Case Info: P6 (female)

DiseaseAssertion: Carrier

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0003125, HP:0001928, HP:0001892

CaseHPOFreeText: Low FVIII levels (in vitro results were similar to the WT control and led to a normal specific activity (82.7% ± 9.0)), abnormal blood coagulation, mild bleeding tendency

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

CasePreviousTesting: Molecular Analysis included a southern blot assay, PCR, dHPLC and a multiplex ligation-dependent probe amplification analysis. Plasmid mutagenesis, plasmid transfection and in silico analysis were also performed.

Gene: F8

Variant: NM_000132.4:c.6095T>C

CAID: CA414904631

gnomAD: Absent/Not Reported

Case#: 020-2006

DiseaseAssertion: Hemophilia A, mild

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: 5% < FVIII:C < 40%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification

Gene: F8

Variant: NM_000132.3:c.1492G>A

LegacyVariant:

ClinVar: No

CAID: CA255109

gnomAD:

Case#: 035-2022

DiseaseAssertion: Hemophilia A, mild

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: 5% < FVIII:C < 40%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification

Gene: F8

Variant: NM_000132.3:c.5954G>A

LegacyVariant:

ClinVar: No

CAID: CA414905715

gnomAD:

Case#: 020-2027

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification

Gene: F8

Variant: NM_000132.3:c.5253A>C

LegacyVariant:

ClinVar: No

CAID: CA414911240

gnomAD:

Case#: 091-2008

DiseaseAssertion: Hemophilia A, moderate

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: 1% < FVIII:C < 5%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification

Gene: F8

Variant: NM_000132.3:c.142A>G

LegacyVariant:

ClinVar: No

CAID: CA414920432

gnomAD:

Case#: 001-2051

DiseaseAssertion: Hemophilia A, moderate

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: 1% < FVIII:C < 5%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification

Gene: F8

Variant: NM_000132.3:c.2134C>A

LegacyVariant:

ClinVar: No

CAID: CA414904092

gnomAD:

Case#: 042-1001

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification

Gene: F8

Variant: NM_000132.3:c.2144+2A>G

LegacyVariant:

ClinVar: No

CAID: No

gnomAD:

Case#: Heit_Proband_HB541 (assumed male, AmerIndian from Peru)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity (FIX:C: <1 %)

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.128G>A (p.Arg43Gln)

ClinVar: 810864

CAID: CA414435539

gnomAD: Absent/Not Reported

Case#: 29

DiseaseAssertion: Hemophilia A

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FVIII:C 10/8/14%, Mild Phenotype, No inhibitors present

CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing

Gene: F8

Variant: NM_000132.3:c.6118T>G (p.Cys2040Gly)

ClinVar: NA

CAID: CA414904332

gnomAD: Not reported

Case#: 42

DiseaseAssertion: Hemophilia B

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FIX:C 4% (Moderate Phenotype)

CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing

Gene: F9

Variant: NM_000133.4(F9):c.422G>A (p.Cys141Tyr)

ClinVar: 811510 https://www.ncbi.nlm.nih.gov/clinvar/variation/811510/

CAID: CA414438897

gnomAD: Not reported

Case#: 3

DiseaseAssertion: Hemophilia B, severe

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0011858

CaseHPOFreeText: FIX:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing

Gene: F9

Variant: NM_000133.3:c.128G>A

LegacyVariant:

ClinVar: No

CAID: CA414435539

gnomAD:

Case#: 16

DiseaseAssertion: Hemophilia B, mild

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0011858

CaseHPOFreeText: FIX:C = 12%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing

Gene: F9

Variant: NM_000133.3:c.881G>A

LegacyVariant:

ClinVar: No

CAID: CA255368

gnomAD:

Case#: 10

DiseaseAssertion: Hemophilia B, moderate

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0011858

CaseHPOFreeText: FIX:C = 2.5%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing

Gene: F9

Variant: NM_000133.3:c.571C>T

LegacyVariant:

ClinVar: No

CAID: CA255340

gnomAD:

Case#: 10

DiseaseAssertion: Hemophilia B, moderate

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FIX:C = 1.8%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All exons, UTRs, exon-intron junction regions, and the promotor of F9 were amplified by PCR and analyzed by direct DNA sequencing

Gene: F9

Variant:

LegacyVariant: NM_000133.3:c.880C>T

ClinVar: No

CAID: CA255344

gnomAD:

Case#: 4

DiseaseAssertion: Hemophilia B, severe

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FIX:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All exons, UTRs, exon-intron junction regions, and the promotor of F9 were amplified by PCR and analyzed by direct DNA sequencing

Gene: F9

Variant: NM_000133.3:c.520G>C

LegacyVariant:

ClinVar: No

CAID: CA414439517

gnomAD:

Case#: Miller_Proband 2 (male)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.128G>A (p.Arg43Gln)

ClinVar: 810864

CAID: CA414435539

gnomAD: Absent/Not Reported

PMID: 8320491

Gene: F9

HGNC: 3551

Case#: 1, male, 30 years old, Chinese

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.36C>A

LegacyVariant:

ClinVar: No

CAID: CA414920668

gnomAD:

Case#: 84, male, 48 years old, Chinese

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.5821A>C

LegacyVariant:

ClinVar: No

CAID: CA414906679

gnomAD:

Case#: 20, male, 36 years old, Chinese

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.5953C>T

LegacyVariant:

ClinVar: 10300

CAID: CA255191

gnomAD:

PMID: 16270648

Gene: F9

HGNC: 3551

Case#: Cz16, Italy (Calabria)

DiseaseAssertion: Hemophilia A

FamilyInfo: Sporadic

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FVII:C 4%

CasePreviousTesting: Polymerase chain reaction (PCR) analysis, Long PCR for detecting the intron 22 inversion was performed, Direct cycle sequence analysis using the Taq dye-deoxy terminator method

Gene: F8

Variant: NM_000132.3:c.1538-18G>A

ClinVar: 811357 https://www.ncbi.nlm.nih.gov/clinvar/variation/811357/

CAID: CA873354114

gnomAD: Not reported

PMID: 31547094

Gene: F8

NoEvidence: No patients or variants mentioned here in this article

PMID: 22639855

Gene: F9

HGNC: 3551

PMID: 29450643

Gene: F9

HGNC: 3551

PMID: 8217825

Gene: F9

HGNC: 3551

PMID: 31318198

Gene: F8

NoEvidence: This paper does not mention Hemophilia A or F8. No patients and no variants included.

