent with loss-of-function rather than dominant negative effect.

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 8659519

Case#: Gong_2001_Proband_3, no reported gender, age or national origin

CasePresentingHPOs: HP:0004349 (Reduced bone mineral density)

CaseHPOFreeText: The proband has been diagnosed with osteoporosis-pseudoglioma syndrome segregating with an autosomal recessive mode of inheritance. This implies a combination of ophthalmologic and radiographic features, but these have not been described in detail.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genome-wide linkage mapping with 160 SSRP markers was performed on three different consanguineous kindreds (from Finland, South Africa, and Italy) (fig. 1), but it is not clear whether this proband was a member of one of these kindreds.

CaseMethod1: Linkage analysis with additional markers around a strong candidate marker

CaseMethod2: Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus

CaseGenotypingMethod: Genotyping appears to have been limited to Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus.

Variant: The patient harbors the NM_002335.4(LRP5):c.1468del (p.Asp490fs) variant in the homozygous state.

ClinVar: 6270

gnomAD: The NM_002335.4(LRP5):c.1468del (p.Asp490fs) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LRP5):c.1468del (p.Asp490fs) is a frameshift variant in exon 7 out of 23 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal ~70% of the protein product.

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 8659519

Case#: Ebenezer_2005_Family_A_Patient_III.4, male, age not specified, family origin reported to be British

CasePresentingHPOs: HP:0025710 (Late young adult onset), HP:0000662 (Nyctalopia), HP:0007663 (Reduced visual acuity), HP:0000613 (Photophobia), HP:0007803 (Monochromacy), HP:0031624 (Moderate myopia), HP:0001103 (Abnormal macular morphology), HP:0000533 (Chorioretinal atrophy), HP:0500087 (Peripapillary atrophy), HP:0025159 (Hypoautofluorescent retinal lesion), HP:0030844 (Undetectable pattern electroretinogram), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude)

CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa, with the family exhibiting an X-linked pattern of inheritance. Cone ERG was more severely reduced than rod ERG.

CaseNotHPOs: HP:0007769 (Peripheral retinal degeneration), HP:0000639 (Nystagmus)

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and family members were not genotyped outside of the RPGR locus.

CaseMethod1: Sanger sequencing of exon 15 of RPGR

CaseMethod2: N/A

CaseGenotypingMethod: The proband and family members were genotyped by Sanger sequencing of exon 15 of RPGR, but not by genome-wide methods.

Variant: The proband harbors the NM_001034853.2(RPGR):c.2847_2848inv (p.Glu949_Glu950delinsAspTer) variant in the hemizygous state.

ClinVar: 9917

gnomAD: The variant was not found in gnomAD v.2.1.1.

VariantEvidence: NM_001034853.2(RPGR):c.2847_2848inv (p.Glu949_Glu950delinsAspTer) is an indel in the final exon (exon 15) that introduces a premature stop codon. Although it is not predicted to trigger nonsense-mediated decay, it at least disrupts ~18% of the C-terminus of the protein product.

CaseAddInfo: The proband is a member of Family A (shown in Figure 1), which includes four other affected genotype-positive males and four carrier females who showed RPE abnormalities.

CasePMIDs: N/A

Case#: Manes_2013_Family_NA1863_Proband_II:1, male, age between 25 and 45 years at time of report, national origin reported as Italian

CasePresentingHPOs: HP:0007677 (Vitelliform-like macular lesions), HP:0030631 (Hyperautofluorescent macular lesion), HP:0008179 (Decreased Arden ratio of electrooculogram, specifically 1.53 and 1.61 in each eye), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude)

CaseHPOFreeText: The patient has been diagnosed with vitelliform macular dystrophy, and has very mildly reduced visual acuity (20/22).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing appears to have been limited to Sanger sequencing-based screening of exon 7 of IMPG1.

CaseMethod1: Sanger sequencing of the 17 exons and flanking intronic sequences

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping appears to have included Sanger-based sequencing of the 17 exons and intronic flanking sequences of the IMPG1 locus.

Variant: The proband harbors the NM_001563.4(IMPG1):c.807+1G>T variant in the homozygous state.

ClinVar: 162134

gnomAD: The NM_001563.4(IMPG1):c.807+1G>T variant was found in gnomAD v2.1.1 at a frequency of 0.000008855 (1/112932) in the European non-Finnish population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/6-76728434-C-A

VariantEvidence: NM_001563.4(IMPG1):c.807+1G>T is a canonical splice site variant in intron 7 that does not have evidence confirming an impact on the gene product.

CaseAddInfo: The proband has a similarly affected younger sister who shares the same genotype. Parents are clinically unaffected heterozygous carriers but each harbor tiny extramacular deposits in the fundus. Consanguinity is reported in this family.

CasePMIDs: N/A

FamilyLabel: Manes_2013_Family_MTP327

Family#PresentingHPOs: HP:0007677 (Vitelliform-like macular lesions), HP:0030469 (Abnormal dark-adapted electroretinogram, specifically reduced)

FamilyPresentingHPOFreeText: The affected family members have been diagnosed with vitelliform macular dystrophy.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: The family is reportedly French.

Ethnicity: Not specifically described

Race: Not specifically described

Family#PreviousTesting: Previous genotyping included Sanger sequencing of BEST1 and PRPH2, followed by genome-wide scan using a 250K SNP Affymetrix array, which identified a shared 95.2 Mb haplotype on chromosome 6p12.1-q24.3 (encompassing 705 genes) in all affected family members. The candidate loci ELOVL4 and MCDR1 were then subjected to Sanger sequencing.

Family#Method1: Whole-exome sequencing of seven affected family members

Family#Method2: Sanger sequencing of IMPG1 to confirm the presence of the variant.

Family#GenotypingMethod: Whole-exome sequencing of seven affected family members was performed, followed by Sanger sequencing of IMPG1 to confirm the presence of the variant.

Affected: 8 genotyped

Unaffected: 4 genotyped

Segregations: 11 segregations are shown by the pedigree in Figure 1A.

PublishedLOD: 3.02 (for the D6S1622 marker on chromosome 6q13)

eLOD: N/A

AddSegregationInfo: All genotype-positive individuals were phenotype-positive in this family.

ProbandLabel: Manes_2013_Family_MTP327_Proband

Variant: The affected family members harbor the NM_001563.4(IMPG1):c.713T>G (p.Leu238Arg) variant in the heterozygous state.

ClinVar ID: 162133

gnomAD: This variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_001563.4(IMPG1):c.713T>G (p.Leu238Arg) is a missense site variant lacking evidence of a deleterious impact on the gene product.

FamilyAddInfo: The family's national origin has been reported as French. Age of onset ranged from 20 to 45 years.

FamilyPMIDs: N/A

Case#: Bech-Hansen_2000_Family_R5_proband, male, age and race not mentioned, national origin in the United States

CasePresentingHPOs: HP:0030640 (Complete congenital stationary night blindness), HP:0030469 (Abnormal dark-adapted electroretinogram)

CaseHPOFreeText: At least one of two ERG abnormalities were observed in each affected family member; absence of rod psychophysical dark adaptation and/or absence of rod ERG with low-intensity blue flash.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Linkage analysis was originally performed in PMID: 2574143 using 17 X-chromosomal restriction fragment length polymorphism markers.

CaseMethod1: Agarose gel electrophoresis of the relevant PCR product to monitor segregation in the proband and family members

CaseMethod2: Sanger sequencing of PCR amplified exons from NYX

CaseGenotypingMethod: Linkage analysis was initially performed in PMID: 2574143 using 17 X-chromosomal restriction endonuclease-based markers. The proband and family members were then subjected to gel electrophoresis analysis of PCR products and Sanger sequencing to identify the variant.

Variant: The proband harbors the NM_001378477.3(NYX):c.70_93del (p.Arg24_Ala31del) variant on the X chromosome.

ClinVar: 99841

gnomAD: NM_001378477.3(NYX):c.70_93del (p.Arg24_Ala31del) has a maximum allele frequency of 0.0001018 (1/9823, with no males or homozygous females) in the European non-Finnish population https://gnomad.broadinstitute.org/variant/X-41332781-GGCCTGCGCCCGCGCTTGTCCCGCC-G

VariantEvidence: This in-frame deletion variant does not have experimental evidence of impact on the protein product, but is a recurrent variant observed in multiple apparently unrelated families (PMID: 2574143 and Figure 5 from this paper).

CaseAddInfo: Family phenotypes were described in PMID: 2574143.

CasePMIDs: PMID: 2574143

FamilyLabel: Bech-Hansen_2000_Family_R5

Family#PresentingHPOs: HP:0030640 (Complete congenital stationary night blindness), HP:0030469 (Abnormal dark-adapted electroretinogram)

Family#PresentingHPOFreeText: At least one of two ERG abnormalities were observed in each affected family member; absence of rod psychophysical dark adaptation and/or absence of rod ERG with low-intensity blue flash

FamilyNotHPOs: N/A

CountryOrigin: The United States

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: Linkage analysis was originally performed in PMID: 2574143 using 17 X-chromosomal restriction fragment length polymorphism markers.

Family#Method1: Agarose gel electrophoresis of the relevant PCR product to monitor segregation in family members

Family#Method2: Sanger sequencing of PCR amplified exons from NYX

Family#GenotypingMethod: Linkage analysis was initially performed in PMID: 2574143 using 17 X-chromosomal restriction endonuclease-based markers. Family members were then subjected to gel electrophoresis analysis of PCR products and Sanger sequencing to identify the variant.

Affected: 4

Unaffected: 5

Segregations: 6 segregations (all consistent) among genotyped individuals are shown in this paper (pedigree in Fig. 3).

PublishedLOD: 7.35 (in PMID: 2574143, combined from 7 families)

eLOD: 1.8

AddSegregationInfo: N/A

ProbandLabel: Bech-Hansen_2000_Family_R5_proband

Variant: Affected male family members harbor the NM_001378477.3(NYX):c.70_93del (p.Arg24_Ala31del) variant on the X chromosome.

ClinVar: 99841

gnomAD: NM_001378477.3(NYX):c.70_93del (p.Arg24_Ala31del) has a maximum allele frequency of 0.0001018 (1/9823, with no males or homozygous females) in the European non-Finnish population https://gnomad.broadinstitute.org/variant/X-41332781-GGCCTGCGCCCGCGCTTGTCCCGCC-G

FamilyAddInfo: Family phenotypes were described in PMID: 2574143.

FamilyPMIDs: PMID: 2574143

Case#: Allen_2003_Familly_X03_Proband, male, age not mentioned, British national origin

CasePresentingHPOs: HP:0007642 (Congenital stationary night blindness), HP:0007663 (Reduced visual acuity), HP:0031624 (Moderate myopia), HP:0007984 (Electronegative electroretinogram)

CaseHPOFreeText: ERG with absent scotopic oscillatory potential, subnormal ON response

CaseNotHPOs: N/A

CaseNotHPOFreeText: Normal OFF response

CasePreviousTesting: N/A

CaseMethod1: Sanger sequencing of PCR-amplified exons from NYX and CACNA1F

CaseMethod2: Haplotype analysis using microsatellite markers surrounding the NYX locus

CaseGenotypingMethod: The proband and family members were subjected to Sanger sequencing of NYX to identify the variant, followed by microsatellite-based haplotype analysis of families sharing the same variant.

Variant: The proband harbors the NM_022567.2(NYX):c.37+1G>C (p.=) variant on the X chromosome.

CAID: CA412988630

gnomAD: NM_022567.2(NYX):c.37+1G>C (p.=) was not found in gnomAD.

VariantEvidence: This splice site variant disrupts a canonical splice site between the two coding exons (exon 2 and exon 3), and is therefore predicted to disrupt the protein product.

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Allen_2003_Familly_X04_Proband, male, age not mentioned, British national origin

CasePresentingHPOs: HP:0007642 (Congenital stationary night blindness), HP:0007663 (Reduced visual acuity), HP:0031624 (Moderate myopia), HP:0007984 (Electronegative electroretinogram)

CaseHPOFreeText: ERG with absent scotopic oscillatory potential, subnormal ON response

CaseNotHPOs: N/A

CaseNotHPOFreeText: Normal OFF response

CasePreviousTesting: N/A

CaseMethod1: Sanger sequencing of PCR-amplified exons from NYX and CACNA1F

CaseMethod2: Haplotype analysis using microsatellite markers surrounding the NYX locus

CaseGenotypingMethod: The proband and family members were subjected to Sanger sequencing of NYX to identify the variant, followed by microsatellite-based haplotype analysis of families sharing the same variant.

