FamilyLabel: Morimura_1998_Family_7828

FamilyPresentingHPOs: HP:0000546 (Retinal degeneration)

FamilyPresentingHPOFreeText: While specific phenotypes are not provided, the diagnosis of retinitis pigmentosa indicates that the affected family members maintained central vision during the first decade of life and subsequently experienced severe vision loss.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: The Dominican Republic

Ethnicity: Not mentioned

Race: Not mentioned

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

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

Affected: 5

Unaffected: 5

Segregations: The pedigree (Figure 2A) shows 10 segregations, with none inconsistent.

PublishedLOD: N/A

eLOD: 3.03

AddSegregationInfo: While four of the affected family members are compound heterozygotes at the RPE65 locus, one harbors homozygous variants.

ProbandLabel: Morimura_1998_Patient_III-4

Variant: Four affected individuals are compound heterozygotes harboring the NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser) and NM_000329.3(RPE65):c.1207_1210dup (p.Glu404fs) variants, while one affected individual is homozygous for the NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser) variant.

ClinVar: 13118, 98831

gnomAD: Neither the NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser) variant nor the NM_000329.3(RPE65):c.1207_1210dup (p.Glu404fs) variant is found within gnomAD.

FamilyAddInfo: The two variants were confirmed to be in trans, and heterozygous carriers were found to be unaffected. Potential consanguinity between the parents was not reported, at least within the first generation of the pedigree.

FamilyPMIDs: N/A

FamilyLabel: Gliem_2015_Family_3

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 fourth or fifth decade of life, with dark adaptation problems being the first symptoms, central and/or midperipheral chorioretinal atrophy, and central fibrosis or focal fibrotic changes, thinning of choroid

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: Germany

Family#PreviousTesting: 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*

Family#GenotypingMethod: Sanger sequencing of PCR products from the TIMP3 and RP1L1 genes, confirming that the TIMP3 variant co-segregated with the disease.

Affected: 2

Unaffected: 2

Segregations: 2

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: The number of affected individuals / segregations was insufficient to estimate a LOD score.

ProbandLabel: Gliem_2000_Family_3_patient_III.5

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

CAID: CA411540149

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: N/A

FamilyPMIDs: N/A

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

FamilyLabel: Olivier_2021_Family_A

Family#PresentingHPOs: HP:0030629 (Perifoveal ring of hyperautofluorescence), HP:0011510 (Drusen),

FamilyPresentingHPOFreeText: The affected family members have been diagnosed with retinitis pigmentosa, with severity ranging from mild to severe, depending on the family member.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: Younger family members were thought to be "pre-clinical", with only mild symptoms such as a subtle non-physiological autofluorescence ring and some drusen-like lesions in the posterior pole.

CountryOrigin: The family is reportedly French.

Ethnicity: Not specifically described

Race: N/A

Family#PreviousTesting: Panel-based genetic testing was performed, focusing on retinitis pigmentosa-associated genes. Subsequent testing used whole exome sequencing of four affected and one unaffected patient (II:1, II:2, II:3, III:3 and III:4).

Family#Method1: whole-exome sequencing

Family#Method2: Sanger sequencing of the candidate genes is assumed but not described.

Family#GenotypingMethod: Panel-based genetic testing was performed, focusing on retinitis pigmentosa-associated genes. Subsequent testing used whole exome sequencing of four affected and one unaffected patient (II:1, II:2, II:3, III:3 and III:4). Sanger sequencing of the candidate genes is assumed but not described.

Affected: 10 genotyped

Unaffected: 4 genotyped

Segregations: 9 segregations are shown by the pedigree in Figure 1.

PublishedLOD: N/A

eLOD: 2.7

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

ProbandLabel: Olivier_2021_Family_Proband_IV-8

Variant: The affected family members harbor the NM_001563.4:c.1824+1G>A variant in the heterozygous state.

CAID: CA3898050

gnomAD: This variant is found in gnomAD v2.1.1 at a frequency of 0.00002980 (1 / 33554 alleles total in the Latino / Admixed American population. https://gnomad.broadinstitute.org/variant/6-76660278-C-T

VariantEvidence: NM_001563.4:c.1824+1G>A is a canonical splice site variant predicted to have a severe impact on the gene product.

FamilyAddInfo: The family's national origin has been reported as French.

FamilyPMIDs: N/A

FamilyLabel: Liu_2007_Family

Family#PresentingHPOs: HP:0006934 (Congenital nystagmus), HP:0007750 (Hypoplasia of the fovea), HP:0000483 (Astigmatism), HP:0007663 (Reduced visual acuity)

FamilyPresentingHPOFreeText: The affected family members have been diagnosed with congenital nystagmus segregating with an X-linked mode of inheritance. While all members exhibit nystagmus, some members have foveal hypoplasia (4 out of 5 affected males), myopia, amblyopia, and/or mottling of the retinal pigmentation as well.

FamilyNotHPOs: HP:0001000 (Abnormality of skin pigmentation), HP:0009887 (Abnormality of hair pigmentation), HP:0012805 (Iris transillumination defect), HP:0007894 (Hypopigmentation of the fundus)

FamilyNotHPOFreeText: One family member was subjected to functional MRI and did not show abnormalities of the optic nerve head.

CountryOrigin: China

Ethnicity: Chinese

Race: Not specifically described

Family#PreviousTesting: Linkage mapping has been performed in affected and unaffected family members using 33 polymorphic markers along the entire X chromosome. Haplotype analysis identified a shared region of approximately 10.6 Mb in all affected males.

Family#Method1: Linkage mapping and haplotype analysis

Family#Method2: Sanger sequencing of 21 candidate genes in the linkage region

Family#GenotypingMethod: Linkage mapping has been performed in affected and unaffected family members using 33 polymorphic markers along the entire X chromosome. Haplotype analysis identified a shared region of approximately 10.6 Mb in all affected males. Sanger sequencing was then performed for 21 candidate genes in the linkage region, followed by RFLP analysis in a subset of affected and unaffected family members.

Affected: 4 fully genotyped, 9 total

Unaffected: 7 fully genotyped

Segregations: 8 segregations are shown by the pedigree in Figure 2B.

PublishedLOD: 8.89 (associated with the DXS987 marker on chromosome Xp22)

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Liu_2007_Family_Patient_V-10

Variant: The affected male family members harbor the NM_000273.3(GPR143):c.266C>T (p.Ser89Phe) variant in the hemizygous state.

ClinVar: 10522

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

VariantEvidence: NM_000273.3(GPR143):c.266C>T (p.Ser89Phe) is a missense variant in exon 2 of 9 total, and is located in a transmembrane domain but does not have experimental evidence of gene impact.

FamilyAddInfo: The family is not reported to be consanguineous.

FamilyPMIDs: N/A

Family 10 - Patient 10

FamilyPresentingHPOs: HP:0007340, HP:0003701, HP:0003327, HP:0040081, HP:0002111

HPOsFreeText: muscle pathology with vacuolar myopathy

FamilyNotHPOs: HP:0010628, HP:0002015, HP:0003691, HP:0003306, HP:0002650

Ethnicity: Iranian

ProbandLabel:

FamilyAddInfo: onset at 38yo, diagnosis at 50yo, MRC sum score = 73, patient required use of NIV

FamilyPreviousTesting: Respiratory Evaluation: FVC = 65%, CK = 551 U/L, muscle pathology examined, DBS enzyme activity (with inhibition) = 0.12 μmol/L/h

FamilyGenotypingMethod: GAA analyzed with Sanger Sequencing for entire coding region and conserved exon-intron splice junctions, PCR performed for deletion screening

VariantAllele1: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

VariantAllele2: NM_000152.3:c.2596delG

CAID: CA891834514, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA891834514

gnomAD: n/a

Family 4 - Patients 4a and 4b

FamilyPresentingHPOs: HP:0007340, HP:0003701, HP:0000467, HP:0003327, HP:0010628, HP:0002015, HP:0003306, HP:0002111, HP:0011807, HP:0003554, HP:0002111, HP:0100298, HP:0040081

HPOsFreeText: myopathic muscle unit action potentials, 4b muscular pathology with mild atrophy of type 1 and 2 fibers with many moth‐eaten fibers, no vacuoles, no glycogen excess

FamilyNotHPOs: HP:0003691, HP:0002650

NotHPOsFreeText:

Ethnicity: Iranian

ProbandLabel: 4a, female, 7yo at onset, 30yo at diagnosis

FamilyAddInfo: 4b (male) dx at 23yo, 4a MRC sum score = 84, 4b MRC sum score = 86, both patients required use of NIV

FamilyPreviousTesting: Respiratory Evaluation: 4a FVC = 29%, 4b FVC = 66%, 4a CK = 760 U/L, 4b CK = 3,257 U/L, muscle pathology (examined only in 4b), DBS enzyme activity (with inhibition) for 4a = 0.1 μmol/L/h, for 4b = 0.13 μmol/L/h, NCS, EMG

FamilyGenotypingMethod: GAA analyzed with Sanger Sequencing for entire coding region and conserved exon-intron splice junctions, PCR performed for deletion screening

VariantAllele1: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

VariantAllele2: NM_000152.3:c.1650delG

Clinvar: n/a

CAID: CA627699787, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA627699787

gnomAD: n/a

Family 2 - Patient 2

FamilyPresentingHPOs: HP:0002355, HP:0003701, HP:0000467, HP:0009027, HP:0010628, HP:0002015, HP:0002111

HPOsFreeText:

FamilyNotHPOs: HP:0003691, HP:0003306, HP:0002650

NotHPOsFreeText:

Ethnicity: Iranian

ProbandLabel: Patient 2, male

FamilyAddInfo: 2yo at onset, 9yo at diagnosis MRC sum score = 73, NIV prescribed due to reduced FVC

FamilyPreviousTesting: Respiratory evaluation: FVC = 23%, CK = 83 U/L, Normal muscle pathology exams, DBS enzyme activity (with inhibition) = 0.14 μmol/L/h

FamilyGenotypingMethod: GAA analyzed with Sanger Sequencing for entire coding region and conserved exon-intron splice junctions, PCR performed for deletion screening

Variant: NM_000152.3:c.2040+2dup

ClinVar: n/a

CAID: CA891834512, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA891834512

gnomAD: n/a

Family 5 - Patients 5a and 5b

FamilyPresentingHPOs: HP:0009027, HP:0000467, HP:0003327, HP:0003691, HP:0002650, HP:0040081, HP:0100284

HPOsFreeText: Myotonic discharges in paraspinal, tibialis anterior, first dorsal interosseous, and biceps muscles, Myopathic muscle unit action potentials, 5b muscular pathology with Severe lysosomal vacuolar myopathy with prominent glycogen excess

FamilyNotHPOs: HP:0010628, HP:0002015, HP:0003306

Ethnicity: Iranian

ProbandLabel: 5a, male, 10yo at onset, 12yo at diagnosis

FamilyAddInfo: 5b (female) dx at 15 yo, 5a MRC sum score = 94, 5b MRC sum score = 91

FamilyPreviousTesting: Respiratory Evaluation: 5a FVC = 91%, 5b FVC = 106%, 5a CK = 1,202 U/L, 5b CK = 907 U/L, muscle pathology (examined only in 5b), DBS enzyme activity (with inhibition) for 5a = 0.5 μmol/L/h, for 5b = 0.6 μmol/L/h, NCS, EMG

FamilyGenotypingMethod: GAA analyzed with Sanger Sequencing for entire coding region and conserved exon-intron splice junctions, PCR performed for deletion screening

Variant: NM_000152.3:c.1837T>G

ClinVar: n/a

CAID: CA401369569, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401369569

gnomAD: n/a

FamilyLabel: Perrault_2012_Family_FIV

Family#PresentingHPOs: HP:0003593 (Infantile onset), HP:0000639 (Nystagmus), HP:0007663 (Reduced visual acuity)

Family#PresentingHPOFreeText: Staining of ciliary axonemes for acetylated alpha-tubulin detected an absence of cilia in a high percentage of cultured fibroblast cells, relative to control patients. Affected family members have been diagnosed with Mainzer-Saldino syndrome.