Case#: A16

DiseaseAssertion: Hemophilia A, mild

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 7, FVIII:AG = 23, assay discrepancy present (OSA>CSA)

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: Coding region and intron/exon bound-aries of the F8 gene were amplified from all patient samples and directly sequenced using primers

Gene: F8

Variant: NM_000132.4:c.5879G>A

LegacyVariant:

ClinVar: No

CAID: CA255019

gnomAD:

Case#: Lin_Patient 3 (assumed male, Chinese origin)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: None

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity (FIX:C: <1 ; FIX:Ag: 38)

CaseNotHPOs: N/A

CasePreviousTesting: None

Gene: F9

Variant: NM_000133.4:c.128G>A (p.Arg43Gln)

ClinVar: 810864

CAID: CA414435539

gnomAD: Absent/Not Reported

Case#: 20

DiseaseAssertion: Hemophilia A

FamilyInfo: Sporadic

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: Severe

CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit

Gene: F8

Variant: NM_000132.3:c.1487C>G (p.Pro477Arg)

ClinVar: NA

CAID: CA414912766

gnomAD: Not reported

Case#: Quadros_Proband_ ID_#2

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: None

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity

CaseNotHPOs: None

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.112A>C (p.Asn38His)

ClinVar: Absent

CAID: CA414435439

gnomAD: Absent/Not Reported

Case#: Liu_Proband_316 (assumed male; Chinese)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.82T>G (p.Cys28Gly)

ClinVar: Absent

CAID: CA414434482

gnomAD: Absent/Not Reported

Case#: Hadalin_2021_Family_1_Patient_III-1, male, 31 years old at first examination, family origin in Slovenia

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000545 (Myopia), HP:0008020 (Cone dystrophy), HP:0007663 (Reduced visual acuity), HP:0012230 (Rhegmatogenous retinal detachment), HP:0000603 (Central scotoma), HP:0007814 (Retinal pigment epithelial mottling), HP:0008043 (Retinal arteriolar constriction), HP:0000543 (Optic disc pallor), HP:0030602 (Abnormal fundus autofluorescence imaging), HP:0200070 (Peripheral retinal atrophy), HP:0030465 (Undetectable light-adapted electroretinogram), HP:0000613 (Photophobia), HP:0011504 (Bull's eye maculopathy), HP:0007737 (Bone spicule pigmentation of the retina),

CaseHPOFreeText: The patient received a diagnosis of cone dystrophy. Myopia was present from childhood, while visual loss occurred in the early 30's.

CaseNotHPOs: N/A

CaseNotHPOFreeText: Dark-adapted ERG was normal at the time of the study.

CasePreviousTesting: The patient and an apparently unrelated proband from another family were subjected to whole-exome sequencing.

CaseMethod1: Whole-exome sequencing

CaseMethod2: Haplotype analysis using SNPs on the X chromosome

CaseGenotypingMethod: The patient and a proband from another family not known to be related were subjected to whole-exome sequencing, followed by haplotype analysis using SNPs on the X chromosome.

Variant: The patient harbors the NM_001034853.2(RPGR):c.3457T>A (p.Ter1153Lys) variant in the hemizygous state.

ClinVar: 931960

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

VariantEvidence: NM_001034853.2(RPGR):c.3457T>A (p.Ter1153Lys) is a stop-loss variant that triggers an extension of the C-terminus of RPGR by 38 amino acids. It is not predicted to undergo nonsense-mediated decay, and its inheritance pattern with largely unaffected female carriers is consistent with loss-of-function.

CaseAddInfo: The proband is a member of Family 1, with the mother being a female carrier with mild myopia, and an apparently affected maternal grandfather. Two other patients not known to be close relatives but harboring the same founder variant within a 29-megabase shared region received the same diagnosis of cone dystrophy.

CasePMIDs: N/A

Case: Shamieh_FamilyA_II:2; CIC00173

CasePresentingHPOsFreeText: Rod-cone dystrophy, Each subject underwent an ophthalmic exami- nation with clinical assessment as previously described. The three affected individuals with KIZ variants in this study were all diagnosed with RCD in their late teens on the basis of night blindness followed by changes in mid- peripheral visual fields and undetectable responses in a full-field electroretinogram by approximately 35 years of age.

CasePreviousTesting: At a time when next-generation sequencing (NGS) approaches were not commonly used, index subject CIC00173 II.2 (family A, Figure 1) was excluded upon screening by microarray analysis and direct Sanger sequencing for known mutations in EYS and C2orf71 (a major and a minor gene, respectively, implicated in RCD). 11,12 Because exon ORF15 in RPGR (MIM 312610) is not targeted by existing NGS panels,13 we also analyzed it by Sanger sequencing but found no pathogenic variant. Subsequently, we performed targeted NGS on the index subject’s DNA by using a panel of 120 genes previously found to carry mutations in retinal diseases (this panel was modified and improved since our previous study). This survey did not reveal any pathogenic variant, and we therefore proceeded to WES.

CaseGenotypingMethod: In the present study, we applied whole-exome sequencing (WES) to five members (including one affected by RCD) of a consanguineous family (family A).

Variant: c.226C>T (p.Arg76*); homozygous

ClinVarID: or CAID: CA151548

gnomAD: Variant present at a frequency of 0.006316 in the Ashkenazi Jewish (9658 alleles tested) and 0.001173 in the Latino populations.

AddCaseInfo: consanguineous family. Both parents and the sister of the proband each carried one copy of the variant, but none were affected with RCD. To investigate whether the stop variant represents a founder alteration, we performed haplotype analysis for each of the index subjects (CIC00173 II.2 from family A) and CIC01611 II.1 from family B) by selecting 11 microsat- ellite DNA markers flanking the KIZ locus. 25 These markers were distributed over a physical distance of z7.38 Mb, cor- responding to z10.5 cM (genetic distance according to Marshfield genetic maps). Both subjects were found to share a common haplotype of five polymorphic microsa- tellites (DS20S54, DS20S63, DS20S190, DS20S868, and DS20S180) flanking KIZ and spanning z1.75 cM (1.18 Mb) (Figure 1). This result suggests that c.226C>T (p.Arg76*) is most likely a founder mutation causing autosomal-recessive RCD in the southern European population

VariantEvidence: We detected a homozygous nonsense mutation, c.226C>T (p.Arg76*), in the third exon of KIZ, coding for centrosomal protein kizuna (KIZ)

Case#: Jespersgaard_2019_Patient_165, gender and age not specified, origin likely to be Danish based on cohort

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa, as part of a larger group of generalized non-syndromic retinal dystrophies. Detailed phenotypes are not described.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Next-generation sequencing was performed focusing on a targeted panel of 125 genes known to be linked to inherited retinal disease.

CaseMethod1: NGS panel

CaseMethod2: N/A

CaseGenotypingMethod: Next-generation sequencing was performed focusing on a targeted panel of 125 genes known to be linked to inherited retinal disease. It is not clear whether Sanger sequencing was used to validate the genotyping of this particular case.

Variant: The proband harbors the NM_000440.3(PDE6A):c.1620+1G>A variant in the homozygous state.

ClinVar: 636054

gnomAD: The NM_000440.3(PDE6A):c.1620+1G>A variant is found in gnomAD v2.1.1 at a frequency of 0.00003267 (1/30608) in the South Asian population https://gnomad.broadinstitute.org/variant/5-149275918-C-T

VariantEvidence: The NM_000440.3(PDE6A):c.1620+1G>A variant disrupts a canonical splice site in intron 12, but does not have experimental confirmation of exon skipping or frameshift.