Variant: The proband harbors the NM_022567.2 (NYX):c.339_353del (p.Glu114_Ala118del) variant on the X chromosome.

CAID: CA2573050968

gnomAD: NM_022567.2 (NYX):c.339_353del (p.Glu114_Ala118del) was not found in gnomAD.

VariantEvidence: NM_022567.2:c.339_353del is an in-frame deletion variant that removes 5 amino acids from the center of the polypeptide sequence. It is a recurrent variant reported here in multiple apparently unrelated British families (X04 and X06).

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Parry_2009_Family_MEP49_patient_IV:5, male, age not specified, family origin reported to be Pakistani

CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0007663 (Reduced visual acuity), HP:0007401 (Macular atrophy), HP:0000580 (Pigmentary retinopathy), HP:0007769 (Peripheral retinal degeneration), HP:0008323 (Abnormal light- and dark-adapted electroretinogram)

CaseHPOFreeText: The proband was diagnosed with cone-rod dystrophy, with family showing autosomal recessive mode of inheritance. Most affected members of the proband's family had white patches around the optic disc and in the posterior pole.

CaseNotHPOs: HP:0000639 (Nystagmus), HP:0000613 (Photophobia)

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and his family have been initially genotyped by autozygosity mapping with both 10k and 250k Affymetrix SNP arrays and microsatellite markers.

CaseMethod1: Autozygosity mapping

CaseMethod2: Sanger sequencing

CaseGenotypingMethod: The proband and his family have been initially genotyped by autozygosity mapping with both 10k and 250k Affymetrix SNP arrays and microsatellite markers. Sanger sequencing of the ADAM9 locus then identified the variants.

Variant: The proband harbors the NM_003816.3(ADAM9):c.766C>T (p.Arg256Ter) variant in the homozygous state.

ClinVar: 6877

gnomAD: This variant is found in gnomAD v2.1.1 at a frequency of 0.00003267 (1/30608) in the South Asian population, with no homozygotes. https://gnomad.broadinstitute.org/variant/8-38880696-C-T

VariantEvidence: NM_003816.3(ADAM9):c.766C>T (p.Arg256Ter) is a nonsense variant in exon 9 of 21, and is therefore predicted to result in nonsense-mediated decay.

CaseAddInfo: The proband's family is known to be consanguineous, with the parents being first cousins (pedigree shown in Figure 2).

CasePMIDs: N/A

Case#: Parry_2009_Family_MOL0172_patient_IV:3, male, age not specified, family origin reported to be Tunisian Jewish

CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0007663 (Reduced visual acuity), HP:0007401 (Macular atrophy), HP:0000580 (Pigmentary retinopathy), HP:0007769 (Peripheral retinal degeneration), HP:0008323 (Abnormal light- and dark-adapted electroretinogram)

CaseHPOFreeText: The proband was diagnosed with cone-rod dystrophy, with family showing autosomal recessive mode of inheritance. Most affected members of the proband's family had white patches around the optic disc and in the posterior pole.

CaseNotHPOs: HP:0000639 (Nystagmus), HP:0000613 (Photophobia)

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and his family have been initially genotyped by autozygosity mapping with both 10k and 250k Affymetrix SNP arrays and microsatellite markers.

CaseMethod1: Autozygosity mapping

CaseMethod2: Sanger sequencing

CaseGenotypingMethod: The proband and his family have been initially genotyped by autozygosity mapping with both 10k and 250k Affymetrix SNP arrays and microsatellite markers. Sanger sequencing of the ADAM9 locus then identified the variants.

Variant: The proband harbors the NM_003816.3(ADAM9):c.490C>T (p.Arg164Ter) variant in the homozygous state.

ClinVar: 6878

gnomAD: This variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_003816.3(ADAM9):c.490C>T (p.Arg164Ter) is a nonsense variant in exon 6 of 21, and is therefore predicted to result in nonsense-mediated decay.

CaseAddInfo: The proband's family is known to be consanguineous, with the father being the mother's uncle (pedigree shown in Figure 2).

CasePMIDs: N/A

FamilyLabel: DeBenedictis_2020_Family_1

Family#PresentingHPOs: HP:0000662 (Nyctalopia), HP:0000518 (Cataract), HP:0000964 (Eczema), HP:0007663 (Reduced visual acuity), HP:0011510 (Drusen), HP:0007703 (Abnormality of retinal pigmentation), HP:0007894 (Hypopigmentation of the fundus)

Family#PresentingHPOFreeText: Onset in 5th decade of life, initial diagnosis not with SFD but with retinitis pigmentosa.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: Features of syndromic retinal dystrophy

CountryOrigin: N/A

Ethnicity: Proband has Dutch ancestry on maternal (affected) side and North Irish / English on paternal (unaffected) side.

Race: Caucasian

Family#PreviousTesting: Limited (non genome-wide) genetic testing confirming absence of pathogenic variants in 13 different genes; RHO, PRPH2/RDS, RP1, IMPDH1, PRPF31, PRPF, PRPF8, NR2E3, SNRNP200, TOPORS, KLHL7, RPGR, and RP2.

Family#Method1: Limited genetic testing for 13 candidate genes

Family#Method2: N/A

Family#GenotypingMethod: next-generation sequencing analysis of an 856-gene retinal dystrophy panel

Affected: 2

Unaffected: 0

Segregations: There was 1 segregation reported, while consanguinity was not mentioned. The pedigree was not depicted.

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: DiBenedetto_Patient_1

Variant: NM_000362.5(TIMP3):c.410A>G (p.Tyr137Cys)

CAID: CA411539826

gnomAD: The variant is not found in gnomAD.

FamilyAddInfo: The proband has a number of family members diagnosed with retinitis pigmentosa (son, sister, brother, mother, maternal grandmother, and maternal great-uncle ). The pattern was consistent with autosomal dominant inheritance. His sister underwent treatment for choroidal neovascularization at age 73.

FamilyPMIDs: N/A

Case#: Bandah-Rozenfeld_2010_MOL0732_proband, female, age 63 years at time of diagnosis, ethnic origin reported as Israeli Christian Arab

CasePresentingHPOs: HP:0008002 (Abnormality of macular pigmentation), HP:0030613 (Abnormal foveal morphology on macular OCT), HP:0030557 (Best corrected visual acuity 0.4 LogMAR), HP:0000603 (Central scotoma), HP:0031729 (Moderate hypermetropia), HP:0000518 (Cataract)

CaseHPOFreeText: The patient has been diagnosed with mild maculopathy. "Abnormal foveal morphology" refers to elevation of the photoreceptor layer in foveal region by OCT analysis. The "cataract" specifically refers to mild nuclear sclerosis.

CaseNotHPOs: HP:0000512 (Abnormal electroretinogram), HP:0000551 (Color vision defect)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of autozygosity mapping.

CaseMethod1: Homozygosity mapping

CaseMethod2: Sanger sequencing of the 19 exons of the IMPG2 gene

CaseGenotypingMethod: Genotyping consisted of autozygosity mapping followed by Sanger sequencing of the 19 exons of the IMPG2 gene.

Variant: The patient harbors the NM_016247.4(IMPG2):c.370T>C (p.Phe124Leu) variant in the homozygous state.

ClinVar: 3550

gnomAD: The NM_016247.4(IMPG2):c.370T>C (p.Phe124Leu) variant is found in gnomAD v2.1.1 at a maximum allele frequency of 0.0001318 (17/129010, with 0 homozygotes) in the European (non-Finnish) population. https://gnomad.broadinstitute.org/variant/3-101023121-A-G

VariantEvidence: NM_016247.4(IMPG2):c.370T>C (p.Phe124Leu) is a missense variant in exon 3 of 19 that does not have evidence of impact on the protein product.

CaseAddInfo: The family is consanguineous, with the parents being first cousins.

CasePMIDs: A publication by a separate group referred to this case as autosomal recessive vitelliform macular dystrophy, but did not indicate the existence of any additional details about the case (PMID: 25085631).

FamilyLabel: Gong_1996_Three_Families

Family#PresentingHPOs: N/A

FamilyPresentingHPOFreeText: The affected family members have been diagnosed with osteoporosis-pseudoglioma syndrome segregating with an autosomal recessive mode of inheritance. This implies a combination of ophthalmologic and radiographic features, but these have not been described in detail.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: The three families are reportedly of Finnish, South African, and Italian descent, respectively.

Ethnicity: Not specifically described

Race: Not specifically described

Family#PreviousTesting: Genome-wide linkage mapping with 160 SSRP markers was performed on three different consanguineous kindreds (from Finland, South Africa, and Italy) (fig. 1).

Family#Method1: Genome-wide linkage analysis

Family#Method2: Further linkage analysis with additional markers around a strong candidate marker

Family#GenotypingMethod: Genome-wide linkage mapping with 160 SSRP markers was performed on three different consanguineous kindreds (from Finland, South Africa, and Italy) (Fig. 1). Further linkage testing with additional markers around a strong candidate marker yielded a LOD score of 5.99 for Dl1S987. The region consisted of a 13-cM genetic interval on chromosome 11q12-13.

Affected: 7 genotyped

Unaffected: 5 genotyped

Segregations: 5 segregations are shown by the three pedigrees in Figure 1.

PublishedLOD: 5.99 (for the Dl1S987 marker)

eLOD: N/A

AddSegregationInfo: While only one of the families would individually be eligible for inclusion in segregation evidence using an estimated LOD score, the published LOD score is sufficient for their inclusion.

ProbandLabel: N/A (Probands have been incorporated into the later Gong 2001 publication and will be scored in connection to that article.)

Variant: The affected family members harbor three different variants, each in the homozygous state.

ClinVar: N/A

gnomAD: N/A

VariantEvidence: N/A

FamilyAddInfo: All three families are reportedly consanguineous.

FamilyPMIDs: N/A

Case#: Mykykyn_2002_Proband_D, gender not specified, age not described, family origin reported as from Turkish

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband has been previously diagnosed with Bardet-Biedl syndrome based on at least three of the following features; obesity, polydactyly, renal anomalies, retinopathy, hypogonadism, and/or mental retardation.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and their affected and unaffected family members were subjected to mapping of the disease-associated locus to chromosome 11, followed by PCR- and Sanger sequencing-based genotyping of chromosome 11 markers.

CaseMethod1: linkage mapping

CaseMethod2: Sanger sequencing of BBS1

CaseGenotypingMethod: The proband and their affected and unaffected family members were subjected to linkage mapping of the disease-associated locus to chromosome 11, followed by PCR- and Sanger sequencing-based genotyping of chromosome 11 markers. Sanger sequencing of BBS1 was subsequently used to identify the variant.

Variant: The proband harbors the NM_024649.5(BBS1):c.851del (p.Tyr284fs) variant in the homozygous state.

ClinVar ID: 12146

gnomAD: The variant is found in gnomAD v2.1.1 at a frequency of 0.00001758 (2 alleles out of 113768 total alleles, with 0 homozygotes) in the European non-Finnish population https://gnomad.broadinstitute.org/variant/11-66290946-TA-T?dataset=gnomad_r2_1

VariantEvidence: NM_024649.5(BBS1):c.851del (p.Tyr284fs) is a frameshift variant in exon 10 of 17 that is predicted to trigger nonsense mediated decay or to at least truncate the C-terminal 52% of the protein product.

CaseAddInfo: The proband's family is described as consanguineous.

CasePMIDs: N/A

Case: Weber_1994_Family_B_Patient_V-1, male, country of origin Canada (PMID:7920634), genealogy indicating Irish descent (PMID: 2695876)

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo:

CasePresentingHPOs: HP:0030506 (Yellow/white lesions of the retina), HP:0030604 (Abnormal fundus fluorescein angiography), HP:0011506 (Choroidal neovascularization), HP:0000533 (Chorioretinal atrophy), HP:0200070 (Peripheral retinal atrophy)

CaseHPOFreeText: Yellow/white lesions were present within fundus specifically. Angiography showed mottled hypofluorescence. Chorioretinal atrophy was described as showing peripheral progression.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: N/A

CasePreviousTesting: Linkage analysis using short tandem repeat markers derived from genomic regions shown to contain loci involved in macular degeneration (PMID:7920634).

GenotypingMethod: Sanger sequencing

PreviouslyPublished: PMID:2695876, PMID:7920634

SupplementalData: N/A

Variant: The variant is NM_000362.5(TIMP3):c.610A>T, p.Ser204Cys, which was first referred to in PMID:7894485 as "Ser181Cys" (due to the removal of a 23-amino acid N-terminal signal peptide from the polypeptide sequence) but encodes Ser204Cys in the full/updated polypeptide sequence.