FamilyNotHPOs: HP:0001410 (Decreased liver function), HP:0012211 (Abnormal renal physiology)

FamilyNotHPOFreeText: IFT140 protein localization along the ciliary axoneme was unaffected in patient FIV3, however, two components of the anterograde transport IFT-B complex, IFT88 and IFT46, were aberrantly localized. They were evenly distributed along the cilium instead of primarily localized at the base and the tip of the cilium, suggesting an alteration in retrograde ciliary transport.

CountryOrigin: Saudi Arabia

Ethnicity: Not described.

Race: Not described.

Family#PreviousTesting: N/A

FamilyMethod1: Ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes)

Family#Method2: Sanger sequencing of the 29 coding exons of IFT140.

Family#GenotypingMethod: The family 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

Affected: 3

Unaffected: 3

Segregations: 2 segregation were reported. The pedigree can be found in Figure S1. The family was described as consanguineous.

PublishedLOD: N/A

eLOD: 1.50

AddSegregationInfo: N/A

ProbandLabel: Perrault_2012_patient_FIV3

Variant: Affected individuals harbor the NM_014714.4(IFT140):c.1990G>A (p.Glu664Lys) variant in a homozygous state.

ClinVar: 31679

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

FamilyAddInfo: The parents of the affected family members are reportedly consanguineous (first cousins).

FamilyPMIDs: N/A

FamilyLabel: Weber_1994_Family_M

Family#PresentingHPOs: HP:0011506 (Choroidal neovascularization), HP:0025094 (Disciform macular scar), HP:0007663 (Reduced visual acuity)

FamilyHPOFreeText: Choroidal neovascular invasion of the macula was bilateral. This occurred early in the presentation and led to the disciform scar and loss of central vision.

FamilyNotHPOs: N/A

CountryOrigin:

Family#PreviousTesting:

Family#GenotypingMethod: Sanger sequencing of Weber_1994_Family_M_patient_IV-2

Affected: 1

Unaffected: 1

Segregations: N/A

PublishedLOD:

eLOD: Insufficient information available

AddSegregationInfo: Absence of segregation info from the family is due to the fact that genotyping was limited to only the proband and one unaffected control.

ProbandLabel: Weber_1994_Family_M_patient_IV-2

Variant: NM_003490.4:c.711+5602T>C, p.Tyr191Cys

ClinVar: 12677

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: Variant was first referred to in PMID:7894485 as "Tyr168Cys" but encodes Tyr191Cys in the updated polypeptide sequence.

FamilyPMIDs: PMID:2000899

FamilyLabel: Weber_1994_Family_B

Family#PresentingHPOs: 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)

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

FamilyNotHPOs: N/A

CountryOrigin: Canada (PMID:7920634), genealogy indicating Irish descent (PMID: 2695876)

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

Family#GenotypingMethod: Sanger sequencing of Weber_1994_Family_B_patient_V-1

Affected: 1

Unaffected: 1

Segregations: N/A

PublishedLOD: A multipoint LOD Score of 7.43 was published for the interval between tandem repeat markers D22S275 and D22S274 on chromosome 22q13, a region that includes the TIMP3 locus (PMID:7920634).

eLOD: Insufficient information available

AddSegregationInfo: N/A

ProbandLabel: Weber_1994_Family_B_patient_V-1

Variant: The variant is NM_000362.5(TIMP3):c.610A>T, p.Ser204Cys

ClinVar: 12676

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: Variant was first referred to in PMID:7894485 as "Ser181Cys" but encodes Ser204Cys in the updated polypeptide sequence. A more detailed pedigree is available from an earlier publication (PMID:7920634), but genotyping was not performed at that time, resulting in a lack of segregation data.

FamilyPMIDs: PMID:2695876, PMID:7920634

FamilyLabel: Mancini_2015_Family_ATA-7-TO

FamilyPresentingHPOs: HP:0003596 (Middle age onset), HP:0002355 (Difficulty walking), HP:0001260 (Dysarthria), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0001272 (Cerebellar atrophy), HP:0006855 (Cerebellar vermis atrophy), HP:0008278 (Cerebellar cortical atrophy), HP:0001251 (Ataxia), HP:0002317 (Unsteady gait), HP:0000639 (Nystagmus), HP:0001310 (Dysmetria), HP:0007350 (Hyperreflexia in upper limbs), HP:0002395 (Lower limb hyperreflexia)

FamilyPresentingHPOFreeText: Presentation was in the middle of the 6th decade of life.

FamilyNotHPOs: HP:0410280 (Pediatric onset), HP:0003474 (Somatic sensory dysfunction)

FamilyNotHPOFreeText: N/A

CountryOrigin: Italy (North-West)

Ethnicity: Italian

Race: Not mentioned

Family#PreviousTesting: Previous testing was limited to molecular tests ruling out Friedreich Ataxia and Spinocerebellar Ataxia types 1 and 2.

Family#Method1: N/A

Family#Method2: N/A

Family#GenotypingMethod: Whole exome sequencing of the proband and the affected sibling. Homozygosity was assumed due to the consanguinity of the family, contributing to the decision to focus on the variant in CLN5. This variant was confirmed by Sanger sequencing of PCR products from exon 4 of the CLN5 gene in both affected family members and an additional unaffected sibling. Parents were not subjected to genotyping.

Affected: 2

Unaffected: 1

Segregations: 1 segregation was reported, with none inconsistent (see pedigree in Figure 1A). The patient's family is consanguineous, with the parents being first cousins.

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Mancini_2015_Patient_III-5

Variant: The proband is homozygous for the NM_006493.4(CLN5):c.788G>A (p.Ser263Asn) variant.

ClinVar: 183049 (homozygous)

gnomAD: The maximum allele frequency for the NM_006493.4(CLN5):c.788G>A (p.Ser263Asn) variant is 0.000008805 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/13-77574815-G-A

FamilyAddInfo: N/A

FamilyPMIDs: N/A

FamilyLabel: Felbor_1997_Family_1

Family#PresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0001089 (Iris atrophy), HP:0007703 (Abnormality of retinal pigmentation), HP:0000501 (Glaucoma)

FamilyHPOFreeText: Early onset of visual loss between the second and fourth decade of life, with the first sign in young family members being uneven or absent pigmentation in the extreme fundus periphery. Affected individuals experienced progressive vision loss, iris atrophy, and glaucoma in some cases.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: Finland

Family#PreviousTesting: Single-stranded conformational analysis (SSCA) of the coding and promoter regions of TIMP3, detecting a mobility shift in exon 5 that was specific to affected individuals. Sanger sequencing of PCR products from exon 5 of the TIMP3 gene, in samples from the proband and a control individual.

Family#GenotypingMethod: Enzymatic digestion of TIMP3 exon 5 PCR products with the HaeIII restriction endonuclease.

Affected: 9

Unaffected: 9

Segregations: 8

PublishedLOD: Maximum LOD score, Zmax, was reported as 3.03 (at theta = .001, for the D22S281 marker, previously linked to the TIMP3 locus in PMID:8919688)

eLOD: 2.4

AddSegregationInfo: N/A

ProbandLabel: Felbor_1997_Family_1_patient_III-4

Variant: Affected patients harbor the NM_000362.5(TIMP3):c.565G>T (p.Gly189Cys) missense variant.

ClinVar: 12679

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: This highly consanguineous family was previously proposed to show an autosomal recessive pattern of inheritance (not previously observed for Sorsby fundus dystrophy). The family has been genotyped for the first time in this study, revealing segregation of disease phenotypes with a heterozygous variant in TIMP3, with autosomal dominant inheritance.

FamilyPMIDs: PMID:7148944, PMID:2387082

FamilyLabel: Danciger_2001_Family

Family#PresentingHPOs: HP:0011463 (Childhood onset), HP:0007663 (Reduced visual acuity), HP:0001141 (Severely reduced visual acuity), HP:0007994 (Peripheral visual field loss), HP:0000545 (Myopia), HP:0000483 (Astigmatism), HP:0000523 (Subcapsular cataract)

FamilyPresentingHPOFreeText: The affected family members have been diagnosed with severe cone-rod dystrophy segregating with an autosomal recessive mode of inheritance.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: Brazil

Ethnicity: Brazilian

Race: Not described

Family#PreviousTesting: Linkage mapping has been performed in affected and unaffected family members using short tandem repeat markers across the genome.

Family#Method1: Linkage mapping using short tandem repeat markers

Family#Method2: Haplotype analysis with markers within an 8-cM region of chromosome 8p11.

Family#GenotypingMethod: Linkage mapping has been performed in affected and unaffected family members using short tandem repeat markers across the genome, followed by haplotype analysis within the linkage region. A subsequent publication sequenced 10 out of 34 genes within the linkage region and found homozygous variants in ADAM9 in particular (PMID: 19409519).

Affected: 5

Unaffected: 7

Segregations: 7 segregations are shown by the pedigree in Figure 1.

PublishedLOD: 7.6 (associated with the D8S1769 and GATA101H09 short tandem repeat markers on chromosome 8p11)

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Danciger_2001_Family_Patient_A

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.

FamilyAddInfo: The family is known to be consanguineous, with the parents of affected individuals being second cousins.

FamilyPMIDs: PMID: 19409519

FamilyLabel: van_Huet_2014_Family_F, family national origin reported as from Pakistan

Family#PresentingHPOs: HP:0410280 (Pediatric onset), HP:0000662 (Nyctalopia), HP:0000545 (Myopia), HP:0007663 (Reduced visual acuity), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), 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: Pakistan

Ethnicity: Not mentioned

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 consanguineous, with the parents being first cousins. The pedigree is shown in Figure 1.

PublishedLOD: N/A

eLOD: 1.50

AddSegregationInfo: N/A

ProbandLabel: van_Huet_2014_Patient_F-II:2

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.

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

FamilyPMIDs: N/A

FamilyLabel: van_Huet_2014_Family_B, ethnic origin reported as Iraqi Jewish

Family#PresentingHPOs: HP:0011463 (Childhood onset), HP:0000545 (Myopia), HP:0007663 (Reduced visual acuity), HP:0007787 (Posterior subcapsular cataract), 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: Iraq

Ethnicity: Reported as Iraqi Jewish

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: 0

Segregations: Two segregations are reported in the family, with none inconsistent. The family is apparently consanguineous, with the parents being first cousins. The pedigree is shown in Figure 1.

PublishedLOD: N/A

eLOD: 1.20

AddSegregationInfo: N/A

ProbandLabel: van_Huet_2014_Patient_B-II:1

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.

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

FamilyPMIDs: 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

FamilyLabel: Tabata_1998_Family_Ch

Family#PresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0025094 (Disciform macular scar), HP:0000529 (Progressive visual loss)

FamilyHPOFreeText: Onset of decreased central vision was seen in the 6th or 7th decade of life (between the ages of 52 and 66), although abnormal findings on ophthalmoscopy (early macular degeneration) found in 4th decade of life.

FamilyNotHPOs: HP:0007994 (Peripheral visual field loss)

FamilyNotHPOFreeText: Although central vision was progressively lost, peripheral fundi remained uninvolved and affected individuals continued to walk unguided into the 8th decade of life and beyond.