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Pattnaik_2015_Proband, male, age 10 years, family national origin described as Jordanian

CasePresentingHPOs: Nyctalopia HP:0000662, Childhood onset HP:0011463, Severely reduced visual acuity HP:0001141, Granular macular appearance HP:0007793, Retinal arteriolar constriction HP:0008043, Retinal degeneration HP:0000546, Abnormal choroid morphology (hypertrophy) HP:0000610

CaseHPOFreeText: The proband has been diagnosed at different times with Stargardt disease, retinitis pigmentosa, cone-rod dystrophy, and Leber congenital amaurosis, first presenting with night vision difficulties at age 2 years. Small focal sub-RPE deposits were observed.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was initially genotyped by PCR-based screening for known LCA-associated variants and next-generation sequencing focused on a 19-gene LCA panel.

CaseMethod1: PCR-based screening for known LCA-associated variants as well as next-generation sequencing of a 19-gene LCA panel

CaseMethod2: Sanger sequencing of gaps and low-coverage regions as well as for confirmation of the variants detected by other methods.

CaseGenotypingMethod: The proband was initially genotyped by PCR-based screening for known LCA-associated variants and next-generation sequencing focused on a 19-gene LCA panel. Sanger sequencing of gaps and low-coverage regions as well as for confirmation of the variants detected by other methods.

Variant: The individual is homozygous for the NM_002242.4(KCNJ13):c.158G>A (p.Trp53Ter) variant.

ClinVar: 224857

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

VariantEvidence: Heterologous expression of the NM_002242.4(KCNJ13):c.158G>A (p.Trp53Ter) variant in CHO-K1 cells revealed that the variant channel retained very little ability to enable the flow of current, with the measurement of -68.8pA more comparable to the negative control (-42.4pA) than to the wild-type control (-588.7pA).

CaseAddInfo: The family history does not reportedly indicate consanguinity.

CasePMIDs: N/A

GroupName: Lebrun_2009_Group_1

GroupPresentingHPOs: HP:0001251 (Ataxia), HP:0001250 (Seizure), HP:0002463 (Language impairment), HP:0011463 (Childhood onset)

GroupNotHPOs: N/A

NumberMales: 3

NumberFemales: 1

CountryOrigin: One family is from the United Kingdom, while the other family's country of origin is not mentioned

Ethnicity: One family is of Pakistani ethnic origin, while the second family is of Afghan ethnic origin

Race: Not clearly described, but both families have origins within a similar region of Asia.

AgeRange: Onset occurred between the ages of 2 and 5

TotalNumber: 4

FamilyInfo: 4

NoFamily: 0

VariantCount: 4

NonVariant: 0

OtherVariant: 0

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

GroupMethod1: SNP array-based homozygosity mapping was performed, revealing 7 homozygous candidate regions in the affected members from the (consanguineous) family. These regions were analyzed for candidate NCL genes, finding CLN5 as the most likely candidate for further genotyping.

GroupMethod2: N/A

GroupGenotypingMethod: CLN5 mRNA was reverse transcribed, PCR-amplified, and subjected to Sanger sequencing.

GroupAddInfo: N/A

Case#: Lebrun_2009_Patient_2, male, age 2-3 at onset, age 15 at death, family ethnicity reported as Afghan

CasePresentingHPOs: HP:0001251 (Ataxia), HP:0002474 (Expressive language delay), HP:0001250 (Seizure), HP:0011463 (Childhood onset), HP:0011421 (Death in adolescence)

CaseHPOFreeText: Onset was at age 2-3, with the first presenting phenotypes being ataxia and delay in speech development. Seizures began at age 4. Death occurred at age 15.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The extent of previous testing within this patient is unclear.

CaseMethod1: N/A

CaseMethod2: N/A

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

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

ClinVar: 56530

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

VariantEvidence: The missense variant introduces an additional cysteine into the protein product, potentially disrupting folding and three-dimensional structure. Immunofluorescent detection of the exogenously expressed variant in COS7 cells shows aberrant localization to the ER in contrast to the wild-type localization to the lysosome (Figure 3).

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

CasePMIDs: N/A

Case#: Pusch_2000_Familly_9606_Proband, male, age and race not mentioned

CasePresentingHPOs: HP:0030640 (Complete congenital stationary night blindness), HP:0007663 (Reduced visual acuity), HP:0031624 (Moderate myopia), HP:0007984 (Electronegative electroretinogram)

CaseHPOFreeText: ERG with absent oscillatory-potential wavelets

CaseNotHPOs: HP:0001098 (Abnormal fundus morphology), HP:0030473 (Abnormal light-adapted flicker electroretinogram)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Sanger sequencing of PCR amplified exons from NYX

CaseMethod2: N/A

CaseGenotypingMethod: The proband and family members were subjected to Sanger sequencing of NYX to identify the variant.

Variant: The proband harbors the NM_001378477.3(NYX):c.90C>A (p.Cys30Ter) variant on the X chromosome.

ClinVar: 11422

gnomAD: NM_001378477.3(NYX):c.90C>A (p.Cys30Ter) was not found in gnomAD.

VariantEvidence: This nonsense variant is located in exon 2/3 and is predicted to trigger NMD. It introduces a premature stop codon that would truncate 93% of the protein product.

CaseAddInfo: This variant appears not only in Family 9606, but also in Family 2438T, yet is not suspected to be a founder alelle.

CasePMIDs: N/A

Selection B- Gene function is consistent with phenotype.

GOterm: GO:0047555 (3',5'-cyclic-GMP phosphodiesterase activity)

FunctionalEvidence: Purified PDE6C hydrolyzed cGMP with a Km and kcat slightly lower than trypsin-activated bovine rod PDE6 (Figure 7A).

FunctionalHPO: HP:0000551 (Color vision defect), HP:0030465 (Undetectable light-adapted electroretinogram)

PMID: 19801642

Gene: PDE6C

HGNC: 8787

Disease: cone dystrophy 4

MONDO: 0013129

InheritancePattern: recessive

Prevalence: cone dystrophy in general is estimated to have a prevalence of 1 in 40,000 (PMID: 30578485).

Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.

Case#: IV-2, M, Age of Diagnosis: 33 y.o., Ethnicity: Arab-Muslim origin.

CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0007401 (Macular atrophy), HP:0100014 (Epiretinal membrane), HP:0001696 (Situs inversus totalis), HP:0007688 (Undetectable light- and dark-adapted electroretinogram)

CaseHPOFreeText: Proband has consanguineous parents.

Proband was noted to find have visual acuity of 0.2 in the right eye (RE) and 0.4 in the left eye (LE), and his Goldmann visual fields were constricted to 10°–12° with the V4e target.

Interestingly, all three siblings displayed a marked component of macular atrophy, including smaller and larger atrophic patches, as well as epiretinal membranes with wrinkling of the retina (Figures 2A–2D). Neither photopic nor scotopic electroretinogram (ERG) responses were detectable.

Audiometric testing was within normal limits in all three siblings, and computed-tomography imaging revealed full thoracic and abdominal situs inversus in individuals IV-1 and IV-2 but normal situs composition (situs solitus) in individual IV-3.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: Homozygosity mapping.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_012106.4:c.101-1G>C.

ClinVar: 65473.