ClinVar: 12676

gnomAD: Variant is absent from gnomAD.

VariantEvidence: Variant adds a Cys residue to TIMP3 and is predicted to disrupt tertiary structure.

FamilyLabel: Naessens_2019_Family_1

FamilyPresentingHPOs: HP:0011510 (Drusen)

FamilyHPOFreeText: Relatively late onset of phenotypes between ages 49 and 74. Drusen / deposits were universal except for 3 individuals between the ages of 37 and 47.

**FamilyNotHPOs: N/A

FamilyNotHPOFreeText: Pulmonary involvement

CountryOrigin: Belgium

Family#PreviousTesting: Yes, SSCP and Sanger sequencing were both previously performed (PMID:10873973), but results were negative (no TIMP3 variant found).

Family#Method1: SSCP of all five exons, plus the promoter and 3'UTR of TIMP3

Family#Method2: Sanger sequencing of PCR-amplified exon 5 of TIMP3

Family#GenotypingMethod: PCR amplification of all 5 coding exons of TIMP3, followed by Sanger sequencing

Affected: 18

Unaffected: 29

Segregations: 23

PublishedLOD: N/A

eLOD: 6.9

AddSegregationInfo: N/A

ProbandLabel: Naessens_2019_Family_1_patient_IV:31

Variant: The variant is NM_000362.5(TIMP3):c.113C>G (p.Ser38Cys), a missense variant predicted to introduce a new cysteine-encoding codon into exon 1.

ClinVar: 843268

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: Family was previously genotyped in PMID:10873973, but SSCP analysis of all 5 exons and Sanger sequencing of exon 5 were not sufficient at that time to detect the variant in exon 1.

FamilyPMIDs: PMID:10873973

Case: Naessens_2019_Family_1_Patient_IV:31, female, age of onset 51 years old, country of origin Belgium

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo: Familial variant appears to come from a founder mutation shared by other families in Belgium and northern France with a distant common ancestor.

CasePresentingHPOs: HP:0011510 (Drusen), HP:0000613 (Photophobia), HP:0000572 (Visual loss)

CaseHPOFreeText: Relatively late onset of phenotypes (at age 51, presenting with photophobia). Drusen was described as widespread around the vascular arcades.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: Pulmonary involvement

CasePreviousTesting: Yes, SSCP and Sanger sequencing were both previously performed (PMID:10873973), but results were negative (no TIMP3 variant found).

CaseMethod1: SSCP of all five exons, plus the promoter and 3'UTR of TIMP3

CaseMethod2: Sanger sequencing of PCR-amplified exon 5 of TIMP3

GenotypingMethod: PCR amplification of all 5 coding exons of TIMP3, followed by Sanger sequencing

PreviouslyPublished: PMID:10873973

SupplementalData: Supplementary Table S3 from this paper (PMID: 30668888) provides some of the proband phenotype details.

Variant: The variant is NM_000362.5(TIMP3):c.113C>G (p.Ser38Cys), a missense variant predicted to introduce a new cysteine-encoding codon into exon 1.

ClinVar: 843268

gnomAD: Variant is absent from gnomAD.

VariantEvidence: Variant adds a Cys residue to TIMP3 and is predicted to disrupt tertiary structure. Patient fibroblasts reveal no change in expression of the variant at the mRNA level, no dimerization of the variant under non-reducing conditions, and no defect in its localization to the ECM. Variant showed a minor increase in glycosylation. An in vitro transcription and translation study found that the variant forms an aberrant intramolecular disulfide bond between the introduced Ser38Cys residue and Cys36 of TIMP3 (Figure 7). Aberrant intramolecular disulfide bonding caused by this variant would be consistent gain-of-function and an autosomal dominant mechanism of inheritance.

Case: Naessens_2019_Family_3_Patient_II:1, male, age of onset 53 years old, country of origin Belgium

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo: Family member genotypes and phenotypes are not available, but variant appears to come from a founder mutation shared by other families in Belgium and northern France with a distant common ancestor.

CasePresentingHPOs: HP:0011510 (Drusen), HP:0000572 (Visual loss), HP:0007401 (Macular atrophy), HP:0011506 (choroidal neovascularization), HP:0007703 (Abnormality of retinal pigmentation)

CaseHPOFreeText: Relatively late onset of phenotypes (at age 53, presenting with nyctalopia). Drusen was described as calcified around the vascular arcades. CNV was active. Macular atrophy was patchy. Intraretinal pigment migration was observed from midperiphery towards periphery.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: Pulmonary involvement

CasePreviousTesting: N/A

GenotypingMethod: PCR amplification of all 5 coding exons of TIMP3, followed by Sanger sequencing

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S3 from this paper (PMID: 30668888) provides some of the proband phenotype details.

Variant: The variant is NM_000362.5(TIMP3):c.113C>G (p.Ser38Cys), a missense variant predicted to introduce a new cysteine-encoding codon into exon 1.

ClinVar: 843268

gnomAD: Variant is absent from gnomAD.

VariantEvidence: Variant adds a Cys residue to TIMP3 and is predicted to disrupt tertiary structure. Patient fibroblasts reveal no change in expression of the variant at the mRNA level, no dimerization of the variant under non-reducing conditions, and no defect in its localization to the ECM. Variant showed a minor increase in glycosylation. An in vitro transcription and translation study found that the variant forms an aberrant intramolecular disulfide bond between the introduced Ser38Cys residue and Cys36 of TIMP3 (Figure 7). Aberrant intramolecular disulfide bonding caused by this variant would be consistent gain-of-function and an autosomal dominant mechanism of inheritance.

Case#: Georgiou_2024_Family_NY01_Proband_P10, female, reported at age 56 years, family origin not reported

CasePresentingHPOs: HP:0011003 (High myopia), HP:0030558 (Best corrected visual acuity 0.5 LogMAR), HP:0000518 (Cataract)

CaseHPOFreeText: BCVA began at 0.51 logMAR and progressed to 0.54 logMAR. The proband had posterior chamber intraocular lenses. Myopia developed by age 7 years.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was by either next-generation sequencing panel, whole exome sequencing, or whole genome sequencing, but was unspecified.

CaseMethod1: NGS panel / WES / WGS

CaseMethod2: Sanger sequencing of RBP3

CaseGenotypingMethod: Previous genotyping by either next-generation sequencing panel, whole exome sequencing, or whole genome sequencing was followed by Sanger sequencing of RBP3.

Variant: The individual harbors the NM_002900.3(RBP3):c.2824C>T (p.Gln942Ter) variant in the homozygous state.

ClinVar ID: 1069291

gnomAD: The variant is found in gnomAD version 4.1.1 at a frequency of 0.00001332 (1 / 75072) in the African / African-American population https://gnomad.broadinstitute.org/variant/chr10-47351308-C-T?dataset=gnomad_r4

VariantEvidence: NM_002900.3(RBP3):c.2824C>T (p.Gln942Ter) is a nonsense variant within exon 1 of 4 that is predicted to trigger nonsense-mediated decay.

CaseAddInfo: Potential consanguinity within the proband's family and their geographic origin have not been commented on.

CasePMIDs: N/A

Case#: Georgiou_2024_Family_GC29680_Proband_P09, female, reported at age 30 years, family origin reported as from Bangladesh

CasePresentingHPOs: HP:0011003 (High myopia), HP:0030558 (Best corrected visual acuity 0.5 LogMAR)

CaseHPOFreeText: BCVA began at 0.39 logMAR and progressed to 0.54 logMAR.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was by either next-generation sequencing panel, whole exome sequencing, or whole genome sequencing, but was unspecified.

CaseMethod1: NGS panel / WES / WGS

CaseMethod2: Sanger sequencing of RBP3

CaseGenotypingMethod: Previous genotyping by either next-generation sequencing panel, whole exome sequencing, or whole genome sequencing was followed by Sanger sequencing of RBP3.

Variant: The individual harbors the NM_002900.3(RBP3):c.3399T>G (p.Tyr1133Ter) variant in the homozygous state.

ClinVar ID: 3675731

gnomAD: The variant is found in gnomAD version 4.1.1 at a frequency of 0.00001098 (1 / 91070) in the South Asian population https://gnomad.broadinstitute.org/variant/chr10-47357112-T-G?dataset=gnomad_r4

VariantEvidence: NM_002900.3(RBP3):c.3399T>G (p.Tyr1133Ter) is a nonsense variant within exon 4 of 4 that is predicted to trigger nonsense-mediated decay.

CaseAddInfo: Potential consanguinity within the proband's family has not been commented on.

CasePMIDs: N/A

Case#: Georgiou_2024_Family_GC19393_Proband_P06, female, reported at age 14 years, family origin reported as from Pakistan

CasePresentingHPOs: HP:0011003 (High myopia), HP:0030555 (Best corrected visual acuity 0.2 LogMAR)

CaseHPOFreeText: BCVA began at 0.20 logMAR and progressed to 0.30 logMAR.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was by either next-generation sequencing panel, whole exome sequencing, or whole genome sequencing, but was unspecified.

CaseMethod1: NGS panel / WES / WGS

CaseMethod2: Sanger sequencing of RBP3

CaseGenotypingMethod: Previous genotyping by either next-generation sequencing panel, whole exome sequencing, or whole genome sequencing was followed by Sanger sequencing of RBP3.

Variant: The individual harbors the NM_002900.3(RBP3):c.160C>T (p.Gln54Ter) variant in the homozygous state.

ClinVar ID: 964958

gnomAD: The variant is found in gnomAD version 4.1.1 at a frequency of 0.0003184 (29 / 91094) in the South Asian population https://gnomad.broadinstitute.org/variant/10-47348644-C-T?dataset=gnomad_r4

VariantEvidence: NM_002900.3(RBP3):c.160C>T (p.Gln54Ter)) is a nonsense variant within exon 1 of 4 that is predicted to trigger nonsense-mediated decay.

CaseAddInfo: Potential consanguinity within the proband's family has not been commented on.

CasePMIDs: N/A

Case#: Xiao_2023_Family_2_Proband, male, age 0.5 years, family origin reported as from Yi ethnic group from Yunnan, China

CasePresentingHPOs: Infantile onset HP:0003593, Pigmentary retinopathy HP:0000580, Mild myopia HP:0025573

CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa with onset at 0.3 years of age.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing in the proband consisted of whole exome sequencing.

CaseMethod1: whole exome sequencing

CaseMethod2: Sanger sequencing of the coding regions of PRPF4

CaseGenotypingMethod: Genotyping of the proband initially consisted of whole exome sequencing, followed by Sanger sequencing of the coding regions of PRPF4.

Variant: The proband harbors the NM_001244926.2(PRPF4):c.1270G>A (p.Gly424Ser) variant in the heterozygous state.

ClinVar ID: 1395419

gnomAD: The NM_001244926.2(PRPF4):c.1270G>A (p.Gly424Ser) variant is found in gnomAD v4.1.0 at a frequency of 0.00008729 (103 alleles / 1180028 total alleles, with 0 homozygotes) in the European (non-Finnish) population https://gnomad.broadinstitute.org/variant/9-113290914-G-A?dataset=gnomad_r4

VariantEvidence: NM_001244926.2(PRPF4):c.1270G>A (p.Gly424Ser) is a missense variant with no direct evidence of an abnormal impact on the PRPF4 protein.

CaseAddInfo: The proband has apparently unaffected parents.

CasePMIDs: N/A

Case#: Al-khuzaei_2020_Patient_III, female, 10 years old at presentation of symptoms, 16 years old at time of report, racial origin indicated as Caucasian

CasePresentingHPOs: Photophobia HP:0000613, Photopsia HP:0030786, Nyctalopia HP:0000662, Constriction of peripheral visual field HP:0001133, Yellow/white lesions of the macula HP:0030500, Hyperautofluorescent retinal lesion HP:0025158, Photoreceptor layer loss on macular OCT (ellipsoid zone loss with preservation of the central retina) HP:0030609, Undetectable dark-adapted electroretinogram HP:0030474, Abnormal timing of light-adapted single flash electroretinogram HP:0030482, Abnormal amplitude of light-adapted single flash electroretinogram HP:0030481, Abnormal dark-adapted dim flash electroretinogram HP:0030471, Abnormal amplitude of dark-adapted dim flash electroretinogram HP:0030476, Ring scotoma HP:0030529, Patchy atrophy of the retinal pigment epithelium HP:0007791

CaseHPOFreeText: The proband has a diagnosis of enhanced S-cone sensitivity.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was performed by next-generation sequencing with a 111-gene panel.