CountryOrigin: Japan

Family#PreviousTesting: PCR-based heteroduplex analysis using gel electophoresis

Family#GenotypingMethod: Sanger sequencing

Affected: 2

Unaffected: 3

Segregations: N/A

PublishedLOD: N/A

eLOD: Insufficient information available

AddSegregationInfo: N/A

ProbandLabel: Tabata_1998_Family_Ch_patient_1

Variant: NM_000362.5:c.439-2dup (TIMP3) is predicted to disrupt a splice acceptor site at the junction of intron 4 and exon 5.

CAID: CA1139771334

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: While Family Ue and Family Ch are two distinct families, united by the NM_000362.5:c.439-2dup (TIMP3) variant harbored by their affected family members, they share a geographical place of origin within Japan (PMID:9760202).

FamilyPMIDs: N/A

FamilyLabel: Tabata_1998_Family_Ue

Family#PresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0025094 (Disciform macular scar)

FamilyHPOFreeText: Onset of decreased central vision was seen in the 8th decade of life (between the ages of 71 and 75).

FamilyNotHPOs: HP:0007994 (Peripheral visual field loss)

FamilyNotHPOFreeText: Although central vision was decreased, peripheral fundi remained uninvolved.

CountryOrigin: Japan

Family#PreviousTesting: PCR-based heteroduplex analysis using gel electophoresis

Family#GenotypingMethod: Sanger sequencing

Affected: 3

Unaffected: 0

Segregations: N/A

PublishedLOD: N/A

eLOD: Insufficient information available

AddSegregationInfo: N/A

ProbandLabel: Tabata_1998_Family_Ue_patient_1

Variant: NM_000362.5:c.439-2dup (TIMP3) is predicted to disrupt a splice acceptor site at the junction of intron 4 and exon 5.

CAID: CA1139771334

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: While Family Ue and Family Ch are two distinct families, united by the NM_000362.5:c.439-2dup (TIMP3) variant harbored by their affected family members, they share a geographical place of origin within Japan (PMID:9760202).

FamilyPMIDs: N/A

FamilyLabel: Gu_1997_Family_PMK18

FamilyPresentingHPOs: HP:0410280 (Pediatric onset), HP:0007663 (Reduced visual acuity), HP:0001098 (Abnormal fundus morphology)

FamilyPresentingHPOFreeText: Onset is early and course of disease is severe. The appearance of the fundus in adulthood is considered characteristic of retinitis pigmentosa.

FamilyNotHPOs: N/A

CountryOrigin: India

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: Previous testing consisted of linkage analysis using microsatellite repeat markers (D152803, DJS1665, D1S438 and DJS1728) associated with the RPE65 locus.

Family#Method1: Linkage analysis

Family#GenotypingMethod: PCR products from affected and control family members were screened by restriction digest analysis using the Msel endonuclease.

Affected: 5

Unaffected: 4

Segregations: 7 segregations were reported, with one inconsistent (patient V-8 is heterozygous while the other affected patients are all homozygous). The pedigree (Figure 1) shows consanguinity between the parents of each affected individual.

PublishedLOD: N/A

eLOD: 2.91

AddSegregationInfo: N/A

ProbandLabel: Gu_1997_Family_PMK18_Patient_V-1

Variant: 4 out of 5 affected individuals are homozygous for the variant.

ClinVar: 98893

gnomAD: The NM_000329.3(RPE65):c.858+1G>T variant is not shown in gnomAD.

FamilyAddInfo: The family pedigree shows consanguinity in the parents of all affected individuals.

FamilyPMIDs: N/A

FamilyLabel: Gu_1997_Family_PMK30

FamilyPresentingHPOs: HP:0410280 (Pediatric onset), HP:0000662 (Nyctalopia), HP:0000505 (Visual impairment), HP:0008047 (Abnormality of the vasculature of the eye), HP:0000648 (Optic atrophy), HP:0007737 (Bone spicule pigmentation of the retina)

FamilyPresentingHPOFreeText: Onset of severe visual impairment between age 3 and age 7, progressing between the ages of 5 and 12. Vision was limited to counting fingers (at a distance of 1-3 meters) or seeing hand movements. Onset of severe

FamilyNotHPOs: N/A

CountryOrigin: India

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: Previous testing consisted of linkage analysis using microsatellite repeat markers.

Family#Method1: PCR products from 2 affected and 1 control family members were screened by single-strand conformation polymorphism (SSCP) analysis. After discovery of a band shift for exon 10, those two patients were subjected to Sanger sequencing.

Family#Method2: A PCR-based assay was used to detect the variant of interest by introducing a BspMI restriction site into the wild-type PCR product.

Family#GenotypingMethod: Restriction enzyme-based screening of exon 10 PCR products

Affected: 4

Unaffected: 4

Segregations: 6 segregations were reported, with none inconsistent. The pedigree (Figure 1) shows consanguinity between the parents of each affected individual.

PublishedLOD: The LOD score was 3.57 at a 0.00 recombination fraction (for microsatellite repeat polymorphism D1S1665).

eLOD: 2.31

AddSegregationInfo: N/A

ProbandLabel: Gu_1997_Family_PMK30_Patient_V-5

Variant: Affected individuals are homozygous for the NM_000329.3(RPE65):c.1087C>A (p.Pro363Thr) variant.

ClinVar: 13117

gnomAD: The maximum allele frequency for the NM_000329.3(RPE65):c.1087C>A (p.Pro363Thr) variant is 0.0001307 (within the South Asian population, with no homozygotes). https://gnomad.broadinstitute.org/variant/1-68903911-G-T

FamilyAddInfo: The family pedigree shows consanguinity in the parents of all affected individuals.

FamilyPMIDs: N/A

FamilyLabel: Corton_2010_Family_RP-72

Family#PresentingHPOs: HP:0410280 (Pediatric onset), HP:0000662 (Nyctalopia), HP:0000540 (Hypermetropia), HP:0007663 (Reduced visual acuity), HP:0001133 (Constriction of peripheral visual field), HP:0000550 (Undetectable electroretinogram), HP:0007737 (Bone spicule pigmentation of the retina), HP:0007401 (Macular atrophy), HP:0007843 (Attenuation of retinal blood vessels), HP:0000543 (Optic disc pallor)

FamilyPresentingHPOFreeText: The affected family members have been diagnosed with retinitis pigmentosa segregating with an autosomal recessive mode of inheritance.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: Spain / Galicia

Ethnicity: Spanish

Race: Not specifically described

Family#PreviousTesting: N/A

Family#Method1: Haplotype analysis

Family#Method2: Sanger sequencing of 3 candidate genes; PDE6A, PDE6B, and RHO

Family#GenotypingMethod: Haplotype analysis was performed in affected and unaffected family members to identify candidate regions of homozygosity in all affected individuals. Sanger sequencing was then performed on PCR products of exons and flanking regions from the PDE6A, PDE6B, and RHO loci.

Affected: 4

Unaffected: 5 fully genotyped

Segregations: 4 segregations are shown by the pedigree in Figure 1a.

PublishedLOD: N/A

eLOD: 2.43

AddSegregationInfo: N/A

ProbandLabel: Corton_2010_Family_RP-72_patient_IV:2

Variant: The affected family members harbor the NM_000440.3(PDE6A):c.2053G>A (p.Val685Met) variant in the homozygous state.

ClinVar: 29874

gnomAD: In gnomAD v2.1.1, NM_000440.3(PDE6A):c.2053G>A (p.Val685Met) has a frequency of 0.00008531 (11/128938) in the European non-Finnish population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/5-149263074-C-T

VariantEvidence: A mutation equivalent to this variant in the homozygous nmf28/nmf28 mouse model caused grainy abnormalities in fundus pigmentation associated with loss of most photoreceptor cells shortly after birth, as well as loss of cGMP-PDE6 activity resulting in increased intracellular cGMP levels (PMID: 18849587).

FamilyAddInfo: The family includes multiple consanguineous unions, including the proband's parents, and three affected paternal aunts.

FamilyPMIDs: N/A

FamilyLabel: Hull_2016_Family_1

Family#PresentingHPOs: HP:0003581 (Adult onset), HP:0007663 (Reduced visual acuity), HP:0000533 (Chorioretinal atrophy)

Family#PresentingHPOFreeText: N/A

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

CountryOrigin: Irish ancestry

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: Variants in REP1 and PRPH2 were initially excluded.

Family#Method1: Candidate gene sequencing

Family#Method2: Bidirectional, targeted Sanger sequencing within the RPE65 locus

Family#GenotypingMethod: Bidirectional Sanger sequencing of exon 13 of the RPE65 gene and flanking sequences

Affected: 2

Unaffected: 0

Segregations: 1 segregation was reported. The pedigree can be found in Figure 5. The possibility of family consanguinity was not mentioned.

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Hull_2016_Patient_1.1

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: N/A

FamilyLabel: Hull_2016_Family_2

Family#PresentingHPOs: HP:0003581 (Adult onset), HP:0007663 (Reduced visual acuity)

Family#PresentingHPOFreeText: N/A

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

CountryOrigin: Irish ancestry

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: Variants in REP1 and PRPH2 were initially excluded.

Family#Method1: Candidate gene sequencing

Family#Method2: Bidirectional, targeted Sanger sequencing within the RPE65 locus

Family#GenotypingMethod: Bidirectional Sanger sequencing of exon 13 of the RPE65 gene and flanking sequences

Affected: 3

Unaffected: 2

Segregations: 3 segregations were reported. 1 inconsistent segregation was observed, with a genotype-positive individual who did not exhibit phenotypes. The pedigree can be found in Figure 5. The possibility of family consanguinity was not mentioned.

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: 1 genotype-positive family member was phenotype-negative, but had an affected child.

ProbandLabel: Hull_2016_Patient_2.1

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: The possibility of family consanguinity was not mentioned.

FamilyPMIDs: N/A

FamilyLabel: Marlens_1997_Family_1

FamilyPresentingHPOs: HP:0030506 (Yellow/white lesions of the retina), HP:0000580 (Pigmentary retinopathy), HP:0007843 (Attenuation of retinal blood vessels), HP:0000543 (Optic disc pallor), HP:0001141 (Severely reduced visual acuity)

FamilyPresentingHPOFreeText: Pigmentary deposits, Attenuation of retinal blood vessels, and Optic disc pallor were all mild/moderate.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: Not specified

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: All RPE65 coding exons and flanking sequences were PCR-amplified and subjected to single-strand conformation analysis. Exon 10 was identified as a likely candidate to harbor a variant. All 14 exons of RPE65 were PCR-amplified and subjected to Sanger sequencing in both affected family members and their parents.

Family#GenotypingMethod: Screening of PCR products from affected and unaffected family members for the variants of interest was performed using SSCA for the maternal variant and AlwNI restriction digest for the paternal variant.

Affected: 2

Unaffected: 1

Segregations: The pedigree (Figure 1c) shows 1 segregation, with none inconsistent.

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Marlhens_1997_Patient_III-2

Variant: Affected individuals are compound heterozygous for the NM_000329.3(RPE65):c.1067del (p.Asn356fs) (maternal) and NM_000329.3(RPE65):c.700C>T (p.Arg234Ter) (paternal) variants.

ClinVar: 98821, 13114

gnomAD: The maximum allele frequency for the NM_000329.3(RPE65):c.1067del (p.Asn356fs) variant is 0.00005458 (within the East Asian population, with no homozygotes). https://gnomad.broadinstitute.org/variant/1-68903930-AT-A The maximum allele frequency for the NM_000329.3(RPE65):c.700C>T (p.Arg234Ter) variant is 0.00008676 (within the Latino / Admixed American population, with no homozygotes). https://gnomad.broadinstitute.org/variant/1-68905269-G-A

FamilyAddInfo: The two variants were confirmed to be in trans, and heterozygous carriers were found to be unaffected. Potential parental consanguinity was not mentioned.