CAID: CA10575604.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: "When she was 36 years old, his older sister (IV-1; Figure 1A) had severely impaired vision: she could detect hand motion in the RE and had bare light perception in the LE. There were no significant refractive errors. Mild posterior subcapsular cataracts were present, and fundoscopy revealed optic-disc pallor, mild-to-moderate bone-spicule-like pigmentation in the midperiphery, and attenuated retinal blood vessels, all typical signs of RP. Interestingly, all three siblings displayed a marked component of macular atrophy, including smaller and larger atrophic patches, as well as epiretinal membranes with wrinkling of the retina (Figures 2A–2D)."

Case#: Ashkenazy_2023_Proband, female, age 18 at time of report, family origin unknown due to adoption but reported in the United States

CasePresentingHPOs: Snowflake vitreoretinal degeneration HP:0011533, High myopia HP:0011003, Retinoschisis HP:0030502, Rhegmatogenous retinal detachment HP:0012230, Abnormal vitreous humor morphology HP:0004327, Full-thickness macular hole HP:0031152

CaseHPOFreeText: The patient exhibited fibrillar vitreous structure, crystalline retinopathy, and optic nerve flattening.

CaseNotHPOs: Corneal guttata HP:0012038, Presenile cataracts HP:0007819

CaseNotHPOFreeText: Perivascular sheathing was absent.

CasePreviousTesting: Genotyping of the proband was not described in detail, but reportedly did not include whole exome sequencing, due to the specificity of the phenotype. Genes implied to have been possibly examined were COL2A1, COL11A1, and CSPG2.

CaseMethod1: Sanger sequencing of KCNJ13

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping of the proband was not described in detail, but reportedly did not include whole exome sequencing, due to the specificity of the phenotype. Genes implied to have been possibly examined were COL2A1, COL11A1, and CSPG2. Sanger sequencing of KCNJ13 was performed.

Variant: The individual harbors the NM_002242.4(KCNJ13):c.484C>T (p.Arg162Trp) variant in the heterozygous state.

ClinVar: 6585

gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.0000008536 (1 / 1,171,470) in the European (non-Finnish) population https://gnomad.broadinstitute.org/variant/chr2-232768790-G-A?dataset=gnomad_r4

VariantEvidence:NM_002242.4(KCNJ13):c.484C>T (p.Arg162Trp) is a missense variant that has functional evidence of electrophysiological abnormalities and loss of sensitivity to different K+ concentrations, when exogenously expressed in CHO cells (PMID: 18179896, Figure 2).

CaseAddInfo: The proband may or may not be a relative of the family previously reported with the same variant in PMID: 18179896, as both appear to have received medical care in the United States.

CasePMIDs: N/A

Case: Shamieh_CIC07875

CasePresentingHPOsFreeText: RCD

CasePreviousTesting:

CaseGenotypingMethod: The next generation sequencing (NGS) panel was selected from the SureSelect Human All ExonKits Version 4 (Agilent, Massy, France) and covers 198 IRD genes in total. Identified variants in KIZ (NM_018474.4) were validated by direct Sanger sequencing, and co-segregation analyses was performed in the DNA of available family members as previously described [ 9 ]. Similarly, the presence of the two mutations c.52G>T, p.Glu18 and c.119_122del, p.Lys40Ilefs14 in the fibroblast cell line of patient CIC01225 was confirmed by direct Sanger sequencing using genomic primers and conditions as previously described [9]

Variant: c.226C>T (p. R76*) homozygous

ClinVarID: or CAID: CA151548

gnomAD: 0.001173 frequecny in the Latino population

AddCaseInfo:

PreviouslyPublished:

VariantEvidence:

ExperimentName: "Variant overexpression in zebrafish causes defects in visual function."

NonHumanModel: Danio rerio

GeneAlteration: The model animals have been subjected to microinjection of PRPF4 mRNA (either wild-type or harboring the p.Pro315Leu variant), with expression levels comparable to the endogenous gene.

ModelPhenotype: Photoreceptor layer loss on macular OCT HP:0030609, Inner retinal layer loss on macular OCT HP:0030620, Photoreceptor outer segment loss on macular OCT HP:0030610

HumanPhenotype: Constriction of peripheral visual field HP:0001133, Reduced visual acuity HP:0007663,, Decreased light- and dark-adapted electroretinogram amplitude HP:0000654. Retinal degeneration HP:0000546, Macular degeneration HP:0000608, Optic disc pallor HP:0000543, Attenuation of retinal blood vessels HP:0007843, Pigmentary retinopathy HP:0000580

ModelEvidence: The variant causes severely disrupted photoreceptors in the retina (Figure 5D), reduced rhodopsin staining (rod marker) in the IS/OS layer (Figures 5E-5J) and other deformities such as malformed brains, short trunks, cardiac edema and curved body axis, at higher levels than in the wild-type control (Figures 5B and 5C). The retinal transcripts opn1lw1, gnat2, rs1, snrpg, prph2b, gnb3, and rho were decreased in the variant-expressing zebrafish (Figure 5K), while the splicing factor transcripts prpf4, prpf3, prpf31, prpf6, prpf8, snrnp200, eftud2, and sart1 were increased (Figures 5A, 5L).

ModelVariant: This model introduced the disease-associated variant NM_001244926.2(PRPF4):c.941C>T (p.Pro314Leu) in the heterozygous state (ClinVar ID: 143057).

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: next-generation sequencing

CaseMethod2: Sanger sequencing of PRPF4

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

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

ClinVar ID: 143057

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

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

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

CasePMIDs: N/A

PMID: 26359340

Gene: IFT140

HGNC: 29077

Disease: Retinitis pigmentosa 80

MONDO: 0054708

InheritancePattern: autosomal recessive

Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of Retinitis pigmentosa with a recessive mode of inheritance is estimated to be 65-85% (between 1 in 3,500 and 1 in 6,500).

Penetrance: Disease caused by biallelic IFT140 variants appears to be fully penetrant.

PMID: 9642234

Gene: TIMP3

HGNC: 11822

Disease: Sorsby fundus dystrophy (SFD), also known as Sorsby's fundus dystrophy, Sorsby pseudoinflammatory fundus dystrophy, or hemorrhagic macular dystrophy

MONDO: 0007640

InheritancePattern: Autosomal Dominant

Prevalence: Estimated at 1 in 220,000 (PMID: 28847738)

Penetrance: Fully penetrant, onset between the third and sixth decades of life

PMID: 20673862

Gene: IMPG2

HGNC: 18362

Disease: retinitis pigmentosa 56

MONDO: 0013314

InheritancePattern: semi-dominant

Prevalence: Vitelliform macular dystrophy in general is estimated to have a prevalence of 1 in 5,500 (PMID: 27120116).

Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete, while heterozygous carriers of deleterious variants show incomplete penetrance and variable expressivity.

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

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

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

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of autozygosity mapping.

CaseMethod1: Homozygosity mapping

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

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

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

ClinVar: 3550

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

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

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

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

Case#: 12DG0507_III:2, M, Age: N/A., Ethnicity: N/A.

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy/Retinitis pigmentosa)

CaseHPOFreeText: N/A.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_021831.6:c.826C>T (p.Arg276Trp).

ClinVar: 242933.

CAID: CA10584034.

gnomAD: Frequency: 0.000002470. Link: https://gnomad.broadinstitute.org/variant/chr2-27055171-C-T?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: The proband had two affected brothers.

CasePMIDs: N/A.