CaseMethod1: Next-generation sequencing with a 111-gene panel.

CaseMethod2: Sanger sequencing of NR2E3

CaseGenotypingMethod: Genotyping was performed by next-generation sequencing with a 111-gene panel, followed by Sanger sequencing of NR2E3.

Variant: The individual harbors the maternal NM_014249.4(NR2E3):c.119-2A>C and paternal NM_014249.4(NR2E3):c.639_640insT (p.Pro214fs) variants in the compound heterozygous state.

ClinVarID: 191059, 1455685

gnomAD: The NM_014249.4(NR2E3):c.119-2A>C variant is found in gnomAD version 4.1.0 at a frequency of 0.001359 in the Ashkenazi Jewish population and 0.0007992 in the European (non-Finnish) population (919 / 1,149,942), with no homozygotes observed. https://gnomad.broadinstitute.org/variant/chr15-71811481-A-C?dataset=gnomad_r4 The NM_014249.4(NR2E3):c.639_640insT (p.Pro214fs) variant is found in gnomAD v4.1.1 at a frequency of 0.000008846 (1 allele / 113,042 total alleles) in the European (non-Finnish) population, with 0 homozygotes. https://www.ncbi.nlm.nih.gov/clinvar/variation/1455685/

VariantEvidence: NM_014249.4(NR2E3):c.119-2A>C is a canonical splice acceptor site variant adjacent to exon 2 of 6, which is an out-of-frame exon that could potentially trigger nonsense-mediated decay if skipped. This paper shows mRNA evidence that the variant triggers exon 2 skipping and introduces a premature stop codon in exon 3. NM_014249.4(NR2E3):c.639_640insT (p.Pro214fs) is a frameshift variant in exon 5 of 8 that introduces a premature stop codon and is predicted to trigger nonsense-mediated decay.

CaseAddInfo: The proband has unaffected heterozygous carrier parents.

CasePMIDs: N/A

Case#: Bernal_2008_Proband_B-256, male, age 13 years at time of report, national origin from Spain

CasePresentingHPOs: Nyctalopia HP:0000662, Progressive visual loss HP:0000529, Reduced visual acuity HP:0007663, Retinoschisis HP:0030502, Nummular pigmentation of the fundus HP:0030505, Undetectable light- and dark-adapted electroretinogram HP:0007688

CaseHPOFreeText: The proband has a diagnosis of Goldmann–Favre syndrome, and had peripheral retinoschisis and macular cysts in both eyes.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of NR2E3.

CaseMethod1: Sanger sequencing of NR2E3

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping was performed by Sanger sequencing of NR2E3.

Variant: The individual harbors the NM_014249.4(NR2E3):c.932G>A (p.Arg311Gln) variant in the homozygous state.

ClinVarID: 5532

gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.003986 in the Ashkenazi Jewish population, with a 118 alleles / 29604 total alleles and 1 homozygote. The variant also has a frequency of 0.0009829 in the Admixed American population. https://gnomad.broadinstitute.org/variant/chr15-71813573-G-A?dataset=gnomad_r4

VariantEvidence: NM_014249.4(NR2E3):c.932G>A (p.Arg311Gln) is a missense variant that is a well-known founder and has been reported in patients from multiple studies with diverse presentations. The variant partially disrupts the ability of NR2E3 to form stable dimers (PMID: 11071390).

CaseAddInfo: The proband has two unaffected heterozygous parents.

CasePMIDs: N/A

Case#: Bernal_2008_Proband_B-316, female, age 47 years at time of report, national origin from Spain

CasePresentingHPOs: Nyctalopia HP:0000662, Progressive visual loss HP:0000529, Reduced visual acuity HP:0007663, Severe constriction of peripheral visual field HP:0030526, Undetectable light- and dark-adapted electroretinogram HP:0007688

CaseHPOFreeText: The proband has a diagnosis of retinitis pigmentosa, and had clusters of large, clumped pigment deposits in the midperiphery of both eyes.

CaseNotHPOs: Macular schisis HP:0011511

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of NR2E3.

CaseMethod1: Sanger sequencing of NR2E3

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping was performed by Sanger sequencing of NR2E3.

Variant: The individual harbors the NM_014249.4(NR2E3):c.1034_1038del (p.Ala344_Leu345insTer) variant in the homozygous state.

ClinVarID: 5534

gnomAD: The variant was not found in gnomAD version 4.1.0.

VariantEvidence: NM_014249.4(NR2E3):c.1034_1038del (p.Ala344_Leu345insTer) is a frameshift variant that introduces a premature stop codon in exon 7 of 8 and is predicted to trigger nonsense-mediated decay.

CaseAddInfo: The proband has two affected siblings who share the same homozygous genotype and one unaffected heterozygous sibling. Parents have not been genotyped, but were indicated as consanguineous.

CasePMIDs: N/A

Case#: Bernal_2008_Proband_B-30, female, age 30 years at time of report, national origin from Spain

CasePresentingHPOs: Nyctalopia HP:0000662, Childhood onset HP:0011463, Reduced visual acuity HP:0007663, Constriction of peripheral visual field HP:0001133

CaseHPOFreeText: The proband has a diagnosis of retinitis pigmentosa, and had hypopigmented clumped lesions in the posterior pole of both eyes.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of NR2E3.

CaseMethod1: Sanger sequencing of NR2E3

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping was performed by Sanger sequencing of NR2E3.

Variant: The individual harbors the NM_014249.4(NR2E3):c.119-2A>C variant in the homozygous state.

ClinVarID: 191059

gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.001359 in the Ashkenazi Jewish population and 0.0007992 in the European (non-Finnish) population (919 / 1,149,942), with no homozygotes observed. https://gnomad.broadinstitute.org/variant/chr15-71811481-A-C?dataset=gnomad_r4

VariantEvidence: NM_014249.4(NR2E3):c.119-2A>C is a canonical splice acceptor site variant adjacent to exon 2 of 6, which is an out-of-frame exon that could potentially trigger nonsense-mediated decay if skipped. This paper shows mRNA evidence that the variant triggers exon 2 skipping and introduces a premature stop codon in exon 3.

CaseAddInfo: The proband has an affected sibling who shares the same homozygous genotype.

CasePMIDs: N/A

Case#: Danciger_2001_Family_Patient_A, gender not specified, age 48 years at the time of the report, family origin reported to be Brazilian

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0001141 (Severely reduced visual acuity), HP:0007994 (Peripheral visual field loss), HP:0000545 (Myopia), HP:0007703 (Abnormality of retinal pigmentation), HP:0007843 (Attenuation of retinal blood vessels), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude), HP:0000483 (Astigmatism), HP:0000523 (Subcapsular cataract)

CaseHPOFreeText: The proband was diagnosed with severe cone-rod dystrophy.

CaseNotHPOs: HP:0000543 (Optic disc pallor)

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and his family have been initially genotyped by linkage mapping using short tandem repeat markers across the genome.

CaseMethod1: Linkage mapping using short tandem repeat markers

CaseMethod2: Sanger sequencing

CaseGenotypingMethod: The proband and his family have been initially genotyped by linkage mapping using short tandem repeat markers across the genome. Haplotype analysis was then performed within the linkage region. Finally, a subsequent publication on the same family sequenced 10 out of 34 genes within the linkage region and found homozygous variants in ADAM9 in particular (PMID: 19409519).

Variant: The affected family members harbor the NM_003816.3(ADAM9):c.1130+1G>A variant in the homozygous state.

ClinVar: 6876

gnomAD: This variant was not found in gnomAD v2.1.1.

VariantEvidence: The NM_003816.3(ADAM9):c.1130+1G>A variant is predicted to disrupt a canonical splice site in intron 11.

CaseAddInfo: The proband's family is known to be consanguineous, with the parents being second cousins.

CasePMIDs: PMID: 19409519

Case#: Chen_2014_Proband_AD01-II:3, male, age 15 years at time of first exam for poor night vision, age 58 years at time of report, family origin reported as Han Chinese

CasePresentingHPOs: Nyctalopia HP:0000662, Constriction of peripheral visual field HP:0001133, Reduced visual acuity HP:0007663, Cataract HP:0000518, Retinal degeneration HP:0000546, Macular degeneration HP:0000608, Optic disc pallor HP:0000543, Attenuation of retinal blood vessels HP:0007843, Pigmentary retinopathy HP:0000580, Central thinning of the outer nuclear layer of the retina HP:6000367, Decreased light- and dark-adapted electroretinogram amplitude HP:0000654

CaseHPOFreeText: The proband has been diagnosed with autosomal dominant retinitis pigmentosa, with features including complete loss of outer/inner segments (OS/IS) by OCT. Patient fibroblasts showed increased expression of PRPF3, PRPF6, PRPF8, PRPF31, EFTUD2, SART1, and PRPF4 itself.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing in the proband included next-generation sequencing targeted to a large number of known variants in all known retinal disease-related genes.

CaseMethod1: next-generation sequencing

CaseMethod2: Sanger sequencing of PRPF4

CaseGenotypingMethod: Genotyping of the proband included next-generation sequencing targeted to a large number of known variants in all known retinal disease-related genes, followed by Sanger sequencing analysis of all coding regions of PRPF4.

Variant: The proband harbors the NM_001244926.2(PRPF4):c.941C>T (p.Pro314Leu) variant in the heterozygous state.

ClinVar ID: 143057

gnomAD: The NM_001244926.2(PRPF4):c.941C>T (p.Pro314Leu) variant is found in gnomAD v4.1.0 at a frequency of 0.000003390 (4 alleles / 1179980 total alleles, with 0 homozygotes) in the European (non-Finnish) population https://gnomad.broadinstitute.org/variant/9-113288183-C-T?dataset=gnomad_r4

VariantEvidence: NM_001244926.2(PRPF4):c.941C>T (p.Pro314Leu) is a missense variant. When over-expressed in zebrafish, the variant causes severely disrupted photoreceptors in the retina and other deformities such as malformed brains, short trunks, cardiac edema and curved body axis, unlike the wild-type control.

CaseAddInfo: The proband has two similarly affected siblings (with onset in their 20's) and an unaffected child (approximately age 10 years) who also harbor the variant.

CasePMIDs: N/A

Case#: Yzer_2006_Patient_21067, female, age 6 months at diagnosis, family origin not described

CasePresentingHPOs: HP:0003593 (Infantile onset), HP:0000486 (Strabismus), HP:0000565 (Esotropia), HP:0008043 (Retinal arteriolar constriction), HP:0000543 (Optic disc pallor), HP:0012426 (Optic disc drusen), HP:0012643 (Foveal hypopigmentation), HP:0007703 (Abnormality of retinal pigmentation), HP:0000639 (Nystagmus), HP:0000613 (Photophobia), HP:0007663 (Reduced visual acuity), HP:0000550 (Undetectable electroretinogram)

CaseHPOFreeText: The individual is described as having Leber congenital amaurosis.

CaseNotHPOs: HP:0000662 (Nyctalopia), HP:0000563 (Keratoconus)

CaseNotHPOFreeText: Fundus was described as largely normal.

CasePreviousTesting: An LCA-specific microarray ChIP was used for initial genotyping, using antisense oligos to screen for 301 known disease-associated variants 6 LCA genes (AIPL1, CRB1, CRX, GUCY2D, RPE65, and RPGRIP1) and two early-onset RP genes (LRAT and MERTK).

CaseMethod1: Sanger sequencing of PCR products from each of the 20 exons of GUCY2D.

CaseMethod2: N/A

CaseGenotypingMethod: The individual was initially screened using an LCA-specific microarray ChIP with antisense oligos to detect 301 known disease-associated variants 6 LCA genes (AIPL1, CRB1, CRX, GUCY2D, RPE65, and RPGRIP1) and two early-onset RP genes (LRAT and MERTK). Subsequent genotyping was performed by Sanger sequencing of PCR products from all 20 exons of the GUCY2D locus.

Variant: The individual is compound heterozygous for the NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) and NM_000180.4(GUCY2D):c.2837C>T (p.Ala946Val) variants.

ClinVar: 98563, 98576

gnomAD: The NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant exhibits a maximum allele frequency of 0.0002943 in gnomAD version 2.1.1 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7917236-C-T The NM_000180.4(GUCY2D):c.2837C>T (p.Ala946Val) variant exhibits a maximum allele frequency of 0.00004013 in gnomAD version 2.1.1 (in the African / African-American population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7918713-C-T

VariantEvidence: Multiple publications have found functional defects in the NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant. PMID: 25477517 shows defective binding to its interacting partner RD3, while PMID: 20050595 and PMID: 23035049 show reduced basal enzymatic activity and inability to interact with the activity-stimulating binding partner GCAP1. Evidence for the pathogenicity of the NM_000180.4(GUCY2D):c.2837C>T (p.Ala946Val) variant is limited to computational predictions.