FamilyPMIDs: N/A

FamilyLabel: Meunier_2016_Family_1

Family#PresentingHPOs: HP:0002097 (Emphysema), HP:0011510 (Drusen), HP:0011506 (Choroidal neovascularization), HP:0000529 (Progressive visual loss), HP:0032342 (Reduced forced expiratory volume in one second), HP:0033663 (Air trapping), HP:0033542 (Bronchial wall thickening), HP:0002110 (Bronchiectasis)

FamilyHPOFreeText: Early onset of abnormality in Bruch's membrane thickness. Drusen and choroidal neovascularization occurred between ages 23 and 40 (early onset) and were bilateral. Legal blindness was observed in almost all patients, although anti-VEGF treatment (bevacizumab) administration in one patient was associated with retained eye function. Pulmonary disease (severe emphysema) was late-onset. Patients in the 6th to 8th decades of life showed air trapping on CT scan, had reduced airflow (FEV1) by 28% to 73%, and bronchial abnormalities. Air trapping and hypoxia were detectable as early as the second decade of life and progressed to more severe pulmonary issues in older family members.

FamilyNotHPOs: HP:0025223 (Triggered by smoking), HP:0002099 (Asthma)

FamilyNotHPOFreeText: No history of smoking

CountryOrigin: Family origin was not reported.

Family#PreviousTesting: Clinical exams to detail features of affected family members.

Family#GenotypingMethod: Sanger sequencing of PCR products from TIMP3 exons 1 through 5.

Affected: 7

Unaffected: 2

Segregations: 6

PublishedLOD: N/A

eLOD: 1.8

AddSegregationInfo: N/A

ProbandLabel: Meunier_2016_Family_1_patient_III-1

Variant: NM_000362.5(TIMP3):c.572A>G, p.Tyr191Cys is a missense variant predicted to introduce a new cysteine-encoding codon into exon 5.

ClinVar: 12677

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: N/A

FamilyPMIDs: While the family has not been previously described, the same variant has been published in PMID:7894485 (without reporting pulmonary symptoms).

FamilyLabel: Meunier_2016_Family_2

Family#PresentingHPOs: HP:0000662 (Nyctalopia), HP:0030506 (Yellow/white lesions of the retina), HP:0011510 (Drusen), HP:0007663 (Reduced visual acuity), HP:0000529 (Progressive visual loss), HP:0011506 (Choroidal neovascularization), HP:0007401 (Macular atrophy), HP:0007703 (Abnormality of retinal pigmentation), Bronchial wall thickening HP:0033542

FamilyHPOFreeText: Both eye and lung disease presented at later ages within members of this family. Eye disease onset occurred in the fifth decade of life with nyctalopia as the first presenting phenotype, and drusen / yellow lesions detectable at the posterior pole and in the peripheral retina. Choroidal neovascularization occurred during the 5th and 6th decades of life and led to progressive loss of vision in both eyes. Macular atrophy and retinal pigment abnormalities were also late presenting phenotypes. In addition to bronchial wall thickening, mild cylindrical bronchiectasis and asthma were each observed in one affected family member. Pulmonary symptoms were late in onset and only detected by CT imaging.

FamilyNotHPOs: HP:0025223 (Triggered by smoking), HP:0002097 (Emphysema),

FamilyNotHPOFreeText: No history of smoking

CountryOrigin: Family origin was not reported.

Family#PreviousTesting: Clinical exams to detail features of affected family members.

Family#GenotypingMethod: Sanger sequencing of PCR products from TIMP3 exons 1 through 5.

Affected: 4

Unaffected: 3

Segregations: 3

**PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: Insufficient number of segregations to estimate LOD score.

ProbandLabel: Meunier_2016_Family_2_patient_III-2

Variant: NM_000362.5(TIMP3):c.113C>G (p.Ser38Cys) is a missense variant predicted to introduce a new cysteine-encoding codon into exon 1. Interestingly, it differs from most other published missense variants in that it affects a codon within exon 1 rather than exon 5.

ClinVar: 843268

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: N/A

FamilyPMIDs: Family has not been previously described but the same variant has been published in PMID:23023527, PMID:26493035, and PMID:30668888 (without reporting pulmonary symptoms in either study).

FamilyLabel: Bowne_2011_Family_TCD-H

Family#PresentingHPOs: N/A

Family#PresentingHPOFreeText: Family members were provisionally diagnosed with choroideremia prior to genotyping.

FamilyNotHPOs: N/A

CountryOrigin: Ireland

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: Candidate gene sequencing of the CHM locus to exclude the initial diagnosis of choroideremia

Family#Method1: Two-point linkage analysis of the RPE65 locus, as well as haplotype analysis using STR genotypes surrounding the variant of interest

Family#Method2: Candidate gene sequencing

Family#GenotypingMethod: Sanger sequencing of the RPE65 locus

Affected: 3

Unaffected: N/A

Segregations: 2 segregations were reported. The pedigree can be found in Figure 1c. Consanguinity of the family was not mentioned.

PublishedLOD: 5.3 (in combination with Family TCD-G, which shares a haplotype

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Bowne_2011_Family_TCD-H_Patient_01

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: 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

FamilyLabel: McKay_2005_Family, family ethnic origin reported as white

Family#PresentingHPOs: HP:0000533 (Chorioretinal atrophy), HP:0007903 (Paravenous chorioretinal atrophy), HP:0007663 (Reduced visual acuity), HP:0030469 (Abnormal dark-adapted electroretinogram)

FamilyHPOFreeText: The patient and affected family members have been diagnosed with pigmented paravenous retinochoroidal atrophy. Expressivity is very variable, but all members showed subtle symmetrical chorioretinal atrophy in the inferior quadrant as the presenting feature, with atrophy later becoming more widespread. The proband had optic disc drusen. OCT through an area of bony spicule pigmentation showed that the pigment was located in the superficial neuroretina.

Family#PresentingNotHPOs: HP:0030603 (Abnormal optical coherence tomography)

Family#PresentingNotHPOFreeText: N/A

CountryOrigin: Possibly the United Kingdom

Ethnicity: Not mentioned

Race: White

Family#PreviousTesting: Sanger sequencing of candidate genes associated with retinal degeneration was performed, with only the CRB1 locus specifically identified.

Family#Method1: Sanger sequencing of CRB1

Family#Method2: N/A

Family#GenotypingMethod: Genotyping appears to have been limited to Sanger sequencing of candidate genes associated with retinal degeneration, including the CRB1 locus.

Affected: 6

Unaffected: 1

Segregations: Five segregations are reported in the family, with none inconsistent. The pedigree is shown in Figure 1.

PublishedLOD: 1.8

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: McKay_2005_Family_Proband_III:3

Variant: The affected family members harbor the NM_201253.3(CRB1):c.484G>A (p.Val162Met) variant in the heterozygous state.

ClinVarID: 5738

gnomAD: This variant is found in gnomAD v4.1.1 at a frequency of 0.001610 overall, with a similar frequency in the European (non-Finnish) population and 6 homozygotes overall https://gnomad.broadinstitute.org/variant/chr1-197328835-G-A?dataset=gnomad_r4

FamilyAddInfo: The family has not been reported as consanguineous.

FamilyPMIDs: N/A

FamilyLabel: Perrault_2000_Family_11

Family#PresentingHPOs: N/A

Family#PresentingHPOFreeText: Affected family members are described as having Leber congenital amaurosis.

FamilyNotHPOs: N/A

CountryOrigin: Algeria

Ethnicity: Arab

Race: Not described

Family#PreviousTesting: Linkage mapping of the disease locus to chromosome 17p13.1 (PMID: 7581387, PMID: 8641699)

Family#Method1: Sanger sequencing of PCR products from each of the 20 exons

Family#Method2: N/A

Family#GenotypingMethod: Family members were initially subjected to homozygosity mapping, establishing linkage to chromosome 17p13.1 and particularly between the D17S1353 and D17S1854 markers (PMID: 7581387, PMID: 8641699). Subsequent genotyping was performed by Sanger sequencing of PCR products from the GUCY2D locus.

Affected: 4

Unaffected: 0

Segregations: 3 segregations were reported, with none inconsistent with the proposed mechanism of inheritance (Figure 3a). The family is reportedly consanguineous.

PublishedLOD: N/A

eLOD: 1.81

AddSegregationInfo: N/A

ProbandLabel: Perrault_2000_Family_11_Proband

Variant: Affected individuals are homozygous for the NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) variant.

ClinVar: 9350

gnomAD: The variant exhibits a maximum allele frequency of 0.000008790 in gnomAD version 2.1.1 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7912849-T-C?dataset=gnomad_r2_1

FamilyAddInfo: N/A

FamilyPMIDs: PMID: 7581387, PMID: 8641699

FamilyLabel: Perrault_2000_Family_9

Family#PresentingHPOs: N/A

Family#PresentingHPOFreeText: Affected family members are described as having Leber congenital amaurosis.

FamilyNotHPOs: N/A

CountryOrigin: Algeria

Ethnicity: Arab

Race: Not described

Family#PreviousTesting: Linkage mapping of the disease locus to chromosome 17p13.1 (PMID: 7581387, PMID: 8641699)

Family#Method1: Sanger sequencing of PCR products from each of the 20 exons

Family#Method2: N/A

Family#GenotypingMethod: Family members were initially subjected to homozygosity mapping, establishing linkage to chromosome 17p13.1 and particularly between the D17S1353 and D17S1854 markers (PMID: 7581387, PMID: 8641699). Subsequent genotyping was performed by Sanger sequencing of PCR products from the GUCY2D locus.

Affected: 4

Unaffected: 2

Segregations: 3 segregations were reported, with none inconsistent with the proposed mechanism of inheritance (Figure 3a). The family is reportedly consanguineous.

PublishedLOD: N/A

eLOD: 2.06

AddSegregationInfo: N/A

ProbandLabel: Perrault_2000_Family_9_Proband

Variant: Affected individuals are homozygous for the NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) variant.

ClinVar: 9350

gnomAD: The variant exhibits a maximum allele frequency of 0.000008790 in gnomAD version 2.1.1 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7912849-T-C?dataset=gnomad_r2_1

FamilyAddInfo: N/A

FamilyPMIDs: PMID: 7581387, PMID: 8641699

FamilyLabel: Naessens_2019_Family_2

FamilyPresentingHPOs: HP:0007401 (Macular atrophy), HP:0007769 (Peripheral retinal degeneration)

FamilyHPOFreeText: Relatively late onset of phenotypes within the sixth decade of life or later. Drusen / deposits were seen in the younger (57-year old) family member who had not yet developed phenotypes.

**FamilyNotHPOs: N/A

FamilyNotHPOFreeText: Pulmonary involvement

CountryOrigin: France (northern)

Family#PreviousTesting: N/A

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

Affected: 3

Unaffected: 1

Segregations: 2

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Naessens_2019_Family_2_patient_II:1

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: SNP-based haplotype analysis (Figure 4) of Naessens_2019_Family_2 (this family), Naessens_2019_Family_1, and Naessens_2019_Family_3 (single individual) revealed that all three families inherited this variant as part of a shared region of ~6.4 Mb encompassing the TIMP3 locus. This indicated a founder mutation inherited from a distant but shared common ancestor.

FamilyPMIDs: N/A

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

FamilyLabel Family 28

Family28PresentingHPOs n/a

HPOsFreeText Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid. Affected individuals were not responsive to the treatment, plasma homocysteine levels went unchanged. Patients were given additional oral betaine(3g twice per day) with a low protein diet.

FamilyNotHPOs n/a

NotHPOsFreeText no further sequelae

CountryOrigin n/a

Ethnicity Lebanese

Race n/a

Family28PreviousTesting Free homocystine, methionine, cystine, and cysteine-homo-cysteine mixed disulfide levels were measured by amino acid analyzers and total (free plus bound)homocysteine (tHcys) was measured. Exact values were not provided.