PMID: 37089697

Gene: CTNNB1

HGNC: 2514

Disease: severe intellectual disability-progressive spastic diplegia syndrome

MONDO: 0014035

InheritancePattern: autosomal dominant

Prevalence: The incidence is unknown but estimated to be between 1 in 30,000 and 1 in 40,000 births (PMID: 32168371).

Penetrance: The penetrance of the cognitive impairment phenotype among cases appears to be near-complete, while the exudative vitreoretinopathy phenotype reportedly has a prevalence of ~39% among affected individuals with a syndromic diagnosis.

Case#: Patient 4, 64 years (at report), female

CaseHPOs: HP:0000613, HP:0007663, HP:0000551 (photophobia, reduced visual acuity, color vision defect)

CaseHPOsFreeText: Relatively late onset of disease (first symptoms around age 30 years). 1.7 LogMAR in both eyes. Refractive error was −2.00 sph in both eyes. Fundus exam showed a tigroid aspect with vessel thinning, macular atrophy, and optic pallor. Flash full-field ERG recordings showed a non-detectable response for the photopic component and a reduced response for the scotopic response. MfERG response was markedly reduced but still detectable in both eyes, presenting a residual foveal cone function. OCT macular scan showed a marked foveal thinning with advanced photo-receptor layer disruption (Fig 5)

CaseNotHPOs:

CasePreviousTesting: None mentioned but note that, in this study, DNA from all patients was analyzed by CORD NGS panel.

CaseMethod1: NGS panel

CaseGenotypingMethod: CORD NGS panel - ABCA4, ADAM9, AIPL1, C8orf37, CFAP410 (C21orf2), CACNA1F, CACNA2D4, CDHR1, CEP78, CNGA3, CRX, DRAM2, GUCA1A, GUCY2D, UNC119, IFT81, KCNV2, PDE6C, PITPNM3, POC1B, PROM1, PRPH2, RAB28, RAX2, RIMS1, RPGR, RPGRIP1, SEMA4A, TTLL5.

Variant: c.321G>A (p.Trp107Ter), homozygous

ClinVar: N/A

CAID: CA356373812

gnomAD: The variant is absent in gnomAD.

VariantEvidence: Structural analysis of p.Trp107Ter suggested that truncation of the protein sequence after residue W107 would break up helix α3, resulting in the absence of the C-terminal part of α3, β5, α4, β6, and α5. Missing structural elements β5, β6, and α5 would most probably result in failure to fold correctly or bind GTP/GDP causing degradation.

Case#: Patient 2, male, 33 (at report), 6 years old at onset

CaseHPOs: HP:0000613, HP:0007663, HP:0000551 (photophobia, reduced visual acuity, color vision defect)

CaseHPOsFreeText: BCVA LogMAR 1 for both eyes, refractive error −4.25 sph −2.00 cyl/180° D in right eye and −4.00 sph −2.50 cyl/30° D in left eye. The fundus exam showed normal optic disk, signs of foveal atrophy, and “salt and pepper” peripheral retinopathy. Fundus autofluorescence revealed a dark central area due to the absence of the RPE surrounded by an unusual hyperfluorescent perifoveal ring in both eyes while infrared retinography showed foveal atrophy. OCT imaging revealed a marked reduction of the foveal thickness associated with a photoreceptor layer disruption (Figure 3). Goldmann visual field test showed central scotoma with a mild peripheral constriction.

CaseNotHPOs:

CasePreviousTesting: None mentioned but note that, in this study, DNA from all patients was analyzed by CORD NGS panel.

CaseMethod1: NGS panel

CaseGenotypingMethod: CORD NGS panel - ABCA4, ADAM9, AIPL1, C8orf37, CFAP410 (C21orf2), CACNA1F, CACNA2D4, CDHR1, CEP78, CNGA3, CRX, DRAM2, GUCA1A, GUCY2D, UNC119, IFT81, KCNV2, PDE6C, PITPNM3, POC1B, PROM1, PRPH2, RAB28, RAX2, RIMS1, RPGR, RPGRIP1, SEMA4A, TTLL5.

Variant: c.37del (p.Leu13Ter) homozygous

ClinVar: N/A

CAID: CA2860243

gnomAD: The highest MAF in gnomAD v2.1.1 is 0.00003019 in European non-Finnish (no homozygotes in any population)

VariantEvidence: The variant would either result in nonsense-mediated mRNA decay, or retain few of the structural elements required for correct folding, causing degradation.

CaseAddInfo: Patient 3 is the affected sister of Patient 2. She is affected but has a milder phenotype. The father of these individual is unaffected and heterozygous for the variant. No details are provided about the mother.

PMID: 9501220

Gene: RPE65

HGNC: 10294

Disease: Retinitis pigmentosa 20

MONDO: 0013425

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of recessive Retinitis pigmentosa caused by RPE65 variants is ~2%. (PMID: 9501220) Thus, the prevalence of Retinitis pigmentosa 20 is between 1 in 150,000 and 1 in 200,000.

Penetrance: Fully penetrant, with onset typically in childhood

ExperimentName: The rds mouse harbors loss-of-function variants in the Prph2 gene.

NonHumanModel: Mus musculus

GeneAlteration: The model animals are homozygous for a loss-of-function variant in the Prph2 locus known as retinal degeneration slow (rds). The causal variant appears to encode a p.Gln340Pro missense change that results in the inability to detect the Prph2 protein by antibody.

ModelPhenotype: HP:0000546 (Retinal degeneration), HP:0030610 (Photoreceptor outer segment loss on macular OCT)

HumanPhenotype: HP:0030643 (Vitelliform-like retinal lesions), HP:0000533 (Chorioretinal atrophy), HP:0001105 (Retinal atrophy), HP:0007663 (Reduced visual acuity), HP:0000580 (Pigmentary retinopathy), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0008275 (Abnormal light-adapted electroretinogram), HP:0007843 (Attenuation of retinal blood vessels), HP:0011506 (Choroidal neovascularization), HP:0030499 (Macular drusen)

ModelEvidence: This is a naturally occurring mouse model with homozygous disruption of the Prph2 locus. Phenotypes include progressive degeneration of retina, absence of rods at age 7-10 months, and reduction of the number of rows of photosensitive cell nuclei to only 1-4 rows (described in previous publications PMID: 705766 and PMID: 419532). Other previous publications have reported that the mice exhibit abnormal development of photoreceptor outer segments, as well as subsequent gradual photoreceptor degeneration of photoreceptors that is complete by age 1 year (PMID: 2918924).

ModelVariant: This model did not introduce a disease-associated variant known from an affected human patient, but rather studied a naturally occurring p.Gln340Pro missense variant disrupting the Prph2 locus.

PMID: 28211458

Gene: GPR143

HGNC: 20145

Disease: X-linked recessive ocular albinism

MONDO: 0021019

InheritancePattern: X-linked recessive

Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)

Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.

PMID: 15346351

Gene: LRP5

HGNC: 6697

Disease: osteoporosis-pseudoglioma syndrome

MONDO: 0009820

InheritancePattern: autosomal recessive

Prevalence: osteoporosis-pseudoglioma syndrome is estimated to occur in 1 out of every 2,000,000 live births.