CaseAddInfo: Parents were reported to be consanguineous. Segregation / phasing of two variants was confirmed by parental genotyping.

CasePMIDs: N/A

Case#: Yzer_2006_Patient_20955, female, diagnosed in the weeks after birth, Dutch or Belgian family origin

CasePresentingHPOs: HP:0003593 (Infantile onset), HP:0000639 (Nystagmus), HP:0007663 (Reduced visual acuity), HP:0000563 (Keratoconus), HP:0001483 (Eye poking), HP:0008043 (Retinal arteriolar constriction), HP:0007814 (Retinal pigment epithelial mottling), HP:0007688 (Undetectable light- and dark-adapted electroretinogram)

CaseHPOFreeText: The individual is described as having Leber congenital amaurosis. Retinal pigment epithelium mottling in the mid- and far periphery was minimal.

CaseNotHPOs: HP:0000662 (Nyctalopia), HP:0000613 (Photophobia), HP:0001098 (Abnormal fundus morphology), HP:0000543 (Optic disc pallor), HP:0030825 (Absent foveal reflex)

CaseNotHPOFreeText: N/A

CasePreviousTesting: An LCA-specific microarray ChIP was used for initial genotyping, using antisense oligos to screen for 301 known disease-associated variants 6 LCA genes (AIPL1, CRB1, CRX, GUCY2D, RPE65, and RPGRIP1) and two early-onset RP genes (LRAT and MERTK).

CaseMethod1: Sanger sequencing of PCR products from the relevant exon of GUCY2D.

CaseMethod2: N/A

CaseGenotypingMethod: The individual was initially screened using an LCA-specific microarray ChIP with antisense oligos to detect 301 known disease-associated variants 6 LCA genes (AIPL1, CRB1, CRX, GUCY2D, RPE65, and RPGRIP1) and two early-onset RP genes (LRAT and MERTK). Subsequent genotyping was performed by Sanger sequencing of PCR products from the relevant exon of the GUCY2D locus.

Variant: The individual is homozygous for the NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant.

ClinVar: 98563

gnomAD: The NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant exhibits a maximum allele frequency of 0.0002943 in gnomAD version 2.1.1 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7917236-C-T

VariantEvidence: Multiple publications have found functional defects in the NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant. PMID: 25477517 shows defective binding to its interacting partner RD3, while PMID: 20050595 and PMID: 23035049 show reduced basal enzymatic activity and inability to interact with the activity-stimulating binding partner GCAP1.

CaseAddInfo: Parents were not reported to be consanguineous. Segregation / phasing of two variants was confirmed by parental genotyping.

CasePMIDs: N/A

Case#: Bifari_2016_Patient_3, male, 1 year of age at time of onset, of Saudi ethnicity

CasePresentingHPOs: HP:0003577 (Congenital onset), HP:0000505 (Visual impairment), HP:0000639 (Nystagmus), HP:0040082 (Happy demeanor), HP:0012758 (Neurodevelopmental delay), HP:0001483 (Eye poking), HP:0031729 (Moderate hypermetropia), HP:0025404 (Abnormal visual fixation), HP:0000550 (Undetectable electroretinogram), HP:0000556 (Retinal dystrophy)

CaseHPOFreeText: This proband exhibited photophilia / staring at lights.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: It is not clear whether the patient was previously subjected to genotyping.

GroupName: Morimura_1998_Group_1

GroupPresentingHPOs: HP:0000546 (Retinal degeneration)

FamilyPresentingHPOFreeText: While specific phenotypes are not provided, the diagnosis of Leber congenital amaurosis or retinitis pigmentosa indicates that the affected family members experienced severe vision loss, either at birth / early infancy, or in childhood / adolescence.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

NumberMales: 8

NumberFemales: 9

CountryOrigin: Most residing within the United States or Canada

Ethnicity: Not mentioned

Race: Not mentioned

AgeRange: Not mentioned

TotalNumber: 17

FamilyInfo: 17

NoFamily: 0

VariantCount: 17

NonVariant: 0

OtherVariant: 0

GroupPreviousTesting: All 14 RPE65 exons and flanking sequences were PCR-amplified and subjected to single-strand conformation polymorphism analysis (SSCA).

GroupMethod1: Screening of PCR-products from 14 RPE65 exons by SSCA

GroupMethod2: Sanger sequencing of 14 RPE65 exons

GroupGenotypingMethod: PCR-amplified exons identified by SSCA as candidates to harbor variants were subjected to Sanger sequencing in the probands and their family members.

GroupAddInfo: N/A

Case#: Morimura_1998_Family_9404_Patient_II-3, male, age and family origin not specified

CasePresentingHPOs: HP:0000546 (Retinal degeneration)

CaseHPOFreeText: While specific phenotypes are not provided, the initial diagnosis of Leber congenital amaurosis indicates that the proband was either born blind or lost vision within a period of months after birth.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: All 14 RPE65 exons and flanking sequences were PCR-amplified and subjected to single-strand conformation polymorphism analysis (SSCA).

CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA

CaseMethod2: Sanger sequencing of all 14 exons of RPE65

CaseGenotypingMethod: PCR-amplified exons identified by SSCA as candidates to harbor variants were subjected to Sanger sequencing.

Variant: The proband is a homozygote within the RPE65 locus, harboring the NM_000329.3(RPE65):c.2T>C (p.Met1Thr) variant.

ClinVar: 98861 (homozygous)

gnomAD: The NM_000329.3(RPE65):c.2T>C (p.Met1Thr) variant was not found within gnomAD.

VariantEvidence: NM_000329.3(RPE65):c.2T>C (p.Met1Thr) is a missense variant that disrupts the start codon and is therefore predicted to have gene impact.

CaseAddInfo: Other family members were not genotyped, and potential consanguinity between the parents was not reported.

CasePMIDs: N/A

Case#: Morimura_1998_Family_0748_Patient_II-1, female, age and family origin not specified

CasePresentingHPOs: HP:0000546 (Retinal degeneration)

CaseHPOFreeText: While specific phenotypes are not provided, the initial diagnosis of Leber congenital amaurosis indicates that the proband was either born blind or lost vision within a period of months after birth.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: All 14 RPE65 exons and flanking sequences were PCR-amplified and subjected to single-strand conformation polymorphism analysis (SSCA).

CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA

CaseMethod2: Sanger sequencing of all 14 exons of RPE65

CaseGenotypingMethod: PCR-amplified exons identified by SSCA as candidates to harbor variants were subjected to Sanger sequencing.

Variant: The proband is a homozygote within the RPE65 locus, harboring the NM_000329.3(RPE65):c.643+2T>A variant.

ClinVar: 940479 (homozygous)

gnomAD: The NM_000329.3(RPE65):c.643+2T>A variant is not found within gnomAD.

VariantEvidence: NM_000329.3(RPE65):c.643+2T>A is an intron 6 variant strongly predicted to disrupt a canonical splice donor site (with a delta score of 0.98).

CaseAddInfo: While the variant is known to be homozygous, the proband's parents have not been genotyped. The potential consanguinity of the parents was not mentioned.

CasePMIDs: N/A

Case#: Perrault_2012_Patient_FI1, male, 17 years of age at time of study, ethnicity not specified

CasePresentingHPOs: HP:0000774 (Narrow chest), HP:0030289 (Flattened femoral epiphysis), HP:0006429 (Broad femoral neck), HP:0004979 (Metaphyseal sclerosis), HP:0010230 (Cone-shaped epiphyses of the phalanges of the hand), HP:0003593 (Infantile onset), HP:0000639 (Nystagmus), HP:0008499 (High hypermetropia), HP:0030526 (Severe constriction of peripheral visual field), HP:0008043 (Retinal arteriolar constriction), HP:0000550 (Undetectable electroretinogram), HP:0004322 (Short stature), HP:0000773 (Short ribs), HP:0000900 (Thickened ribs), HP:0003774 (Stage 5 chronic kidney disease), HP:0000107 (Renal cyst), HP:0030532 (Visual acuity test abnormality), HP:0000556 (Retinal dystrophy)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002093 (Respiratory insufficiency), HP:0010454 (Acetabular spurs), HP:0001410 (Decreased liver function), HP:0000929 (Abnormal skull morphology), HP:0040064 (Abnormality of limbs), HP:0001263 (Global developmental delay)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes)

CaseMethod2: Sanger sequencing of the 29 coding exons of IFT140

CaseGenotypingMethod: The patient was genotyped by ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes), confirmed by Sanger sequencing of the 29 coding exons of IFT140

Variant: The patient is a compound heterozygote harboring the NM_014714.4(IFT140):c.1990G>A (p.Glu664Lys) and NM_014714.4(IFT140):c.2399+1G>T variants in IFT140.

ClinVar: 31679, 31680

gnomAD: The NM_014714.4(IFT140):c.1990G>A (p.Glu664Lys) variant is present in gnomAD at a frequency of 0.00004031 in the African / African-American population (1/24806, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1614075-C-T The NM_014714.4(IFT140):c.2399+1G>T variant is present in gnomAD at a frequency of 0.0001231 in the European (non-Finnish) population (14/113764, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1607935-C-A

VariantEvidence: Exogenous expression of the FLAG-tagged p.Glu664Lys variant in the RPE1 (retinal pigment epithelial) cell line revealed an inability to co-localize with gamma-tubulin, indicating a relatively severe defect in localization to the basal body in most cells, relative to other suspected pathogenic missense variants and the wild-type control (Figure 3A). The NM_014714.4(IFT140):c.2399+1G>T variant disrupts a canonical splice donor site and is predicted but not confirmed to trigger skipping of exon 18/31.

CaseAddInfo: The proband's parents are reportedly non-consanguineous.

CasePMIDs: N/A

Case#: Lebrun_2009_Patient_1, male, age 5 at onset, U.K. origin with family ethnicity reported as Pakistani

CasePresentingHPOs: HP:0007010 (Poor fine motor coordination), HP:0007015 (Poor gross motor coordination), HP:0100952 (Enlarged sylvian cistern), HP:0001251 (Ataxia), HP:0001250 (Seizure), HP:0002465 (Poor speech), HP:0007064 (Progressive language deterioration), HP:0011463 (Childhood onset), HP:0000572 (Visual loss), HP:0030511 (Bradyopsia), HP:0000550 (Undetectable electroretinogram), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0002120 (Cerebral cortical atrophy), HP:0001272 (Cerebellar atrophy)

CaseHPOFreeText: Onset was at age 5, with the first presenting phenotypes being motor problems. Marked cerebellar sulcal widening with subarachnoidal space expansion was seen by brain MRI at age 5. Ataxia and language degradation were observed at age 6. Cortical and cerebellar atrophy presented by brain MRI scan at age 7. Visual problems presented at age 7.5, specifically with inability to focus on moving objects. Seizures first presented at age 8.5, along with bilaterally extinguished ERG. Skin biopsy showed fingerprint-type intralysosomal inclusions.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genome-wide methods were not initially used, as clinical phenotypes were consistent with diagnosis of neuronal ceroid lipofuscinosis (NCL). Enzymatic tests ruled out defects in the CLN1, CLN2, and CLN10 loci, while CLN3, CLN6, and CLN8 defects were ruled out by Sanger sequencing of the coding regions. SNP array-based homozygosity mapping was performed, revealing 7 homozygous candidate regions in the affected members from the (consanguineous) family. These regions were analyzed for candidate NCL genes, finding CLN5 as the most likely locus to harbor the causative variant.

CaseMethod1: SNP array-based homozygosity mapping was performed, revealing 7 homozygous candidate regions in the affected members from the (consanguineous) family. These regions were analyzed for candidate NCL genes, finding CLN5 as the most likely candidate for further genotyping.

CaseMethod2: N/A

CaseGenotypingMethod: CLN5 mRNA was reverse transcribed, PCR-amplified, and subjected to Sanger sequencing. This process was performed for both affected and control individuals (parents and unaffected sibling).

Variant: Patient is homozygous for NM_006493.4(CLN5):c.924_925del (p.Leu309fs), (although this variant is referred to in the article as c.1072_1073delTT (p.Leu358AlafsX4)).