FamilyMethod1 PCR

FamilyMethod2 Sanger

FamilyGenotypingMethod PCR amplified then direct sequenced the entire coding region of CBS.

ProbandLabel Case 34

Variant NM_000071.2(CBS):c.19dupC (p.Gln7Profs), homozygous

ClinVar 371345

gnomAD MAF=0.00005473, no homozygotes

FamilyAddInfo n/a

FamilyPMIDs n/a

FamilyLabel Family 5

Family5PresentingHPOs n/a

HPOsFreeText plasma free homocystine was reduced from >80μmol to <10μmol (nv <60μmol) in response to treatment with folate and pyridoxine. Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid.

FamilyNotHPOs HP:0001249

(Intellectual disability)

NotHPOsFreeText n/a

CountryOrigin n/a

Ethnicity Anglo-Celtic

Race n/a

Family5PreviousTesting Free homocystine, methionine, cystine, and cysteine-homo-cysteine mixed disulfide levels were measured by amino acid analyzers and total (free plus bound)homocysteine (tHcys) was measured. Exact values were not provided.

FamilyMethod1 PCR

FamilyMethod2 Sanger

FamilyGenotypingMethod PCR amplified then direct sequenced the entire coding region of CBS.

ProbandLabel Case 7

Variant 1. NM_000071.2(CBS):c.833T>C (p.Ile278Thr), 2. IVS1+insC, compound heterozygous

ClinVar 1. 120, 2. n/a

CAID 2. need more info

gnomAD 1. MAF=0.001432(European(non-Finnish)), no homozygotes, 2. n/a

FamilyAddInfo n/a

FamilyPMIDs n/a

FamilyLabel Family 15

Family15PresentingHPOs n/a

HPOsFreeText Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid. Affected individuals were not responsive to the treatment, plasma homocysteine levels went unchanged. Patients were given additional oral betaine(3g twice per day) with a low protein diet.

FamilyNotHPOs n/a

NotHPOsFreeText n/a

CountryOrigin n/a

Ethnicity Anglo-Celtic

Race n/a

Family15PreviousTesting Free homocystine, methionine, cystine, and cysteine-homo-cysteine mixed disulfide levels were measured by amino acid analyzers and total (free plus bound)homocysteine (tHcys) was measured. Exact values were not provided.

FamilyMethod1 PCR

FamilyMethod2 Sanger

FamilyGenotypingMethod PCR amplified then direct sequenced the entire coding region of CBS.

ProbandLabel Case 18

Variant NM_000071.2(CBS):c.919G>A (p.Gly307Ser), homozygous

ClinVar 117

gnomAD MAF= 0.00041539(Other), no homozygotes

FamilyAddInfo n/a

FamilyPMIDs n/a

FamilyLabel Family 26

Family26PresentingHPOs HP:0001083

(Lens dislocation)

HPOsFreeText Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid. Affected individuals were not responsive to the treatment, plasma homocysteine levels went unchanged. Patients were given additional oral betaine(3g twice per day) with a low protein diet.

FamilyNotHPOs n/a

NotHPOsFreeText n/a

CountryOrigin n/a

Ethnicity Portugese

Race n/a

Family26PreviousTesting Free homocystine, methionine, cystine, and cysteine-homo-cysteine mixed disulfide levels were measured by amino acid analyzers and total (free plus bound)homocysteine (tHcys) was measured. Exact values were not provided.

FamilyMethod1 PCR

FamilyMethod2 Sanger

FamilyGenotypingMethod PCR amplified then direct sequenced the entire coding region of CBS.

ProbandLabel Case 31

Variant NM_000071.2(CBS):c.374G>A (p.Arg125Gln), homozygous

ClinVar 197625

gnomAD MAF= 0.00002326(European(non-Finnish)), no homozygotes

FamilyAddInfo n/a

FamilyPMIDs n/a

FamilyLabel Family 1

Family1PresentingHPOs n/a

HPOsFreeText plasma free homocystine was reduced from >80μmol to <10μmol (nv <60μmol) in response to treatment with folate and pyridoxine. Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid.

FamilyNotHPOs HP:0001249

(Intellectual disability)

NotHPOsFreeText n/a

CountryOrigin n/a

Ethnicity Anglo-Celtic

Race n/a

Family1PreviousTesting Free homocystine, methionine, cystine, and cysteine-homo-cysteine mixed disulfide levels were measured by amino acid analyzers and total (free plus bound)homocysteine (tHcys) was measured. Exact values were not provided.

FamilyMethod1 PCR

FamilyMethod2 Sanger

FamilyGenotypingMethod PCR amplified then direct sequenced the entire coding region of CBS.

ProbandLabel Case 1

Variant NM_000071.2(CBS):c.833T>C (p.Ile278Thr), homozygous

ClinVar 120

gnomAD MAF=0.001432(European(non-Finnish)), no homozygotes

FamilyAddInfo n/a

FamilyPMIDs n/a

FamilyLabel Family 2

Family2PresentingHPOs n/a

HPOsFreeText plasma free homocystine was reduced from >80μmol to <10μmol (nv <60μmol) in response to treatment with folate and pyridoxine. Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid.

FamilyNotHPOs HP:0001249

(Intellectual disability)

NotHPOsFreeText no other sequelae

CountryOrigin n/a

Ethnicity Anglo-Celtic

Race n/a

Family2PreviousTesting Free homocystine, methionine, cystine, and cysteine-homo-cysteine mixed disulfide levels were measured by amino acid analyzers and total (free plus bound)homocysteine (tHcys) was measured. Exact values were not provided.

FamilyMethod1 PCR

FamilyMethod2 Sanger

FamilyGenotypingMethod PCR amplified then direct sequenced the entire coding region of CBS.

ProbandLabel Case 3

Variant 1. NM_000071.2(CBS):c.833T>C (p.Ile278Thr), 2. NM_000071.2(CBS):c.302T>C (p.Leu101Pro), compound heterozygous

ClinVar 1. 120, 2. 189185

gnomAD 1. MAF=0.001432(European(non-Finnish)), no homozygotes, 2. not in gnomAD

FamilyAddInfo n/a

FamilyPMIDs n/a

FamilyGL: N/A

FamilyPresentingHPOs: HP:0012237 (Urocanic aciduria)

HPOsFreeText: N/A

FamilyNotHPOs: HP:0001507, HP:0100543, HP:0010904 (Growth abnormality, Cognitive impairment, Abnormal circulating histidine concentration)

NotHPOsFreeText: N/A

FamilyGenotypingMethod: Genomic DNA was obtained via peripheral blood from the siblings and both parents. PCR and direct sequencing in both forward and reverse directions was used to amplify and sequence the 21 coding exons of UROC1.

FamilyPreviousTesting: Plasma samples from both subjects demonstrated significant elevations in cis-urocanate, trans-urocanate and imidazole propionate; Z-scores for compounds in alternative histidine degradation pathways were found to be within normal limits, including 1-methylhisitidine, imidazole lactate, and 1-methylhistamine; Table 1 shows detailed metabolite levels; Family history was negative for metabolic disorders or any other familial diseases

FamilyAddInfo: Family appears to be asymptomatic, Siblings are confirmed compound heterozygous via parental sequencing (father het for Variant 2, mother het for Variant 1)

Variant1: NM_144639.3:c.356C>G (p.Pro119Arg)

CAID: CA2591587, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2591587

gnomAD: 0.0001596, https://gnomad.broadinstitute.org/variant/3-126227314-G-C

Variant2: NM_144639.3:c.907G>C (p.Ala303Pro)

CAID: CA2591263, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2591263

gnomAD: 0.00009300, https://gnomad.broadinstitute.org/variant/3-126220119-C-G

Affected: 2

Unaffected: 3

AddSegregationInfo: Not enough affected

FamilyPY: White, United Kingdom

FamilyPresentingHPOs: HP:0002131, HP:0001260, HP:0008003, HP:0030453 (Episodic ataxia, Dysarthria, Jerky ocular pursuit movements, Abnormal visual electrophysiology)

HPOsFreeText: N/A

FamilyNotHPOs: HP:0000640, HP:0000648, HP:0003390, HP:0011402, HP:0001272, HP:0002283 (Gaze-evoked nystagmus, Optic atrophy, Sensory axonal neuropathy, Demyelinating sensory neuropathy, Cerebellar atrophy, Global brain atrophy)

NotHPOsFreeText: N/A

FamilyGenotypingMethod: Blood genomic DNA was enriched and whole exome sequenced. Alightment to hg19 and variant filtering was performed with putative pathogenic variants being confirmed via Sanger sequencing.

FamilyPreviousTesting: Underwent brain MRI and CSF examination with oligoclonal band analysis; Negative genetic testing for SCA1, 2, 3, 6, 7, 17 (now known as ATXN1, ATXN2, CACNA1A, ATXN7, and TBP, respectively), DRPLA (now known as ATN1), FA (now known as FXN) and FMR1

FamilyAddInfo: N/A

Variant: NM_004172.5(SLC1A3):c.1496G>A (p.Arg499Gln)

ClinVar: 242994, https://www.ncbi.nlm.nih.gov/clinvar/variation/242994/

gnomAD: 0.0001471, https://gnomad.broadinstitute.org/variant/5-36686238-G-A

Affected: 3

Segregations: 2

AddSegregationInfo: Pedigree in Sup Data, Not enough info provided

FamilyLabel Family S

FamilySPresentingHPOs HP:0002098, HP:0010818, HP:0002280

(Respiratory distress, Generalized tonic seizures, Mega cisterna magna)

HPOsFreeText (neonatal, pre-treatment:) respiratory distress, generalised tonic seizures. (infancy/childhood:) mega cisterna magna

FamilyNotHPOs n/a

CountryOrigin n/a

Ethnicity Arabic

Race n/a

FamilySPreviousTesting Cessation of seizures during pyridoxine therapy

ProbandLabel S1, Female, 15yr report

Variant NM_001182.4(ALDH7A1):c.312+2T>A, homozygous

ClinVar 17997

gnomAD not in gnomAD

FamilyAddInfo parental consanguinity

FamilyPMIDs n/a

FamilyLabel Family H

FamilyHPresentingHPOs HP:0001557, HP:0001941, HP:0002098, HP:0003270, HP:0002013, HP:0001336, HP:0010851, HP:0000750

(Abnormal intrauterine movements, Acidosis, Respiratory distress, Abdominal distension, Vomiting, Myoclonic jerks, EEG with burst suppression, Speech delay)

HPOsFreeText born after 40wks gestation. (neonatal, pre-treatment:) apgar score at 1min:9, 5min:9, acidosis, respiratory distress, abdominal distension, vomiting, onset of myoclonic jerks at 12h, EEG burst suppression. (2d:) introduced to pyridoxine therapy, trial dose/route of 100mg i/v, complete cessation of seizures, ventilated, initial daily dose of 100mg. (infancy/childhood:) speech delay, IQ: 60-70, no seizures on withdrawal from therapy

FamilyNotHPOs n/a

CountryOrigin n/a

Ethnicity Turkish

Race n/a

FamilyHPreviousTesting Administration of pyridoxine relieved patient's seizures.

ProbandLabel H1

Variant NM_001182.4(ALDH7A1):c.518-1G>C, homozygous

ClinVar 17994

gnomAD MAF=0.0006123(European(non-Finnish)), no homozygotes

FamilyAddInfo 1st cousin parents

FamilyPMIDs n/a

FamilyLabel Family C

FamilyCPresentingHPOs HP:0001941, HP:0002098, HP:0000737, HP:0011169, HP:0010818, HP:0001336, HP:0000750

(Acidosis, Respiratory distress, Irritability, Clonic seizures, Generalized tonic seizures, Myoclonic jerks, Speech delay)

HPOsFreeText (neonatal, pre-treatment:) acidosis, respiratory distress, irritability, clonic seizures, generalized tonic seizures, myoclonic jerks. no apnoea, hypotonia, sleepness, or hypotension during pyridoxine therapy. (infancy/childhood:) speech delay.