Penetrance: The penetrance of the phenotype among homozygous or compound heterozygous cases appears to be complete, while heterozygous carriers of deleterious variants appear to be mildly affected.

Case#: Kelsell_1998_CORD6_Family_2_Proband, female, age 45 at time of report, nationality listed as British

CasePresentingHPOs: HP:0007401 (Macular atrophy), HP:0000548 (Cone/cone-rod dystrophy)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Sanger sequencing of PCR products from each of the 18 exons of the GUCY2D locus

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

CaseGenotypingMethod: The proband and her family members were subjected to sequencing of PCR products from each of the 18 exons of the GUCY2D locus. The PCR-amplified product from exon 13 was then subjected to HhaI restriction digest and resolved by agarose gel electrophoresis.

Variant: The proband harbors the NM_000180.4(GUCY2D):c.2512C>T (p.Arg838Cys) variant in the heterozygous state.

ClinVar: 9355

gnomAD: The variant is present in gnomAD at a frequency of 0.000007744 (1/129124) in the European non-Finnish population, with no homozygotes. https://gnomad.broadinstitute.org/variant/17-7918018-C-T

VariantEvidence: NM_000180.4(GUCY2D):c.2512C>T (p.Arg838Cys) is a missense variant located within the coiled-coil domain that mediates GUCY2D dimerization. Codon 838 has proven to be a hot spot disrupted in other families similarly affected with autosomal dominant cone-rod dystrophy (PMID: 11115851, PMID: 12552567, PMID: 26298565). The p.Arg838Cys substitution has been shown to disrupt the calcium sensitivity of GUCY2D and to trigger the inability to inactivate cyclase activity at high physiological calcium ion concentrations (PMID: 11115851).

CaseAddInfo: N/A

CasePMIDs: N/A

ExperimentName: Oxidative stress sensitivity in the homozygous Timp3Ser179Cys Knock-In Mouse

NonHumanModel: Mus musculus (C57Bl/6J background)

GeneAlteration: The gene alteration was constructed in a previous paper (PMID:12147610), in which the mouse Timp3 ortholog was subjected to site-directed mutagenesis to introduce a change equivalent to the human variant encoding the Ser179Cys substitution associated with Sorsby Fundus Dystrophy (PMID:8634721). This variant was introduced into embryonic stem cells by homologous recombination, generating animals for germline transmission of the Timp3Ser179Cys knock-in allele of interest.

ModelPhenotype: HP:0000580 (Pigmentary retinopathy), HP:0007703 (Abnormality of retinal pigmentation)

HumanPhenotype: HP:0007703 (Abnormality of retinal pigmentation)

ModelEvidence: The phenotypes of this model system recapitulate some of the degenerative features of the human model. Sensitivity to oxidative stress was revealed when low-dose sodium iodate triggered RPE degeneration and disorganization in the Timp3 S179C/S179C mice but not the wild-type controls (Figure 4). Rhodamine-phalloidin staining also exhibited an increased area of degeneration in the central region of the RPE in mutant mice but not in the wild-type controls (Figure 5). It is important to point out the caveat that the mice were homozygous for Timp3 Ser179Cys, whereas human patients are heterozygous. This difference in genotype introduces the possibility of loss-of-function effects that are specific to the mouse but absent from the human patients.

ModelVariant: The model variant is a knock-in modification to the mouse Timp3 ortholog that is equivalent to the human NM_000362.5(TIMP3):c.536C>G, (p.Ser179Cys) missense variant (ClinVar:12678).

Case#: P6-PS, F, Age of Report: 26 y.o., Ethnicity: Palestinian origin.

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy/Retinitis pigmentosa), HP:0011505 (Cystoid macular edema), HP:0007663 (Reduced visual acuity), HP:0007787 (Posterior subcapsular cataract), HP:0008542 (Low-frequency hearing loss), HP:0012713 (Moderate hearing impairment),

CaseHPOFreeText: P6-PS is a 26-year-old male patient and was the only affected individual in a consanguineous family of Palestinian origin (Fig. 1d).

He presented the clinical features of RP, with vessel attenuation, RPE dystrophy without BSP, and CME in both eyes (Fig. 2d). He had a visual acuity of 0.5 D in both eyes, posterior subcapsular cataract and unrecordable ERG responses (Table 2). He also complained of mild-to-moderate hearing loss at low to mid frequencies (Fig. 3).

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_021831.6:c.170G>A (p.Trp57Ter).

ClinVar: N/A.

CAID: CA346167763.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case: Gliem_2000_Family_1_patient_II.1, female, country of origin Germany, onset at 47 years of age

DiseaseAssertion: Sorsby's fundus dystrophy

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

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0007663 (Reduced visual acuity), HP:0011510 (Drusen), HP:0000533 (Chorioretinal atrophy)

CaseHPOFreeText: Presentation at age 47 with nyctalopia. Evaluation at age 61 showed drusen deposits in macular area, near optic disk and along vascular arcades, central and midperipheral atrophy, and reduced choroidal thickness.

CaseNOTHPOs: HP:0011506 (Choroidal neovascularization)

CaseNOTHPOFreeText: N/A

CasePreviousTesting: Phenotypic characterization only

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

PreviouslyPublished: N/A

SupplementalData: N/A

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

CAID: CA411540328

gnomAD: Variant is absent from gnomAD.

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

Group Phenotypes

GroupName: Gliem_2015_Group_1

GroupPresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0000533 (Chorioretinal atrophy), HP:0000662 (Nyctalopia)

GroupHPOFreeText: Central and midperipheral atrophy, Central fibrosis, Dark adaptation problems, Progressive loss of visual acuity

GroupNotHPOs: N/A

GroupDemographics

NumberMales: 7

NumberFemales: 13

CountryOrigin: Germany

Ethnicity: Not mentioned

Race: Not mentioned

AgeRange: 52-79 at time of evaluation

TotalNumber: 20

GroupPreviousTesting: N/A

GroupGenotypingMethod Sanger sequencing of PCR products from all 5 exons and flanking splice junctions of the TIMP3 gene.

GroupAddInfo: The group consisted of 3 unrelated families.

PMID: 25766588

Gene: TIMP3

HGNC: 11822

Disease: Sorsby fundus dystrophy (SFD), also known as Sorsby's fundus dystrophy, Sorsby pseudoinflammatory fundus dystrophy, or hemorrhagic macular dystrophy

MONDO: 0007640

InheritancePattern: Autosomal Dominant

Prevalence: Estimated at 1 in 220,000 (PMID: 28847738)

Penetrance: Fully penetrant, onset between the third and sixth decades of life

PMID: 24167615

Gene: TRPM1

HGNC: 7146

Disease: congenital stationary night blindness 1C

MONDO: MONDO:0013183

InheritancePattern: autosomal recessive

Prevalence: Congenital stationary night blindness has an estimated prevalence between 1 in 6,000 (PMID: 31427709) and 1 in 300,000 (PMID: 3487908). However, the prevalence of congenital stationary night blindness 1C specifically is unknown.

Penetrance: Penetrance is thought to be complete.