ClinVar: 56526

gnomAD: The variant is reported to have a maximum allele frequency of 0.0002603 (in the Latino / Admixed American population, with no homozygous individuals). https://gnomad.broadinstitute.org/variant/13-77574801-AAT-A

VariantEvidence: The frameshift variant results in premature truncation and disrupts approximately 14% of the protein product at the C-terminus. Immunofluorescent detection of the exogenously expressed variant in COS7 cells shows aberrant localization to the ER in contrast to the wild-type localization to the lysosome (Figure 3).

CaseAddInfo: The patient's family has some degree of consanguinity, as parents are described as distantly related. Parents were heterozygous for the variant. Family relationships between individuals were verified.

CasePMIDs: N/A

FamilyLabel: Lebrun_2009_Family_2

Family#PresentingHPOs: HP:0001251 (Ataxia), HP:0001250 (Seizure), HP:0000750 (Delayed speech and language development), HP:0011463 (Childhood onset),

Family#PresentingHPOFreeText: Ataxia and delay in speech development were the first presenting phenotypes, with onset between ages 2 and 3. Epileptic seizures first occurred at age 4.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: N/A

Ethnicity: Family is of Afghan ethnic origin.

Race: N/A

Family#PreviousTesting: The extent of previous testing within this family is unclear.

Family#Method1: N/A

Family#Method2: N/A

Family#GenotypingMethod: CLN5 mRNA was reverse transcribed, PCR-amplified, and subjected to Sanger sequencing. This process was performed for both affected and control individuals (parents).

Affected: 2

Unaffected: 2

Segregations: 1 segregation is reported in the family.

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Lebrun_2009_Patient_2

Variant: Both affected patients are homozygous for the NM_006493.4(CLN5):c.990G>T (p.Trp330Cys) variant, (although this variant is referred to in the article as c.1137G>T (p.Trp379Cys)).

ClinVar: 56530

gnomAD: The variant is reported to have a maximum allele frequency of 0.00006484 (in the European non-Finnish population, with no homozygous individuals). https://gnomad.broadinstitute.org/variant/13-77575017-G-T

FamilyAddInfo: The family is consanguineous, as parents are described as first degree cousins. Parents were heterozygous for the variant. Family relationships between individuals were verified.

FamilyPMIDs: N/A

Case#: Jiang_2015_Patient_010097, female, age 4 at time of report, national origin listed as Chinese

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0025573 (Mild myopia), HP:0007663 (Reduced visual acuity), HP:0030329 (Retinal thinning), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude), HP:0007401 (Macular atrophy)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0000662 (Nyctalopia), HP:0000639 (Nystagmus), HP:0000551 (Color vision defect)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing appears to have been limited to clinical phenotyping.

CaseMethod1: Sanger sequencing of PCR products from all exons and flanking regions of the GUCY2D locus

CaseMethod2: HhaI restriction digest of the PCR-amplified exon 13

CaseGenotypingMethod: The proband was genotyped by Sanger sequencing of PCR products from all exons and flanking regions of the GUCY2D locus. Parents were implied to have been genotyped as well. The patient and family members were subjected to additional genotyping through restriction fragment length polymorphism analysis, then confirmation by HhaI restriction endonuclease digestion of PCR products from the relevant exon 13.

Variant: The proband harbors the NM_000180.4(GUCY2D):c.2513G>C (p.Arg838Pro) variant in the heterozygous state.

ClinVar: 811743

gnomAD: The variant was not found in gnomAD.

VariantEvidence: NM_000180.4(GUCY2D):c.2513G>C (p.Arg838Pro) is a missense variant located within the coiled-coil domain that mediates dimerization. Codon 838 has proven to be a hot spot disrupted in other families similarly affected with autosomal dominant cone-rod dystrophy (PMID: 11115851, PMID: 12552567, PMID: 26298565). The variant has been reported in an apparently unrelated family from this same publication.

CaseAddInfo: The proband's parents are unaffected and negative for the variant, indicating that this may be a de novo case. It is uncertain whether genotyping methods were sufficient to confirm paternity and maternity.

CasePMIDs: N/A

Case: Felbor_1996_Patient_G, female, age 33 at onset of symptoms, country of origin Austria

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo:

CasePresentingHPOs: HP:0025582 (Submacular hemorrhage), HP:0025094 (Disciform macular scar), HP:0007663 (Reduced visual acuity), HP:0007722 (Retinal pigment epithelial atrophy), HP:0030491 (Choriocapillaris atrophy), HP:0011510 (Drusen), HP:0000603 (Central scotoma), HP:0011506 (Choroidal neovascularization), HP:0012231 (Exudative retinal detachment), HP:0000512 (Abnormal electroretinogram)

CaseHPOFreeText: N/A

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: Normal rod and cone signals

CasePreviousTesting: N/A

GenotypingMethod: SSCP analysis detecting mobility shift in exon 5 PCR product, followed by Sanger sequencing of exon 5.

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: The variant is NM_000362.5(TIMP3):c.572A>G, p.Tyr191Cys, which is referred to in the paper as "Tyr168Cys" (due to the removal of a 23-amino acid N-terminal signal peptide from the polypeptide sequence). The corrected variant is p.Tyr191Cys in the full/updated polypeptide sequence.

ClinVar: 12677

gnomAD: Variant is absent from gnomAD.

VariantEvidence: Variant adds a Cys residue to TIMP3 and is predicted to disrupt tertiary structure.

FamilyLabel: Gliem_2015_Family_1

Family#PresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0011510 (Drusen), HP:0000533 (Chorioretinal atrophy), HP:0030605 (Abnormal indocyanine green angiography), HP:0012508 (Metamorphopsia), HP:0000662 (Nyctalopia), HP:0011506 (Choroidal neovascularization)

FamilyHPOFreeText: Onset in the fifth or sixth decade of life with dark adaptation problems or metamorphopsia, Indocyanine green angiography showing late-phase hypofluorescence early in the disease process, central and midperipheral atrophy, reduced choroidal thickness, yellow deposits in older affected family members, CNV in some patients but not others

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: Germany

Family#PreviousTesting: N/A

Family#GenotypingMethod: Sanger sequencing of PCR products from all 5 exons and flanking splice junctions of the TIMP3 gene.

Affected: 7

Unaffected: 1

Segregations: 7

PublishedLOD: N/A

eLOD: 2.1

AddSegregationInfo: N/A

ProbandLabel: Gliem_2000_Family_1_patient_II.1

Variant: Patients harbor the NM_000362.5(TIMP3):c.530A>G (p.Tyr177Cys) missense variant.

CAID: CA411540328

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: N/A

FamilyPMIDs: N/A

FamilyLabel: Gliem_2015_Family_2

Family#PresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0011510 (Drusen), HP:0000533 (Chorioretinal atrophy), HP:0011506 (Choroidal neovascularization)

FamilyHPOFreeText: Onset of symptoms in the early fifth or sixth decade of life, with either dark adaptation problems, metamorphopsia, or visual loss being the first symptoms, central and midperipheral atrophy, central fibrosis. Some affected family members were largely asymptomatic into the 6th decade of life, but had central retinal drusen. Choroidal neovascularization was observed in some family members and appeared to be a driver of vision loss.

FamilyNotHPOs: HP:0000662 (Nyctalopia)

FamilyNotHPOFreeText: Dark adaptation problems, early onset of symptoms

CountryOrigin: Germany

Family#PreviousTesting: N/A

Family#GenotypingMethod: Sanger sequencing of PCR products from all 5 exons and flanking splice junctions of the TIMP3 gene.

Affected: 6

Unaffected: 2

Segregations: 12

PublishedLOD: N/A

eLOD: 2.1

AddSegregationInfo: N/A

ProbandLabel: Gliem_2000_Family_2_patient_V.1

Variant: Patients harbor the NM_000362.5(TIMP3):c.545A>G (p.Tyr182Cys) missense variant.

CAID: CA411540365

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: Some of the family members were previously identified by genotyping as having Sorsby fundus dystrophy (PMID:25390527), and are more extensively phenotypically described in this study.

FamilyPMIDs: PMID:25390527

Case: Gliem_2000_Family_3_patient_III.5, male, country of origin Germany, onset at 31 years of age

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo: The variant was inherited by the proband rather than acquired de novo.

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0007663 (Reduced visual acuity), HP:0011510 (Drusen), HP:0000533 (Chorioretinal atrophy), HP:0007737 (Bone spicule pigmentation of the retina),

CaseHPOFreeText: Relatively early presentation at age 31 with nyctalopia and prolonged dark adaptation. Evaluation at age 56 showed widespread central and peripheral atrophy, central fibrosis, and reduced choroidal thickness.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: N/A

CasePreviousTesting: Targeted next-generation sequencing of the proband (for a 74-gene panel of retinal dystrophy genes), identifying the TIMP3 variant as well as a heterozygous c.1107G>A (p.Trp369) variant in RP1L1*

GenotypingMethod: Sanger sequencing of PCR products from the TIMP3 and RP1L1 genes

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Patients harbor the NM_000362.5(TIMP3):c.452A>G (p.Tyr151Cys) missense variant.

CAID: CA411540149

gnomAD: Variant is absent from gnomAD.

VariantEvidence: This missense variant within exon 5 of TIMP3 results in an unpaired Cys residue.

Case#: Xin_Patient_1, sex not mentioned, age 5 at onset, U.S. nationality, ethnic admixture of French / Canadian / Irish / U.K. / Dutch

CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0011463 (Childhood onset)

CaseHPOFreeText: Motor difficulty and visual loss were the phenotypes at presentation (age 5). Seizure and cognitive regression had onset at age 7.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.

CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing

CaseMethod2: as mentioned

CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.

Variant: The patient harbors the NM_006493.4(CLN5):c.524G>A (p.Trp175Ter) and NM_006493.4(CLN5):c.956_959del (p.Lys319fs) variants.

ClinVar: 56544 and 56529

gnomAD: Maximum allele frequency for NM_006493.4(CLN5):c.524G>A (p.Trp175Ter) is 0.00003517 (in the European non-Finnish population, no homozygotes). https://gnomad.broadinstitute.org/variant/13-77570221-G-A Maximum allele frequency for NM_006493.4(CLN5):c.956_959del (p.Lys319fs) is 0.0001148 (in the African / African-American population, no homozygotes). https://gnomad.broadinstitute.org/variant/13-77574979-CACAA-C

VariantEvidence: NM_006493.4(CLN5):c.524G>A (p.Trp175Ter) is a nonsense variant that results in truncation of approximately 51% of the protein product. The NM_006493.4(CLN5):c.956_959del (p.Lys319fs) variant triggers a frameshift that affects the final 40 amino acids (approximately 11%) of the protein product. While both variants occur in the final exon (exon 4) and neither is predicted to trigger NMD, the C-terminal region disrupted in both cases has been shown to be glycosylated and is important for proper localization of the protein (PMID:19309691).

CaseAddInfo: Parents do not appear to have been genotyped, so it is not clear whether the two variants are confirmed to be in trans.

CasePMIDs: N/A

Case#: Xin_Patient_9, sex not mentioned, age 6 at onset, U.S. nationality, Egyptian ethnicity

CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0011463 (Childhood onset), HP:0003736 (Autophagic vacuoles)

CaseHPOFreeText: Motor difficulty was the phenotype at presentation (age 6). Cognitive regression, Seizures, and Visual loss had onset at age 7. EM finding of vacuoles was made specifically in muscle.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.

CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing

CaseMethod2: as mentioned

CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.

Variant: The patient is believed to be homozygous for the NM_006493.4(CLN5):c.772del p.Arg258GlufsTer29 variant.

ClinVar: 56546 (homozygous)

gnomAD: The NM_006493.4(CLN5):c.772del p.Arg258GlufsTer29 variant is absent from gnomAD.

VariantEvidence: NM_006493.4(CLN5):c.772del p.Arg258GlufsTer29 is a frameshift variant that disrupts ~28% of the protein product.

CaseAddInfo: Parents have not been subjected to genotyping, so homozygosity of variants is assumed. This conclusion was supported by failure to detect a deletion, and by family history of consanguinity.

CasePMIDs: N/A

Case#: Xin_Patient_2, sex not mentioned, age 5-6 at onset, U.S. nationality, admixed European non-Finnish ethnicity

CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0011463 (Childhood onset), HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material)

CaseHPOFreeText: Seizure was the phenotype at presentation (age 5). Motor difficulty, visual loss, and cognitive regression had onset at age 6.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.

CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing

CaseMethod2: as mentioned

CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.