FamilyNotHPOs HP:0003270, HP:0002013, HP:0001290, HP:0010851, HP:0002521

(Abdominal distension, Vomiting, Hypotonia, EEG with burst suppression, Hypsarrhythmia)

NotHPOsFreeText (neonatal, pre-treatment:) abdominal distension, vomiting, hypotonia, EEG with burst suppression, hypsarrhythmia

CountryOrigin n/a

Ethnicity Turkish

Race n/a

FamilyCPreviousTesting n/a

ProbandLabel C1

Variant NM_001182.4(ALDH7A1):c.1597delG (p.Ala533Profs), homozygous

ClinVar 17999

gnomAD not in gnomAD

FamilyAddInfo 1st cousin parents

FamilyPMIDs n/a

FamilyLabel Family R

FamilyRPresentingHPOs HP:0000750

(Speech delay)

HPOsFreeText born at 40wks gestational age. (infancy/childhood:) motor problems, speech delay/difficulties

FamilyNotHPOs HP:0025116

(Fetal distress)

CountryOrigin n/a

Ethnicity Asian

Race n/a

FamilyRPreviousTesting n/a

ProbandLabel R1

Variant NM_001182.4(ALDH7A1):c.1224T>G (p.Tyr408Ter), homozygous

ClinVar 18000

gnomAD MAF=0.00006535(South Asian), no homozygotes

FamilyAddInfo first cousin parents

FamilyPMIDs n/a

Family2to4: Maltese

FamilyPresentingHPOs: N/A

HPOsFreeText: N/A

FamilyNotHPOs: HP:0001270, HP:0007018, HP:0001252, HP:0000750, HP:0000252 (Motor delay, Attention deficit hyperactivity disorder, Muscular hypotonia, Delayed speech and language development, Microcephaly)

NotHPOsFreeText: N/A

FamilyGenotypingMethod: Whole exome sequencing was performed as a trio with both parents. Identified DHTKD1 mutations were evaluated for possible effects and filtered for frequencies and predicted pathogenicity. No other candidate genes were found during the WES analysis for either patient sequenced. Sanger sequencing confirmed the proband's siblings are homozygous for the variant and that each parent is a carrier.

FamilyPreviousTesting: Amino acid and organic acid testing showed elevated urinary 2-aminoadipic, 2-ketoadipic, and glutaric acids in the proband as well as in two elder brothers, ages 5 and 7.

FamilyAddInfo: Parents are consanguineous, All three affected siblings are clinically normal

Variant: NM_018706.6:c.915G>C (p.Gln305His)

CAID: CA5407680 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA5407680

gnomAD: Other 0.0001630, https://gnomad.broadinstitute.org/variant/10-12131182-G-C

Affected: 3

Unaffected: 2

AddSegregationInfo: Candidate gene sequencing

FamilyST-VII: Iran

FamilyPresentingHPOs: HP:0002197, HP:0000316, HP:0001889 (Generalized-onset seizure, Hypertelorism, Megaloblastic anemia)

HPOsFreeText: N/A

FamilyNotHPOs: HP:0002904, HP:0001410, HP:0001943, HP:0001257, HP:0001347, HP:0001251, HP:0001276 (Hyperbilirubinemia, Decreased liver function, Hypoglycemia, Spasticity, Hyperreflexia, Ataxia, Hypertonia)

NotHPOsFreeText: N/A

FamilyGenotypingMethod: See Group

FamilyPreviousTesting: See Supp Info for methionine/transaminase values; Normal height, weight and head circumference at birth

FamilyAddInfo: Family is consanguineous, Family is homozygous for this variant

Variant: NM_006721.4(ADK):c.1022A>G (p.His341Arg)

ClinVar: 265772, https://www.ncbi.nlm.nih.gov/clinvar/variation/265772/

gnomAD: Not in gnomAD

Affected: 2

Unaffected: 0

Segregations: 1

AddSegregationInfo: Not enough info

FamilyST-I: Turkey

FamilyPresentingHPOs: HP:0000961, HP:0000825, HP:0001643, HP:0002240, HP:0001395 (Cyanosis, Hyperinsulinemic hypoglycemia, Patent ductus arteriosus, Hepatomegaly, Hepatic fibrosis)

HPOsFreeText: N/A

FamilyNotHPOs: N/A

NotHPOsFreeText: N/A

FamilyGenotypingMethod: See Group

FamilyPreviousTesting: See Supp Info for methionine/transaminase values

FamilyAddInfo: Family is homozygous for this variant

Variant: NM_001123.3:c.905T>C (p.Phe302Ser)

CAID: CA377399030, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA377399030

gnomAD: Not in gnomAD

Affected: 2

Unaffected: 0

Segregations: 1

AddSegregationInfo: Not enough info

FamilyLabel UM Family 2

FamilyUM2PresentingHPOs HP:0012125 (Prostate Cancer)

FamilyNotHPOs n/a

CountryOrigin n/a

Ethnicity n/a

Race n/a

FamilyUM2PreviousTesting Screened nonsense and missense variants in 202 candidate genes comprising ~15.5Mb. Established evidence of linkage of 17q21-22.

Affected 3

Unaffected 1

Segregations n/a

PublishedLOD n/a

eLOD n/a

AddSegregationInfo One female typed negative(cannot have prostate cancer)

ProbandLabel UM2 III-1, Male, 40

Variant NM_006361.5(HOXB13):c.251G>A (p.Gly84Glu)

ClinVar 128031

CAID n/a

gnomAD MAF=0.007574(European(Finnish)), 2 homozygotes

FamilyAddInfo ages rounded to nearest 5 year interval

FamilyPMIDs 17120048

FamilyLabel JHU Family 1

FamilyJHUPresentingHPOs n/a

FamilyNotHPOs n/a

CountryOrigin n/a

Ethnicity n/a

Race n/a

FamilyJHUPreviousTesting Screened nonsense and missense variants in 202 candidate genes comprising ~15.5Mb. Established evidence of linkage of 17q21-22.

Affected 5

Unaffected 1

Segregations n/a

PublishedLOD n/a

eLOD n/a

AddSegregationInfo n/a

ProbandLabel JHU III-14, Male, 50

CasePresentingHPOs HP:0012125 (Prostate Cancer)

Variant NM_006361.5(HOXB13):c.251G>A (p.Gly84Glu)

ClinVar 128031

CAID n/a

gnomAD MAF=0.007574(European(Finnish)), 2 homozygotes

FamilyAddInfo ages rounded to nearest 5 year interval

FamilyPMIDs 17120048

FamilyLabel UM Family 3

FamilyUM3PresentingHPOs HP:0012125 (Prostate Cancer)

FamilyNotHPOs n/a

CountryOrigin n/a

Ethnicity n/a

Race n/a

FamilyUM3PreviousTesting Screened nonsense and missense variants in 202 candidate genes comprising ~15.5Mb. Established evidence of linkage of 17q21-22.

Affected 5

Unaffected 0

Segregations 4

PublishedLOD n/a

eLOD 1.2

AddSegregationInfo n/a

ProbandLabel UM3 III-1, Male, 45

Variant NM_006361.5(HOXB13):c.251G>A (p.Gly84Glu)

ClinVar 128031

CAID n/a

gnomAD MAF=0.007574(European(Finnish)), 2 homozygotes

FamilyAddInfo ages rounded to nearest 5 year interval

FamilyPMIDs 17120048

FamilyLabel UM Family 1

FamilyUM1PresentingHPOs n/a

FamilyNotHPOs n/a

CountryOrigin n/a

Ethnicity n/a

Race n/a

FamilyUM1PreviousTesting Screened nonsense and missense variants in 202 candidate genes comprising ~15.5Mb. Established evidence of linkage of 17q21-22.

Affected 4

Unaffected 0

Segregations n/a

PublishedLOD n/a

eLOD n/a

AddSegregationInfo One female typed positive(cannot have prostate cancer), one male typed positive(has other cancer)

ProbandLabel UM1 III-9, Male, 50

CasePresentingHPOs HP:0012125 (Prostate Cancer)

Variant NM_006361.5(HOXB13):c.251G>A (p.Gly84Glu)

ClinVar 128031

CAID n/a

gnomAD MAF=0.007574(European(Finnish)), 2 homozygotes

FamilyAddInfo ages rounded to nearest 5 year interval

FamilyPMIDs 17120048

Family#PresentingHPOs HP:0001251, HP:0001272

FamilyNotHPOs HP:0001875, HP:0001873, HP:0001903, HP:0005518

Family#PreviousTesting Haplotype analysis by evaluation of STRP markers flanking disease causeing genes such as SCA1-19, AT, TERC, etc. (Table S1).

CountryofOrigin Germany, Ireland, North America

Family#Method1 PCR

Family#GenotypingMethod Allele-specific PCR amplification of the SAMD9L c.2640C>A variant was performed, (SNP)-based genome-wide linkage analysis

Affected 7

Unaffected 4

Segregations 6

eLOD 1.8

ProbandLabel UW-AP:IV-1, M, 18yo onset

CasePreviousTesting MVC(44[0/1]), WBC(87[0/1]), platelets(8.1[0/1])

CaseGenotypingMethod WES then confirmed with Sanger

Variant NM_152703.4(SAMD9L):c.2640C>A (p.His880Gln)

ClinVar 242372

Family#PresentingHPOs HP:0001251, HP:0001272

FamilyNotHPOs HP:0001903, HP:0004808, HP:0001876, HP:0005528

Family#PreviousTesting Studied blastogenic responses to pokeweed mitogen, phytohemagglutinin, and concanav~lin A and rate of unscheduled DNA synthesis in fibroblasts which were normal. II-5 karyotyping showed he had C-monosomy 7.

Family#Method1 Sanger Sequencing

Family#GenotypingMethod Targeted Sanger sequencing of the single large coding exon of SAMD9L

Affected 3

Unaffected 1

Segregations 2*

AddSegregationInfo

ProbandLabel Li-AP:II-4, F, 19 report

Variant NM_152703.4(SAMD9L):c.3587G>C (p.Cys1196Ser)

ClinVar 242373

FamilyAddInfo Italian Mother(asymptomatic), Polish Father and 3 brothers had cerebellar ataxia/atrophy. 2 brothers died with acute mylogenous leukemia, other died with pancytopenia and hypoplastic bone marrow

FamilyPMIDs 6947857

Family#PresentingHPOs HP:0002721, HP:0001905

FamilyNotHPOs HP:0002721, HP:0002141, HP:0002863

CountryOrigin Sweden

Family#PreviousTesting Absolute lymphocyte counts and assays of cytotoxic lymphocyte phenotype and function

Family#Method1 WES

Family#Method2 Sanger

Family#GenotypingMethod WES then variant confirmed with Sanger in I-3, III-1, III-2, II-4, and I-4

Affected 7

Unaffected 3

Segregations 5

eLOD 1.5

ProbandLabel F1:III-1, M, 4yo diagnosis

CasePresentingHPOs HP:0002503, HP:0000639, HP:0002317, HP:0008969, HP:0007340 (in addition to family not presenting)

HPO Free Text: congenital cytomegalovirus infection, trilineage cytopenia and MDS −7 diagnosis at the age of 4 years. Concurrent cellular immunodeficiency with decreased peripheral blood B and NK cell numbers and borderline monocyte numbers. Immunoglobulin (Ig) levels were also low (IgG, 3.36 g/L; IgA, 0.37 g/L; IgM, 0.49 g/L). MDS with −7 and −22 at 4 y of age; severely hypoplastic bone marrow diagnosed as pediatric refractory cytopenia. Hb[102-139(0/9) vs 117-153], MCV[89-95(6/6) vs 75-87], Platelets[87-128(8/9) vs 125-140], WBC[2.4-4.5(9/9) vs 5-15]

Variant NM_152703.4(SAMD9L):c.698C>A (p.Thr233Asn)

CAID CA4343828

VariantEvidence (Figure 5) 293FT cells transfected with p.Arg986Cys showed more limited cell proliferation than WT SAMD9L

FamilyAddInfo Aunt(II-1)/Mother(II-2) have NM_152703.3:c.689A>C(p.Asn230Thr), CA368201553 in cis with index's variant and have milder symptoms. Another aunt(II-4) has a NM_152703.3:c.2957G>T(p.Arg986Leu) and NM_152703.3:c.1204_1208del(p.Leu402ArgfsTer8) with cytopenias.