ExperimentName: Horse model of TRPM1 loss-of-function

NonHumanModel: Equus ferus caballus

GeneAlteration: The horse has homozygous disruption of the TRPM1 gene by a naturally occurring insertion of a 1378 bp transposon in intron 1 (g. 108,297,929_108,297,930 ins1378). A previous publication by the same group has shown that TRPM1 expression is absent from the skin and retina of these horses (PMID: 18660533).

ModelPhenotype: HP:0001053 (Hypopigmented skin patches), HP:0000591 (Abnormal sclera morphology), HP:0000662 (Nyctalopia), HP:0007984 (Electronegative electroretinogram),

HumanPhenotype: HP:0000662 (Nyctalopia), HP:0000545 (Myopia), HP:0000572 (Visual loss), HP:0007984 (Electronegative electroretinogram), HP:0000958 (Dry skin), HP:0000964 (Eczema)

ModelEvidence: The affected horses exhibit night blindness and abnormal dark-adapted ERG with absent b-wave and increased amplitude of a-wave (Figure 1). Both phenotypes are similar to the affected human patients. Melanocyte dysfunction is also shown by unpigmented areas of the skin (Figures 1 and 2) and the sclera of the eye (Figure 2A). These pigment phenotypes do not have a human equivalent, although some affected patients have been reported to have dry skin or a history of eczema (PMID: 19878917).

ModelVariant: The model harbors a naturally occurring variant that does not have an equivalent / orthologous variant reported in human patients.

PMID: 12077706

GeneName: GNAT2

HGNC: 4394

Disease: achromatopsia 4

MonDO ID: MONDO_0013465

Inheritance: autosomal recessive

PMID: 16055928

Gene: RPGR

HGNC: 10295

Disease: RPGR-related retinopathy

MONDO: MONDO:0100437

InheritancePattern: X-linked

Prevalence: The prevalence of RPGR-related retinopathy is calculated to be approximately 1 in 214,000, based on the known incidence of retinitis pigmentosa at 1 in 3,000, the proportion of retinitis pigmentposa that is X-linked at 20%, and the proportion of X-linked retinitis pigmentosa that is RPGR-associated at 70% (PMID: 34985506).

Penetrance: Penetrance is nearly 100% in hemizygous males but is incomplete and dependent upon the variant in heterozygous female carriers.

PMID: 25001182

Gene: PRPH2

HGNC: 9942

Disease: retinitis pigmentosa 7

MONDO: 0011974

InheritancePattern: semi-dominant

Prevalence: The incidence of PRPH2-related cases among inherited retinal dystrophies is reported to range from 3.5% in North America to 10.3% in France (PMID: 36010202).

Penetrance: The penetrance among biallelic cases appears to be complete, while the monoallelic cases exhibit incomplete penetrance (PMID: 36609934).

ExperimentName: Knockin of the p.Tyr141Cys variant into mouse Prph2 results in retinal defects.

NonHumanModel: Mus musculus

GeneAlteration: The model animals are heterozygous for knock-in of the p.Tyr141Cys variant into the Prph2 locus.

ModelPhenotype: HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0000546 (Retinal degeneration), HP:0030610 (Photoreceptor outer segment loss on macular OCT), HP:0012045 (Retinal flecks)

HumanPhenotype: HP:0030643 (Vitelliform-like retinal lesions), HP:0000533 (Chorioretinal atrophy), HP:0001105 (Retinal atrophy), HP:0007663 (Reduced visual acuity), HP:0000580 (Pigmentary retinopathy), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0008275 (Abnormal light-adapted electroretinogram), HP:0007843 (Attenuation of retinal blood vessels), HP:0011506 (Choroidal neovascularization), HP:0030499 (Macular drusen)

ModelEvidence: This knock-in mouse model has normal expression and localization of Prph2 (Fig. 1), but exhibits phenotypes including photoreceptor outer segment loss (Fig. 2), decreased rod ERG (Fig. 3A), and photoreceptor layer degeneration (Fig. 4). Homozygous mice showed decreased cone ERG as well (Figs. 3B, 3C). Yellow retinal flecks were observed in the fundus (Fig. 5). Abnormal high molecular weight complexes containing Prph2 were also observed in western blotting, along with the absence of normal monomers and dimers in the homozygous animals (Figs. 6 and 7).

ModelVariant: This mouse model has introduced a disease-associated variant known from an affected human patient, NM_000322.5(PRPH2):c.422A>G (p.Tyr141Cys), ClinVar ID: 98666.

ExperimentName: Phenotypic characterization of the homozygous Timp3-/- Knock-Out Mouse

NonHumanModel: Mus musculus (C57/Bl6 or CD1 background)

GeneAlteration: A neomycin resistance expression cassette was cloned into plasmid-borne exon 3 of mouse Timp3. The linearized construct was transfected into embryonic stem cells and injected into blastocysts. Animals that had undergone homologous recombination were identified by locus-specific genomic PCR reactions. Predicted loss of Timp3 due to a premature stop codon and nonfunctional mRNA was confirmed at the protein level.

ModelPhenotype: HP:0030605 (Abnormal indocyanine green angiography), HP:0025568 (Abnormal morphology of the choroidal vasculature), HP:0030979 (Dilatation of large choroidal vessels)

HumanPhenotype: HP:0011506 (Choroidal neovascularization)

ModelEvidence: The model showed dilatation of the large choroid vessels, which appeared large and hyperfluorescent during ICG angiography, with balloon-like spots (Figure 3A-3B). While wild-type controls exhibited normal choroidal blood vessel network, Timp3-/- animals had abnormal vessel formations that were strongly dilated or fused (Figures 3C-3H). During in situ zymography, higher local fluorescence intensity indicated increased MMP2 and MMP9 activity in the knockout animals, as expected. Aortic explants from knockout mice showed higher spontaneous microvessel outgrowth than their counterparts from wild-type mice (Figure 6). Rescue assays suggest that the antiangiogenic activity requires the C-terminal region of TIMP3 (Figure 7).

ModelVariant: N/A (Timp3 knockout)

ExperimentName: Knock-in of the p.M390R variant into the mouse Bbs1 gene.

NonHumanModel: Mus musculus

GeneAlteration: The model animals have been subjected to homologous recombination-based knock-in of the p.M390R variant into exon 12 of the endogenous mouse Bbs1 gene. The variant has been studied in the homozygous state.

ModelPhenotype: HP:0032558 (Absent sperm flagella), HP:0010633 (Partial anosmia), HP:0012433 (Abnormal social behavior), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0030610 (Photoreceptor outer segment loss on macular OCT), HP:0030609 (Photoreceptor layer loss on macular OCT), HP:0001513 (Obesity), HP:0002119 (Ventriculomegaly),

HumanPhenotype: HP:0000639 (Nystagmus), HP:0000510 (Rod-cone dystrophy), HP:0007663 (Reduced visual acuity), HP:0000662 (Nyctalopia), HP:0000518 (Cataract), HP:0008323 (Abnormal light- and dark-adapted electroretinogram), HP:0000107 (Renal cyst), HP:0001513 (Obesity), HP:0010442 (Polydactyly), HP:0002463 (Language impairment), HP:0000026 (Male hypogonadism)

ModelEvidence: Sperm flagella were absent (Figures 2A, 2B). Loss of the outer nuclear layer and degeneration of the photoreceptor inner and outer segments were observed in older mice (Figures 2C, 2D). Photoreceptor morphology in the outer segment was also disrupted in TEM images (Figure 2E). Scotopic responses showed a- and b-wave attenuation (Figure 2G), while photopic responses were not significantly different (Figure 2H). Homozygous mice showed obesity relative to wild-type and heterozygous mice (Figure 3). Brain sections showed neuroanatomical defects, especially ventriculomegaly (Figure 4). Brain cilia were morphologically abnormal (Figure 5). Renal cysts and polydactyly were investigated but not observed.