Variant: The patient harbors the NM_006493.4(CLN5):c.524G>A (p.Trp175Ter) and NM_006493.4(CLN5):c.760_947del (p.Thr254CysfsTer10) variants.

ClinVar: 56544

CAID: CA2017997733

gnomAD: Maximum allele frequency for NM_006493.4(CLN5):c.524G>A (p.Trp175Ter) is 0.00003517 (in the European non-Finnish population, no homozygotes). https://gnomad.broadinstitute.org/variant/13-77570221-G-A The NM_006493.4(CLN5):c.760_947del (p.Thr254CysfsTer10) variant is not found in gnomAD.

VariantEvidence: NM_006493.4(CLN5):c.524G>A (p.Trp175Ter) is a nonsense variant that results in truncation of approximately 51% of the protein product. The NM_006493.4(CLN5):c.760_947del (p.Thr254CysfsTer10) variant triggers a frameshift that affects the final 106 amino acids (approximately 29%) of the protein product. While neither variant is predicted to trigger NMD, the C-terminal region disrupted in both cases has been shown to be glycosylated and is important for proper localization of the protein (PMID:19309691).

CaseAddInfo: Parents do not appear to have been genotyped, so it is not clear whether the two variants are confirmed to be in trans.

CasePMIDs: N/A

Case#: Xin_Patient_7, sex not mentioned, age 4 at onset, U.S. nationality, Chinese ethnicity

CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0011463 (Childhood onset)

CaseHPOFreeText: Visual loss was the phenotype at presentation (age 4). Motor difficulty (age 5), Cognitive regression (age 5), and Seizure (age 6) had later onset.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.

CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing

CaseMethod2: as mentioned

CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.

Variant: The patient harbors the NM_006493.4(CLN5):c.473G>C (p.Trp158Ser) and NM_006493.4(CLN5):c.924_925del (p.Leu309AlafsTer4) variants.

ClinVar: 56542, 56526

gnomAD: Both the NM_006493.4(CLN5):c.473G>C (p.Trp158Ser) and NM_006493.4(CLN5):c.924_925del (p.Leu309AlafsTer4) variants are absent from gnomAD.

VariantEvidence: NM_006493.4(CLN5):c.924_925del (p.Leu309AlafsTer4) is a frameshift variant that disrupts approximately 14% of the protein product. The NM_006493.4(CLN5):c.473G>C (p.Trp158Ser) missense variant affects a conserved residue but does not have other evidence of gene impact.

CaseAddInfo: Parents do not appear to have been genotyped, so it is not clear whether the two variants are confirmed to be in trans.

CasePMIDs: N/A

GroupName: Xin_2010_Group_1

GroupPresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration)

GroupNotHPOs: N/A

NumberMales: Not mentioned

NumberFemales: Not mentioned

CountryOrigin: United States (9 patients) or Sweden (1 patient)

Ethnicity: The 10 patients had various ethnicities; Admixture of French Canadian / Irish / U.K. / Dutch, Admixture of European non-Finnish (3 individuals), Hispanic, Chinese, Indian, Egyptian, Pakistani, Swedish

Race: Not mentioned

AgeRange: Between 4 and 17 years of age at onset

TotalNumber: 10

FamilyInfo: 0

NoFamily: 10

VariantCount: 10

NonVariant: 0

OtherVariant: 0

GroupPreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.

GroupMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing

GroupMethod2: as mentioned

GroupGenotypingMethod: 47 original patients with an NCL phenotype but no variant in one of the 5 tested loci were subjected to CLN5 genotyping. PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. 10 patients were identified as harboring CLN5 variants. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.

GroupAddInfo: N/A

FamilyLabel: Pineda-Trujillo_Family_1

Family#PresentingHPOs: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0003621 (Juvenile onset), HP:0000572 (Visual loss), HP:0003678 (Rapidly progressive), HP:0025406 (Asthenia), HP:0200085 (Limb tremor), HP:0000618 (Blindness), HP:0002540 (Inability to walk), HP:0000708 (Behavioral abnormality), HP:0007064 (Progressive language deterioration), HP:0001336 (Myoclonus), HP:0001250 (Seizure), HP:0002120 (Cerebral cortical atrophy), HP:0001272 (Cerebellar atrophy), HP:0002392 (EEG with polyspike wave complexes)

FamilyHPOFreeText: Onset was at age 9 in all family members, with the first presenting phenotype being visual failure rather than mental retardation (as reported elsewhere). Electron microscopy of skin biopsies found inclusions consisting of fingerprint profiles, which were often condensed and sometimes associated with lipid droplets. Tremor was observed in lower limbs. Blindness and inability to walk developed at approximately age 10 (within a year of symptom onset). Behavioral changes, gradual loss of language, myoclonus, and seizures all occurred within months of onset. Seizures were poorly responsive to valproate or clonazepam. Generalized cortical and cerebellar atrophy without signal intensity changes were seen by NMR at CT scans at ages 10-12. EEG specifically showed a generalized pattern of high-voltage polyspike–slow waves.

FamilyNotHPOs: HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0003226 (Rectilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0001922 (Vacuolated lymphocytes), HP:0003457 (EMG abnormality), HP:0100285 (EMG: impaired neuromuscular transmission)

FamilyNotHPOFreeText: N/A

CountryOrigin: Colombia

Ethnicity: Family is reported to have mixed Spanish, Native American, and African ancestry, but no documented northern European ancestry.

Race: Admixture, combining Spanish, Native American, and African ancestry.

Family#PreviousTesting: Previous testing relied on clinical testing to establish neuronal ceroid lipofuscinosis (CLN), then used 10 different microsatellite markers to evaluate the 6 loci known at the time to be associated with CLN. (Note: This list of CLN-associated loci has since expanded from 6 to 8-12 genes.) The pedigree indicates consistent segregation of the disease phenotype with biallelic inheritance of the three markers in the CLN5 locus. CLN genes were then PCR-amplified and subjected to Sanger sequencing, identifying a variant in CLN5. CLN5 PCR products were additionally subjected to PshAI endonuclease digestion, as the variant abolishes a restriction site. Genome-wide analysis methods were not used.

Family#Method1: Linkage analysis with 10 microsatellite markers across 6 candidate loci known to be associated with CLN phenotypes.

Family#Method2: CLN genes (specifically CLN3 and CLN5) were PCR-amplified and subjected to Sanger sequencing, identifying a variant in CLN5.

Family#GenotypingMethod: CLN5 PCR products were subjected to PshAI endonuclease digestion, as the variant abolishes a restriction site. Genome-wide analysis methods were not used.

Affected: 2

Unaffected: 9

Segregations: 1 segregation is reported in the pedigree from Figure 1, with no individuals inconsistent with an autosomal recessive mode of inheritance. The family in question reportedly has multiple consanguinity loops.

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Pineda-Trujillo_Patient_NCL-22

Variant: Both affected patients are homozygous for NM_006493.4(CLN5):c.188G>A (p.Arg63His), (although this variant is referred to in the article as c.1627G>A or p.Arg112His).

ClinVar: 2567

gnomAD: The variant is reported to have a maximum allele frequency of 0.00003274 (in the South Asian population, with no homozygous individuals). https://gnomad.broadinstitute.org/variant/13-77569212-G-A

FamilyAddInfo: N/A

FamilyPMIDs: N/A

Case#: Streeten_2010_patient_A1, male, age 8 years at report, ethnicity reported as Conservative Mennonite from Pennsylvania

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0200026 (Ocular pain), HP:0004322 (Short stature), HP:0000541 (Retinal detachment), HP:0002757 (Recurrent fractures), HP:0004349 (Reduced bone mineral density)

CaseHPOFreeText: The patient has been diagnosed with osteoporosis-pseudoglioma syndrome, and had positive responses to bisphosphonates such as pamidronate.

CaseNotHPOs: HP:0001249 (Intellectual disability), HP:0007832 (Pigmentation of the sclera), HP:0011729 (Abnormality of joint mobility)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genotyping appears to have been limited to the LRP5 locus.

CaseMethod1: Sanger sequencing of 23 PCR-amplified exons and flanking regions of the LRP5 locus

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping appears to have been limited to Sanger sequencing of 23 PCR-amplified exons and flanking regions of the LRP5 locus.

Variant: The patient harbors the NM_002335.4(LRP5):c.1275G>A (p.Trp425Ter) variant in the homozygous state.

ClinVar: 1459979

gnomAD: The NM_002335.4(LRP5):c.1275G>A (p.Trp425Ter) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LRP5):c.1275G>A (p.Trp425Ter) is a nonsense variant in exon 6 of 23 that is predicted to trigger nonsense-mediated decay or to at least disrupt the C-terminal 74% of the protein product.

CaseAddInfo: The patient is part of a large multi-generation extended family with multiple affected homozygous and compound heterozygous members (Figure 1).

CasePMIDs: N/A

FamilyLabel: Hillery_1998_Family_A

FamilyPresentingHPOs: HP:0030129 (Impaired ristocetin cofactor assay activity)

FamilyPresentingHPOFreeText: Decreased ratio of vWFR:Co / VWF:Ag, decreased AVW-1 and AVW-3 antibody bound to VWF.

FamilyNotHPOs: HP:0030131 (Abnormal von Willebrand factor multimer distribution), HP:0030130 (Impaired von Willibrand factor collagen binding activity)

Case19: 1 mo (at biopsy), White

Case 19 (Level 2)

CasePreviousTesting: same as group. found 1.2 nmol/mg protein/18 h propionate incorporation, 1.0 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.655A>T (p.Asn219Tyr)

ClinVar: 1886

CAID: CA249731

gnomAD: 0.0001318 (European non-Finnish)

Variant2: NM_000255.3:c.1332+1delG

ClinVar: 554656

CAID: CA3846920

gnomAD: 0.000008828 (European non-Finnish)

CaseAddInfo: mut0 type, heterozygous mutations, unknown cis or trans

Case18: 2 mo (at biopsy), French Canadian

Case 18 (Level 2)

CasePreviousTesting: same as group. found 0.7 nmol/mg protein/18 h propionate incorporation, 0.7 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.655A>T (p.Asn219Tyr)

ClinVar: 1886

CAID: CA249731

gnomAD: 0.0001318 (European non-Finnish)

__

Variant2: NM_000255.3:c.1240delG (p.Glu414LysfsTer17)

ClinVar: n/a

CAID: CA3846936

gnomAD: 0.000008796 (European Non-Finnish)

CaseAddInfo: mut0 type. Variant 2 is novel. heterozygous mutations, unknown cis or trans.

Case17: 6 y (at biopsy), Black

Case 17 (Level 2)

CasePreviousTesting: same as group. found 0.6 nmol/mg protein/18 h propionate incorporation, 0.6 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.631_633delGAG (p.Glu211del)

ClinVar: n/a

CAID: CA913187321

gnomAD: n/a

Variant2: NM_000255.3:c.682C>T (p.Arg228Ter)

ClinVar: 203855

CAID: CA312778

gnomAD: 0.0002615 (Latino)

CaseAddInfo: mut0 type, heterozygous mutations. Variant 1 is novel. MUT mutations are in trans- demonstrated by RT-PCR of mRNA. Additional variant found in MCEE gene (NM_032601.3:c.428G>A, ClinVar: 336936, CAID: CA1702575, gnomAD: 0.08102 (Latino)) MCEE variant is unlikely to be associated with patient's MMA.

Case16: 5 days (at biopsy), Lao/Thai/Mexican/Portugese

Case 16 (Level 2)

CasePreviousTesting: same as group. found 0.6 nmol/mg protein/18 h propionate incorporation, 0.5 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.581C>T (p.Pro194Leu)

ClinVar: n/a

CAID: CA364404418

gnomAD: n/a

Variant2: NM_000255.3:c.682C>T (p.Arg228Ter)

ClinVar: 203855

CAID: CA312778

gnomAD: 0.0002615 (Latino)

CaseAddInfo: mut0 type, heterozygous mutation, unknown cis or trans

Case15: 3 wks (at biopsy), white

Case (Level 2)

CasePreviousTesting: same as group. found 0.5 nmol/mg protein/18 h propionate incorporation, 0.7 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.572C>A (p.Ala191Glu)

ClinVar: 203854

CAID: CA312777

gnomAD: 0.00006976 (European non-FInnish)

Variant2: NM_000255.3:c.754-2A>G

ClinVar: 552691

CAID: CA364402853

gnomAD: n/a

CaseAddInfo: variant 2 is a novel, splice site mutation. Heterozygous mutations, unknown cis or trans.