FamilyPMIDs 28852709

Family#PresentingHPOs HP:0001999, HP:0003155, HP:0003124, HP:0003141, HP:0012347, HP:0012358, HP:0001399 (Dysmorphic facies, Elevated alkaline phosphatase, High cholesterol, Increased LDL cholesterol, Abnormal protein N-linked glycosylation, Abnormal protein O-linked glycosylation, Liver failure)

HPOsFreeText elevated AT

FamilyNotHPOs n/a

CountryOrigin n/a

Ethnicity Turkish

Race n/a

Family#PreviousTesting Metabolic work up: Elevated AT, ALP, total cholesterol and LDL cholesterol, abnormal N- and O- glycosylation

Family#Method1 Sanger

Family#Method2 n/a

Family#GenotypingMethod Sanger on proband targeting CCDC115

Affected 2

Unaffected 0

Segregations n/a

PublishedLOD n/a

eLOD n/a

AddSegregationInfo consanguinity

ProbandLabel F4-II1, male,9yo death

Case1PreviousTesting Metabolic results: AST 192–669 U/l[normal range, 0–50 U/l], ALT 83–308 U/l [normal range, 0–50 U/l], ALP 702 U/l[normal range, < 360 U/l]

Case2 F4-II2, female, 8yo diagnosis

Case2PreviousTesting Metabolic results: AST 98–422 U/l [normal range, 0–50 U/l], ALT 98–178 U/l [normal range, 0–50 U/l], ALP 710–985 U/l [normal range, < 360 U/l]. AT and CDG profile normalized after liver transplant.

Variant NM_032357.3(CCDC115):c.31G>T (p.Asp11Tyr), homozygous

ClinVar 218963

gnomAD n/a

VariantEvidence n/a

FamilyAddInfo n/a

FamilyPMIDs n/a

Family#PresentingHPOs HP:0001263, HP:0001433, HP:0003155, HP:0012358, HP:0012347, HP:0010837, HP:0001999 (Pyschomotor delay, Hepatosplenomegaly, Abnormal protein O-linked glycosylation, Abnormal protein N-linked glycosylation, Decreased ceruloplasmin, Dysmorphic facies)

HPOsFreeText Elevated aminotranseferases, type 2 CDG

FamilyNotHPOs n/a

CountryOrigin n/a

Ethnicity Turkish

Race n/a

Family#PreviousTesting Metabolic screen indicated elevated AT, bone derived ALP, and low ceruloplasmin.

Family#Method1 WES

Family#Method2 Sanger

Family#GenotypingMethod WES confirmed with Sanger homozygosity in siblings and heterozygosity in parents. Variants with frequency of >0.2%, synonymous variants, deep intronic variants, and variants in UTRs were excluded.

Affected 3

Unaffected 1

Segregations 3

PublishedLOD n/a

eLOD 1.32

AddSegregationInfo consanguinity

ProbandLabel F1-II1, female, 9yo report

Case1PresentingHPOs HP:0001252, HP:0003236 (Hypotonia, Elevated CK)

HPOsFreeText decreased coagulation factors

Case1PreviousTesting Metabolic work up: AST 130–158 U/l [normal range, 0–50 U/l], ALT 85–101 U/l [normal range, 0–50 U/l], and ALP 1,016 –1,193 U/l [normal range, < 360 U/l], serum ceruloplasmin (4 mg/dl [normal range, 15–60 mg/dl]. No change in CD59 and CD55 expression in EBV-transformed lymphoblasts.

Case2 F1-II2, male, 5yo report

Case2PresentingHPOs HP:0003124, HP:0000276, HP:0000508, HP:0000592, HP:0000494, HP:0100295, HP:0001433 (Hypercholesterolemia, Long face, Ptosis, Blue sclera, Downslanting palpebral fissures, Muscle fiber atrophy, Hepatosplenomegaly)

HPOsFreeText Hepatosplenomegaly normalized with age, abnormal coagulation factors

Case2PreviousTesting Metabolic work up: AST 96–436 U/l [normal range, 0–50 U/l], ALT 140–995 U/l [normal range, 0–50 U/l], and ALP 1,070–1,577 U/l [normal range, < 360 U/l], serum ceruloplasmin (4 mg/dl [normal range, 15–60 mg/dl], cholesterol 289 mg/dl [normal range, 120–200 mg/dl]

Variant NM_032357.3(CCDC115):c.92T>C (p.Leu31Ser), homozygous

ClinVar 218967

gnomAD 0.00002384(European (Non-Finnish)), 0.00001086(Total)-3 heterozygotes

VariantEvidence n/a

FamilyAddInfo A third ungenotyped sibling, F1-II4 did not have hypotonia, but otherwise presented similarly.

FamilyPMIDs 29759592

eLOD Family A-2.7, Family B-1.8

Variant Family A- NM_000384.2(APOB):c.9175C>T (p.Arg3059Cys) Family B-NM_000384.2(APOB):c.10182G>T (p.Lys3394Asn)

ClinVar A-69508, B-438310

CAID A-CA066337, B-CA345987169

gnomAD A-0.00003249 link B-n/a

CA3281989

Family#PresentingHPOs HP:0000639, HP:0007256, HP:0001251

FamilyNotHPOs HP:0001260, HP:0000486, HP:0001310

CountryOrigin Sweden

Family#Method1 WES

Family#Method2 Sanger

Family#GenotypingMethod expanded pedigree confirmed to have SAMD9L variants with Sanger

Affected 5

Unaffected 9

Segregations 3*

AddSegregationInfo not to score

ProbandLabel Fam1:IV-3, Female, 38yo reported

Variant NM_152703.4(SAMD9L):c.2956C>T (p.Arg986Cys), NM_152703.3:c.689A>C(p.Asn230Thr)

ClinVar 446530(c.2956), CA368201553(c.689)

FamilyAddInfo at least one member with the variant who is unaffected, but likely due to age (4yo)

FamilyPMIDs 28202457

MiltingF1

FamilyNotHPOs HP:0100660, HP:0004756, HP:0001645, HP:0031317

CountryOrigin Germany

Ethnicity Danish

Family#PreviousTesting: whole genome Family#Method1 PCR

Family#GenotypingMethod Liquid Chromatography screening

Affected 8

Unaffected 6

Segregations 7

eLOD 2.1

ProbandLabel Milting3:1 female

Variant NM_024334.2(TMEM43):c.1073C>T (p.Ser358Leu)

ClinVar 734

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

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

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

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

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

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)

FamilyLabel: Family 1

Family1PresentingHPOs: HP:0001987, HP:0001942, HP:0003128, HP:0002912 (hyperammonemia, metabolic acidosis, lactic acidosis, methylmalonic acidemia)

NotHPOsFreeText: normal plasma total homocysteine

CountryOrigin: China

Ethnicity: Chinese

ProbandLabel: Case35, Case36

Family1 (Level 2)

FamilyPreviousTesting: tandem mass spectrometry for blood levels, gas chromatography-mass spectrometry for urine, NBS

FamilyMethod1: PCR

FamilyGenotypingMethod: genomic DNA extracted from peripheral blood leukocytes from patients and their parents. Exonic ad flanking intronic regions of the MUT gene were amplified through PCR. PCR products were sequenced directly using forward and reverse primers on ABI 3700 sequencer. Mutation analysis using MUT reference NM_000255.3. Nucleotide numbering reflects cDNA numbering (initiation codon= codon1). All detected mutations were confirmed in the patients' parents. Novel variants were screened in 100 alleles from 50 control children. Novel variants were considered pathogenic when predicted to be deleterious by two algorithms.

FamilyAddInfo: counted in group annotation also. identical twins. mut- and mut0 mutation together may explain relatively good clinical condition.

FamilyBJG_F2: Malaysia

FamilyPresentingHPOs: N/A

HPOsFreeText: N/A

FamilyNotHPOs: N/A

NotHPOsFreeText: N/A

FamilyGenotypingMethod: See Group

FamilyPreviousTesting: See Group

FamilyAddInfo: Proband is confirmed homozygous for this variant

Variant: NM_006721.4(ADK):c.89G>A (p.Gly30Glu)

ClinVar: 29605, https://www.ncbi.nlm.nih.gov/clinvar/variation/29605/

gnomAD: Not in gnomAD

Affected: 2

Unaffected: 0

Segregations: 1

AddSegregationInfo: Not enough info

FamilyBJ1: Sweden

FamilyPresentingHPOs: HP:0003235, HP:0011344, HP:0001410, HP:0001508, HP:0001252, HP:0000256, HP:0002007, HP:0000316, HP:0001533, HP:0001250, HP:0002463, HP:0003323, HP:0003202, HP:0002910 (Hypermethioninemia, Severe global developmental delay, Decreased liver function, Failure to thrive, Muscular hypotonia, Macrocephaly, Frontal bossing, Hypertelorism, Slender build, Seizure, Language impairment, Progressive muscle weakness, Skeletal muscle atrophy, Elevated hepatic transaminase)

HPOsFreeText: N/A

FamilyNotHPOs: N/A

NotHPOsFreeText: N/A

FamilyGenotypingMethod: The siblings were subject to whole exome sequencing. Variants were extracted, aligned, and filtered to build a list of candidate genes. These were filtered through a series of restrictions until only five candidate genes were left, with ADK being the only one related to methionine metabolism. To confirm the results, Exon 10 of ADK was Sanger sequenced in the family members and the variant was confirmed in a heterozygous state in both parents.