ModelVariant: This model introduced a disease-associated variant known from affected human patients (NM_024649.5(BBS1):c.1169T>G (p.Met390Arg), ClinVar ID: 12143).

PMID: 9529334

Gene: GPR143

HGNC: 20145

Disease: X-linked recessive ocular albinism

MONDO: 0021019

InheritancePattern: X-linked recessive

Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)

Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.

ExperimentName: Mouse model of Adam9 loss-of-function

NonHumanModel: Mus musculus

GeneAlteration: The mice harbor homozygous knockout of the Adam9 gene by an insertion of a neomycin selection cassette in to the exon encoding amino acids 32 to 66 of Adam9 (PMID: 11839819).

ModelPhenotype: HP:0000546 (Retinal degeneration), HP:0007703 (Abnormality of retinal pigmentation), HP:0030610 (Photoreceptor outer segment loss on macular OCT), HP:0030483 (Reduced amplitude of dark-adapted bright flash electroretinogram a-wave), HP:0007984 (Electronegative electroretinogram), HP:0008323 (Abnormal light- and dark-adapted electroretinogram)

HumanPhenotype: HP:0410280 (Pediatric onset), HP:0007663 (Reduced visual acuity), HP:0007401 (Macular atrophy), HP:0000580 (Pigmentary retinopathy), HP:0007769 (Peripheral retinal degeneration), HP:0008323 (Abnormal light- and dark-adapted electroretinogram), HP:0000548 (Cone/cone-rod dystrophy), HP:0007994 (Peripheral visual field loss), HP:0000545 (Myopia)

ModelEvidence: The affected mice exhibit an abnormal gap between the RPE and the photoreceptor outer segment, which would normally be in contact (Figure 5B). The gap contains macrophages (Figure 5L). Outer nuclear layer thinning is observed (Figure 5D), as well as material deposited between the RPE and Bruch's membrane, which may be analogous to drusen deposits in humans (Figure 5K). These findings collectively show an adhesion defect at the interface between the photoreceptor outer segment and the RPE. This evidence of retinal degeneration was complemented by abnormalities in both rod- and cone-driven ERG responses (Figure 4), matching a feature of the human patients.

ModelVariant: The model harbors a targeted disruption that does not have an equivalent / orthologous variant reported in human patients.

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

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

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

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

CaseNotHPOFreeText: N/A

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

CaseMethod1: Autozygosity mapping

CaseMethod2: Sanger sequencing

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

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

ClinVar: 6877

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

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

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

CasePMIDs: N/A

Case#: Olivier_2021_Family_K_Proband_II:3, male, age 43 years at the time of onset, national origin reported as Spanish

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0001099 (Fundus atrophy), HP:0007737 (Bone spicule pigmentation of the retina)

CaseHPOFreeText: The proband has onset of retinitis pigmentosa at the age of 43 years.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: It is not clear whether previous testing methods included systematic genotyping of loci associated with VMD or RP.

CaseMethod1: Screening of IMPG1 using either gene panel testing or exome sequencing

CaseMethod2: Sanger sequencing-based confirmation

CaseGenotypingMethod: Genotyping is not entirely clear but has at least included panel-based analysis of the IMPG1 locus and Sanger sequencing-based confirmation.

Variant: The proband harbors the NM_001563.4(IMPG1):c.1982G>A (p.Arg661His) variant in the homozygous state.

ClinVar ID: 1056230

gnomAD: The NM_001563.4(IMPG1):c.1982G>A (p.Arg661His) variant is found in gnomAD v2.1.1 at a frequency of 0.00004006 (1/24964) in the African / African-American population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/6-76657093-C-T

VariantEvidence: NM_001563.4(IMPG1):c.1982G>A (p.Arg661His) is a missense variant, which does not have experimental evidence of a functional effect on the protein product.

CaseAddInfo: The patient's affected sister shares the same homozygous genotype.

CasePMIDs: N/A

Case#: Olivier_2021_Family_H_Proband_II:1, male, age 53 years at the time of diagnosis, national origin reported as French

CasePresentingHPOs: HP:0007401 (Macular atrophy), HP:0007737 (Bone spicule pigmentation of the retina)

CaseHPOFreeText: The proband has been diagnosed with maculopathy at the age of 53 years, and exhibits retinal discoloration.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: It is not clear whether previous testing methods included systematic genotyping of loci associated with VMD or RP.

CaseMethod1: Screening of IMPG1 using either gene panel testing or exome sequencing

CaseMethod2: Sanger sequencing-based confirmation

CaseGenotypingMethod: Genotyping is not entirely clear but has at least included panel-based analysis of the IMPG1 locus and Sanger sequencing-based confirmation.

Variant: The proband harbors the NM_001563.4:c.2083G>T (p.Glu695Ter) variant in the heterozygous state.

CAID: CA364770054

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

VariantEvidence: NM_001563.4:c.2083G>T (p.Glu695Ter) is a nonsense variant in exon 15 of 17, which is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 13% of the protein product.

CaseAddInfo: The patient's brother is an unaffected carrier of the variant.

CasePMIDs: N/A

PMID: 23418020

Gene: IFT140

HGNC: 29077

Disease: short-rib thoracic dysplasia 9 with or without polydactyly

MONDO: 0009964

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of short-rib thoracic dysplasia is estimated to be between 1 in 100,000 and 1 in 130,000 births (PMID: 931421).

Penetrance: Disease caused by biallelic IFT140 variants appears to be fully penetrant.

PMID: 29847651

Gene: GPR143

HGNC: 20145

Disease: X-linked recessive ocular albinism

MONDO: 0021019

InheritancePattern: X-linked recessive

Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)

Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.

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

PMID: 24876279

Gene: IMPG2

HGNC: 18362

Disease: retinitis pigmentosa 56

MONDO: 0013314

InheritancePattern: semi-dominant

Prevalence: Vitelliform macular dystrophy in general is estimated to have a prevalence of 1 in 5,500 (PMID: 27120116).

Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete, while heterozygous carriers of deleterious variants show incomplete penetrance and variable expressivity.

FamilyLabel: van_Huet_2014_Family_A, national origin reported as Dutch

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

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

Family#PresentingNotHPOs: N/A

CountryOrigin: Netherlands

Ethnicity: Reported as Dutch

Race: Not mentioned

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

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

Family#Method2: N/A

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

Affected: 3

Unaffected: 3

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

PublishedLOD: N/A

eLOD: 1.50

AddSegregationInfo: N/A

ProbandLabel: van_Huet_2014_Patient_A-II:1

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

ClinVar: 3547

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

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

FamilyPMIDs: N/A

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

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

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

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

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: N/A

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

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

ClinVar: 437938

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

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

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

CasePMIDs: PMID: 20673862