Case13: 21 y (at biopsy), English/Irish

Case (Level 2)

CasePreviousTesting: same as group. found 1.5 nmol/mg protein/18 h propionate incorporation, 1.5 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.572C>A (p.Ala191Glu)

ClinVar: 203854

CAID: CA312777

gnomAD: 0.00006976 (European non-FInnish)

Variant2: NM_000255.3:c.682C>T (p.Arg228Ter)

ClinVar: 203855

CAID: CA312778

gnomAD: 0.0002615 (Latino)

CaseAddInfo: mut0 type, heterozygous mutation, unknown cis or trans

Case12: 6y (at biopsy), no ethnicity recorded

Case (Level 2)

CasePreviousTesting: same as group. found 0.5 nmol/mg protein/18 h propionate incorporation, 1.3 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.556A>G (p.Met186Val)

ClinVar: 551460

CAID: CA3847093

gnomAD: 0.00001760 (European Non-Finnish)

Variant2: NM_000255.3:c.1106G>A (p.Arg369His)

ClinVar: 203846

CAID: CA312764

gnomAD: 0.0001504 (East Asian)

CaseAddInfo: mut- type, heterozygous mutations, unknown cis or trans

Case11: 6y (at biopsy), White/Hispanic

Case (Level 2)

CasePreviousTesting: same as group. found 2.6 nmol/mg protein/18 h propionate incorporation, 7.0 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.566A>T (p.Asn189Ille)

ClinVar: 222915

CAID: CA3847091

gnomAD: 0.000008804 (European Non-Finnish)

Variant2: NM_000255.3:c.655A>T (p.Asn219Tyr)

ClinVar: 1886

CAID: CA249731

gnomAD: 0.0001318 (European non-Finnish)

CaseAddInfo: Variant 1 is novel, unknown cis or trans. mut- type.

Case14: 3 mo (at biopsy), White/Australian

Case (Level 2)

CasePreviousTesting: same as group. found 0.5 nmol/mg protein/18 h propionate incorporation, 0.5 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.572C>A (p.Ala191Glu)

ClinVar: 203854

CAID: CA312777

gnomAD: 0.00006976 (European non-FInnish)

Variant2: NM_000255.3:c.682C>T (p.Arg228Ter)

ClinVar: 203855

CAID: CA312778

gnomAD: 0.0002615 (Latino)

CaseAddInfo: mut0 type, heterozygous mutation, unknown cis or trans

Case10: 6 days (at biopsy), Northern European/Filipino

Case (Level 2)

CasePreviousTesting: same as group. found 0.8 nmol/mg protein/18 h propionate incorporation, 1.2 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.322C>T (p.Arg108Cys)

ClinVar: 1887

CAID: CA249732

gnomAD: 0.0008393 (Latino)

Variant2: NM_000255.3:c.682C>T (p.Arg228Ter)

ClinVar: 203855

CAID: CA312778

gnomAD: 0.0002615 (Latino)

CaseAddInfo: mut0 type, heterozygous mutations, unknown cis or trans.

Case9: 46 days (at biopsy), Hispanic

Case (Level 2)

CasePreviousTesting: same as group. found 0.8 nmol/mg protein/18 h propionate incorporation, 1.2 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.322C>T (p.Arg108Cys)

ClinVar: 1887

CAID: CA249732

gnomAD: 0.0008393 (Latino)

Variant2: NM_000255.3:c.654A>C (p.Gln218His)

ClinVar: 551243

CAID: CA364404273

gnomAD: 0.000008809 (European non-Finnish)

CaseAddInfo: mut0 class, heterozygous mutations, unknown cis or trans.

Case8: 12 days (at biopsy), White/Mexican

Case (Level 2)

CasePreviousTesting: same as group. found 0.8 nmol/mg protein/18 h propionate incorporation, 1.0 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.322C>T (p.Arg108Cys)

ClinVar: 1887

CAID: CA249732

gnomAD: 0.0008393 (Latino)

Variant2: NM_000255.3:c.654A>C (p.Gln218His)

ClinVar: 551243

CAID: CA364404273

gnomAD: 0.000008809 (European non-Finnish)

CaseAddInfo: mut0 class, heterozygous mutations, unknown cis or trans.

Case7: 10 days (at biopsy), White

Case (Level 2)

CasePreviousTesting: same as group. found 0.4 nmol/mg protein/18 h propionate incorporation, 0.5 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.146_147ins279

ClinVar: n/a

CAID: n/a- could not register

gnomAD: n/a

Variant2: NM_000255.3:c.372_374dupGA (p.Lys124_Asp125insGlu)

ClinVar: 203861

CAID: CA312788

gnomAD: 0.000008799

CaseAddInfo: mut0 class. heterozygous mutations. identified to be in trans through cDNA analysis. variant 1 is novel and consists of a 279 base pair insertion.

Case6 2 mo (at biopsy), White

Case (Level 2)

CasePreviousTesting: same as group. found 1.1 nmol/mg protein/18 h propionate incorporation, 3.0 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.129G>A (p.Trp43Ter)

ClinVar: 222908

CAID: CA10575886

gnomAD: n/a

Variant2: NM_000255.3:c.299A>G (p.Tyr100Cys)

ClinVar: 218991

CAID: CA347866

gnomAD: 0.000008793 (European non-Finnish)

CaseAddInfo: mut- class. heterozygous mutations. unknown cis or trans. variant 1 is novel.

Case5: 1y 9 mo (at biopsy), Korean

Case (Level 2)

CasePreviousTesting: same as group. found 0.7 nmol/mg protein/18 h propionate incorporation, 0.7 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.91C>T (p.Arg31Ter)

ClinVar: 92688

CAID: CA249743

gnomAD: 0.00008013 (African)

Variant2: NM_000255.3:c.349G>T (p.Glu117Ter)

ClinVar: 1882

CAID: CA115264

gnomAD: n/a

CaseAddInfo: mut0 class. heterozygous mutations. unknown cis or trans.

Case4: 2 y (at biopsy), Black

Case (Level 2)

CasePreviousTesting: same as group. found 2.1 nmol/mg protein/18 h propionate incorporation, 3.1 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.91C>T (p.Arg31Ter)

ClinVar: 92688

CAID: CA249743

gnomAD: 0.00008013 (African)

Variant2: NM_000255.3:c.323G>A (p.Arg108His)

ClinVar: 100707

CAID: CA235522

gnomAD: 0.00006152 (African)

CaseAddInfo: mut- class. heterozygous mutations. unknown cis or trans. Third variant in TCN2 gene (NM_000355.3:c.89T>G p.Leu30Arg, CAID: CA10184491, ClinVar: 529781, gnomAD: 0.01329 (African))

Case3: 19y (at biopsy), Irish/Scottish/Polish

Case (Level 2)

CasePreviousTesting: same as group. found 1.2 nmol/mg protein/18 h propionate incorporation, 1.2 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.29dupT (p.Leu10PhefsTer39)

ClinVar: 553287

CAID: CA567155988

gnomAD: 0.00003269 (South Asian)

Variant2: NM_000255.3:c.1658delT (p.Val553GlyfsTer17)

ClinVar: n/a

CAID: CA450397348

gnomAD: 0.000008808 (European non-Finnish)

CaseAddInfo: mut0 class. heterozygous mutations. variant 1 is novel. unknown cis or trans.

Case2: 1 mo (at biopsy), Palestinian

Case (Level 2)

CasePreviousTesting: same as group. found 1.5 nmol/mg protein/18 h propionate incorporation, 1.5 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.2T>C (p.Met1Thr)

ClinVar: 222903

CAID: CA10575890

gnomAD: n/a

Variant2: NM_000255.3:c.1630_1631delGGinsTA (p.Gly544Ter)

ClinVar: 203860

CAID: CA312786

gnomAD: 0.0001088 (East Asian)

CaseAddInfo: mut0 class. heterozygous mutations- unknown cis or trans. 3rd mutation in CD320 gene (NM_016579.3:c.658G>A p.Gly220Arg, ClinVar: 136684, CAID: CA289989, gnomAD: 0.3086 (African) )

Case1: 13 mo (at biopsy), no recorded ethnicity

Case (Level 2)

CasePreviousTesting: same as group. found 2.4 nmol/mg protein/18 h propionate incorporation, 4.7 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.1A>G (p.M1?)

ClinVar: n/a

CAID: CA364406084

gnomAD: n/a

Variant2: NM_000255.3:c.2150G>T (p.Gly717Val)

ClinVar: 1881

CAID: CA249729

gnomAD: 0.0006810 (African)

CaseAddInfo: mut- class. heterozygous mutations. unknown cis or trans

Case# Case 3, M, Chinese, 3day onset

CasePresentingHPOs HP:0008344, HP:0001954, HP:0005972, HP:0011968, HP:0008947

CasePreviousTesting Tested blood aa levels with liquid chromatography-mass spectrum spectrometry, several branched chain amino acids were overly abundant. Whole exome targeted capture sequencing was applied for the mutation screening of the suspicious patients. A total of 712 genes associated with inherited metabolic diseases were selected and their coding regions were captured.

CaseMethod1 Whole Exome

CaseMethod2 Sanger

CaseGenotypingMethod validated whole exome findings with sanger and qPCR.

Variant NM_000056.3:c.659del(p.D229fs)

CAID CA658820635

CaseAddInfo Mother was not tested but WES was used in the patient and father

Case# Case 1, F, Chinese, 4day old Age of Onset

CasePresentingHPOs HP:0011968, HP:0001276, HP:0002373, HP:0001954, HP:0008344

CasePreviousTesting Tested blood aa levels with liquid chromatography-mass spectrum spectrometry, several branched chain amino acids were overly abundant. Whole exome targeted capture sequencing was applied for the mutation screening of the suspicious patients. A total of 712 genes associated with inherited metabolic diseases were selected and their coding regions were captured.

CaseMethod1 Whole Exome

CaseMethod2 Sanger

CaseGenotypingMethod validated whole exome findings with sanger and qPCR.

Variant NM_000056.4(BCKDHB):c.508C>T (p.Arg170Cys), NM_000056.3:c.659del

ClinVar 96590 (missense)

CAID CA658820635 (c.659del)

gnomAD 0.00001791 (European(Non-Finnish)), 0.000008123 (Overall)

CasePMIDs missense mentioned in 25381949

Case# Case 5, M, Chinese, 4day onset

CasePresentingHPOs HP:0008344, HP:0040168, HP:0008947, HP:0011968

CasePreviousTesting Tested blood aa levels with liquid chromatography-mass spectrum spectrometry, several branched chain amino acids were overly abundant. Whole exome targeted capture sequencing was applied for the mutation screening of the suspicious patients. A total of 712 genes associated with inherited metabolic diseases were selected and their coding regions were captured.

CaseMethod1 Whole Exome

CaseMethod2 Sanger

CaseGenotypingMethod validated whole exome findings with sanger and qPCR.

Variant NM_000056.3:c.863C>A(p.Ala288Asp), ?

CAID CA364660141 (miss), wait for follow up (exon del)

Case# Patient 13, Female, 1yo diagnosis

Variant NM_000320.2:c.529G>A (p.Y150C)

CAID CA2868077

gnomAD 0.0001831 (Other?)

Case# Patient 5, Female, 4.5mo

Variant NM_000320.2:c.133A>G (p.G18D)

CAID CA356453446

Case# Patient 12, Male, Turkish, 6yo diagnosis

CasePresentingHPOs HP:0004923

CasePreviousTesting screened for BH4 deficiency using dried blood and urine spots, Final di-agnosis was made by measurements of neurotransmitter and pterinmetabolites in cerebrospinal fluid (CSF) and urine, in addition toDHPR enzyme activity, which was assessed in whole red bloodcells

CaseMethod1 PCR

CaseMethod2 DGGE

Variant NM_000320.2:c.371delC(p.S97fs)

CAID CA658795310

VariantEvidence frameshift

Case# Patient 11, Female, 5mo diagnosis

Variant NM_000320.2(QDPR):c.185+3delinsAC (p.W35fs)

CAID CA658795310

VariantEvidence frameshift

Case# Patient 17, Female, Turkish, 2mo diagnosis

CasePresentingHPOs HP:0004923

CasePreviousTesting screened for BH4 deficiency using dried blood and urine spots, Final di-agnosis was made by measurements of neurotransmitter and pterinmetabolites in cerebrospinal fluid (CSF) and urine, in addition toDHPR enzyme activity, which was assessed in whole red bloodcells

CaseMethod1 PCR

CaseMethod2 DGGE

Variant NM_000320.2:c.741A>T(p.R221Ter)

CAID CA658795309

VariantEvidence null