FamilyPreviousTesting: Parents are nonconsanguineous and healthy; Maximum plasma Met values were 455 and 886 μmol/liter, respectively (reference range: 15–35 μmol/liter); Elevated AdoMet and AdoHcy; Sequency analysis of AHCY and enzyme activity was negative for SAHH deficiency; More detailed test values in Table 1

FamilyAddInfo: N/A

Variant: NM_006721.4(ADK):c.953C>A (p.Ala318Glu)

ClinVar: 29603, https://www.ncbi.nlm.nih.gov/clinvar/variation/29603/

gnomAD: 0.00001761, https://gnomad.broadinstitute.org/variant/10-76430016-C-A

Affected: 2

Unaffected: 0

Segregations: 1

AddSegregationInfo: Not enough info

FamilyBJG_F1: Malaysia

FamilyPresentingHPOs: N/A

HPOsFreeText: N/A

FamilyNotHPOs: N/A

NotHPOsFreeText: N/A

FamilyGenotypingMethod: See Group

FamilyPreviousTesting: See Group

FamilyAddInfo: Proband is confirmed homozygous for this variant

Variant: NM_006721.4(ADK):c.704A>C (p.Asp235Ala)

ClinVar: 29604, https://www.ncbi.nlm.nih.gov/clinvar/variation/29604/

gnomAD: Not in gnomAD

Affected: 2

Unaffected: 0

Segregations: 1

AddSegregationInfo: Not enough info

FamilyLabel HCU-103

Family#PresentingHPOs HP:0001249

(Intellectual disability)

HPOsFreeText elevated plasma homocysteine, elevated urinary cysteine

FamilyNotHPOs HP:0001083, HP:0002970, HP:0001010, HP:0000501, HP:0000924

(Ectopia lentis, Genu varum, Hypopigmentation, Glaucoma, Skeletal abnormalities)

NotHPOsFreeText skeletal abnormality/elongated long bones

CountryOrigin Iran

Ethnicity Sistani

Race n/a

Family#PreviousTesting tested for homocysteine in plasma and for cysteine in urine

FamilyMethod1 Sanger

FamilyMethod2 n/a

FamilyGenotypingMethod Sanger sequenced exon 3 of the CBS gene

ProbandLabel HCU-103-4

Variant NM_000071.2(CBS):c.346G>A (p.Gly116Arg), homozygous

ClinVar 188787

gnomAD MAF=0.00002892(Latino), no homozygotes

FamilyAddInfo from the province of Sistan and Baluchestan. no known consanguinity although the affected individuals are homozygous for a founder variant

FamilyPMIDs n/a

FamilyLabel HCU-220

Family#PresentingHPOs HP:0001249, HP:0001083, HP:0002970, HP:0001010, HP:0000924, HP:0001263

(Intellectual disability, Ectopia lentis, Genu varum, Hypopigmentation, Skeletal abnormality, cognitive delay)

HPOsFreeText CBS deficiency diagnosis, skeletal abnormality/elongated long bones, cognitive delay was apparent as early as 2yo

FamilyNotHPOs HP:0000501

(Glaucoma)

CountryOrigin Iran

Ethnicity Sistani

Race n/a

Family#PreviousTesting no other CBS variants were observed after Sanger sequencing

FamilyMethod1 Linkage analysis or Homozygosity mapping (genome-wide)

FamilyMethod2 Sanger

FamilyGenotypingMethod Genome-wide SNP genotyping and whole genome linkage analysis using MERLIN to analyze DNA of the parents and 7 siblings. Homoygosity mapping of the homozygous regions common to the three affected individuals and absent in unaffected individuals then narrowed the homozygous region to a locus including 296 protein coding genes. CBS, being one of those genes, was considered since intellectual disability accompanies homocysteinuria. The 15 coding exons and flanking intronic sequences of the CBS gene were PCR amplified then Sanger sequenced.

ProbandLabel HCU-220-5

Variant NM_000071.2(CBS):c.346G>A (p.Gly116Arg), homozygous

ClinVar 188787

gnomAD MAF=0.00002892(Latino), no homozygotes

FamilyAddInfo family from a remote village in the province of Sistan and Baluchestan. consanguinity-first cousin parents, several heterozygous family members (both parents and 2 siblings) had cardiac disorders such as mitral regurgitation or mitral valve prolapse, but were generally negative for the phenotypes of the affected individuals. Heterozygous sibling HCU-220-3 is the only individual who presented in this study with glaucoma and mitral valve prolapse.

FamilyPMIDs n/a

FamilyPA2: Italy

FamilyPresentingHPOs: HP:0000519, HP:0002020, HP:0002572, HP:0002313, HP:0003693, HP:0002036, HP:0001761, HP:0003487, HP:0009830, HP:0001288, HP:0001348 (Developmental cataract, Gastroesophageal reflux, Episodic vomiting, Spastic paraparesis, Distal amyotrophy, Hiatus hernia, Pes cavus, Babinski sign, Peripheral neuropathy, Gait disturbance, Brisk reflexes)

HPOsFreeText: N/A

FamilyNotHPOs: N/A

NotHPOsFreeText: N/A

FamilyGenotypingMethod: ALDH18A1 was directly sequenced upon investigation for a causal role in SPG9, due to being within the linked region 10q23.3-q24.2, not having been discarded as a candidate gene, and mutations having been known to cause cutis laxa. Previous haplotype analysis also confirmed the linkage to this specific genomic region. This revealed one mutation in each pedigree that strictly co-segregated with the disease. Exome NGS sequencing within the interval showed only two variants were unknown in ExAC with the MYOF substitution unlikely to be disease causing due to poor conservation.

FamilyPreviousTesting: N/A

FamilyAddInfo: Family shows autosomal dominant segregation and haplotyping, Proband is PA2:III-21

FamilyPMIDs: 9973297

Variant: NM_002860.4(ALDH18A1):c.755G>A (p.Arg252Gln)

ClinVar: 217117 https://www.ncbi.nlm.nih.gov/clinvar/variation/217117/

gnomAD: Not in gnomAD

Affected: 11

Unaffected: 15

Segregations: 17

pLOD: 4.83

AddSegregationInfo: Candidate gene sequencing

FamilyPA1: United Kingdom

FamilyPresentingHPOs: HP:0000518, HP:0002493, HP:0004322, HP:0001263, HP:0011842, HP:0002013 (Cataract, Upper motor neuron dysfunction, Short stature, Global developmental delay, Abnormality of skeletal morphology, Vomiting)

HPOsFreeText: N/A

FamilyNotHPOs: N/A

NotHPOsFreeText: N/A

FamilyGenotypingMethod: ALDH18A1 was directly sequenced upon investigation for a causal role in SPG9, due to being within the linked region 10q23.3-q24.2, not having been discarded as a candidate gene, and mutations having been known to cause cutis laxa. This revealed one mutation in each pedigree that strictly co-segregated with the disease. Exome NGS sequencing within the interval showed only two variants were unknown in ExAC with the MYOF substitution unlikely to be disease causing due to poor conservation.

FamilyPreviousTesting: N/A

FamilyAddInfo: Family shows autosomal dominant segregation

FamilyPMIDs: 8779323

Variant: NM_002860.4(ALDH18A1):c.755G>A (p.Arg252Gln)

ClinVar: 217117 https://www.ncbi.nlm.nih.gov/clinvar/variation/217117/

gnomAD: Not in gnomAD

Affected: 7

Unaffected: 3

Segregations: 6

AddSegregationInfo: Candidate Gene Sequencing, Pedigree in Family 1

FamilyLabel Family 1

Family1PresentingHPOs HP:0000924, HP:0000939

(Skeletal anomalies, Osteoporosis)

HPOsFreeText Patients diagnosed with homocystinuria after finding abnormally high homocysteine on urine sample exam.

FamilyNotHPOs n/a

NotHPOsFreeText n/a

CountryOrigin Ireland

Ethnicity n/a

Race n/a

Family1PreviousTesting Tested pretreatment plasma homocysteine in each patient. Pyroxidine treatment dramatically reduced plasma homocysteine in all patients. In patient fibroblasts, no CBS protein was detect on Western blot and CBS assay detected no activity. (PMID: 20329304): "Full hemogram, routine urine analysis, liver function tests, serum ion and iron-binding capacity, plasma magnesium, serum calcium, inorganic phosphate, fasting blood sugars, blood urea nitrogen, and bone marrow examination were all normal". Heavy homocysteine spot was detected on chromatogram of urinary amino acids.

FamilyMethod1 PCR

FamilyMethod2 Sanger

FamilyGenotypingMethod Created a bacteria expression system in E.coli by substituting one of three fragments of (PCR amplified)patient cDNA into WT CBS sequence already subcloned in expression plasmids. Bacteria were screened based on which ones did not have CBS activity. Those that did not have activity were thought to have LOF variants in CBS. Plasmids containing the inactivating fragments were sequenced.

ProbandLabel 1875

Variant 1. NM_000071.2:c.715G>A (p.Glu239Lys),

1. NM_000071.2:c.233C>G (p.Pro78Arg);3. NM_000071.2:c.306G>C (p.Lys102Asn) - 2&3 in cis, compound heterozygous

ClinVar 1. n/a, 2. 188988;3. 188989

CAID 1. CA410600501

gnomAD 1. not in gnomAD, 2. MAF=0.0001631(Other), no homozygotes, 3. MAF=0.0001630(Other), no homozygotes

FamilyAddInfo Father unavailable for study. Mother was clinically/biochemically healthy with an unexplained macrocytosis. Mother had absent CBS activity, but no homocystinuria symptoms and was heterozygous for the Glu239Lys variant. The variant was found in inactive bacteria carrying the BB segment. Presence of the variant was reinforced by amplifying, subcloning, then sequencing her genomic DNA of the region corresponding to BB.

FamilyPMIDs 20329304

FamilySE1: Australia

FamilyPresentingHPOs: HP:0008353 (Neutral hyperaminoaciduria)

HPOsFreeText: N/A

FamilyNotHPOs: N/A

NotHPOsFreeText: N/A

FamilyGenotypingMethod: Five loci were investigated for evidence of linkage to Hartnup due to their established role in amino acid transport including SLC3A2, SLC7A8, SLC1A5, SLC6A18, and SLC6A19. These 5 regions were studied with microsattelite markers and produced linkage only between D5S392 and D5S417, the region with SLC6A18 and 19. SLC6A18 did not increase neutral amino acid uptake in X. laevis oocytes so SLC6A19 was investigated and directly sequenced in the families each of which displayed a causal variant.

FamilyPreviousTesting: SLC1A5 had no causative variants detected.

FamilyAddInfo: Family is asymptomatic except for hyperaminoaciduria

Variant1: NM_001003841.3(SLC6A19):c.1173+2T>G

ClinVar: 449553 https://www.ncbi.nlm.nih.gov/clinvar/variation/449553/

gnomAD: 0.00008019, https://gnomad.broadinstitute.org/variant/5-1217062-T-C?dataset=gnomad_r2_1

Variant2: NM_001003841.3:c.725T>C (p.Leu242Pro)

CAID: CA3182847 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA3182847

gnomAD: 0.0001307, https://gnomad.broadinstitute.org/variant/5-1213639-T-C

Affected: 3

Unaffected: 3

pLOD: 2.68 combined max LOD score for linkage between D5S392 and D5S417

AddSegregationInfo: Pedigree in SuppFig1A, Candidate gene sequencing

FamilySE2: Australia

FamilyPresentingHPOs: HP:0008353 (Neutral hyperaminoaciduria)

HPOsFreeText: N/A

FamilyNotHPOs: N/A

NotHPOsFreeText: N/A

FamilyGenotypingMethod: Five loci were investigated for evidence of linkage to Hartnup due to their established role in amino acid transport including SLC3A2, SLC7A8, SLC1A5, SLC6A18, and SLC6A19. These 5 regions were studied with microsattelite markers and produced linkage only between D5S392 and D5S417, the region with SLC6A18 and 19. SLC6A18 did not increase neutral amino acid uptake in X. laevis oocytes so SLC6A19 was investigated and directly sequenced in the families each of which displayed a causal variant.

FamilyPreviousTesting: SLC1A5 had no causative variants detected.

FamilyAddInfo: Family is asymptomatic except for hyperaminoaciduria

Variant1: NM_001003841.3(SLC6A19):c.517G>A (p.Asp173Asn)

ClinVar: 2019 https://www.ncbi.nlm.nih.gov/clinvar/variation/2019/

gnomAD: 0.003016, https://gnomad.broadinstitute.org/variant/5-1212453-G-A?dataset=gnomad_r2_1

Variant2: NM_001003841.3:c.1501G>A (p.Glu501Lys)

CAID: CA359075496, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA359075496

gnomAD: 0.00006164, https://gnomad.broadinstitute.org/variant/5-1219742-G-A

Affected: 2

Unaffected: 3

pLOD: 2.68 combined max LOD score for linkage between D5S392 and D5S417

AddSegregationInfo: Pedigree in SuppFig1B, Candidate gene sequencing