FamilyLabel: Kajiwara_1991_Family_6935, family national origin not reported

Family#PresentingHPOs: Decreased light- and dark-adapted electroretinogram amplitude HP:0000654

FamilyHPOFreeText: The patient and affected family members have been diagnosed with retinitis pigmentosa.

Family#PresentingNotHPOs: N/A

Family#PresentingNotHPOFreeText: N/A

CountryOrigin: N/A

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: Previous testing consisted of screening of the RHO locus for disease-causing variants.

Family#Method1: Single strand conformation polymorphism analysis of PCR-amplified cDNA products from the PRPH2 gene, followed by Sanger sequencing of the relevant PCR product to identify the variant

Family#Method2: SSCP to genotype family members

Family#GenotypingMethod: Previous testing of this family screening of the RHO locus for variants causing RP, with negative results. Genotyping started with single strand conformation polymorphism analysis of PCR-amplified products from the PRPH2 gene, followed by Sanger sequencing of the relevant PCR product to identify the variant. SSCP was subsequently performed to genotype family members.

Affected: 3

Unaffected: 5

Segregations: Two segregations are reported in the family, with none inconsistent. The family is not reported to be consanguineous. The pedigree is shown in Figure 3c.

PublishedLOD: N/A

eLOD: 2.40

AddSegregationInfo: N/A

ProbandLabel: Kajiwara_1991_Family_6935_Proband

Variant: The affected family members harbor the NM_000322.5(PRPH2):c.554T>C (p.Leu185Pro) variant in the heterozygous state.

ClinVarID: 13165

gnomAD: This variant was found in gnomAD v4.0.0 at a frequency of 0.00003587 (15 alleles / 418142 total alleles, with no homozygotes) in the European non-Finnish population https://gnomad.broadinstitute.org/variant/6-42721781-A-G?dataset=gnomad_r4

FamilyAddInfo: The family has not been reported as consanguineous.

FamilyPMIDs: N/A

FamilyLabel: Kajiwara_1991_Family_6948, family national origin not reported

Family#PresentingHPOs: Decreased light- and dark-adapted electroretinogram amplitude HP:0000654

FamilyHPOFreeText: The patient and affected family members have been diagnosed with retinitis pigmentosa.

Family#PresentingNotHPOs: N/A

Family#PresentingNotHPOFreeText: N/A

CountryOrigin: N/A

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: Previous testing consisted of screening of the RHO locus for disease-causing variants.

Family#Method1: Single strand conformation polymorphism analysis of PCR-amplified cDNA products from the PRPH2 gene, followed by Sanger sequencing of the relevant PCR product to identify the variant

Family#Method2: SSCP to genotype family members

Family#GenotypingMethod: Previous testing of this family screening of the RHO locus for variants causing RP, with negative results. Genotyping started with single strand conformation polymorphism analysis of PCR-amplified products from the PRPH2 gene, followed by Sanger sequencing of the relevant PCR product to identify the variant. SSCP was subsequently performed to genotype family members.

Affected: 8

Unaffected: 7

Segregations: Eight segregations are reported in the family, with none inconsistent. The family is not reported to be consanguineous. The pedigree is shown in Figure 3b.

PublishedLOD: N/A

eLOD: 2.40

AddSegregationInfo: N/A

ProbandLabel: Kajiwara_1991_Family_6948_Proband

Variant: The affected family members harbor the NM_000322.5(PRPH2):c.647C>T (p.Pro216Leu) variant in the heterozygous state.

ClinVarID: 13164

gnomAD: This variant was found in gnomAD v4.0.0 at a frequency of 0.000002856 (1 allele / 350108 total alleles, with no homozygotes) in the European non-Finnish population https://gnomad.broadinstitute.org/variant/6-42704546-G-A?dataset=gnomad_r4

FamilyAddInfo: The family has not been reported as consanguineous.

FamilyPMIDs: N/A

PMID: 23143442

Gene: BBS1

HGNC: 966

Disease: Bardet-Biedl syndrome 1

MONDO: 0008854

InheritancePattern: autosomal recessive

Prevalence: The prevalence of BBS1 variants among Bardet-Biedl syndrome cohorts has been reported as at least 20% (PMID: 19402160), while the prevalence of Bardet-Biedl syndrome overall has been estimated between 1 in 13,500 and 1 in 160,000 live births, depending on the population (PMID: 22713813).

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

PMID: 23580486

GeneName: GNAT2

HGNC: 4394

Disease: achromatopsia 4

MonDO ID: MONDO_0013465

Inheritance: autosomal recessive

PMID: 30668888

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

Case: Naessens_2019_Family_2_Patient_II:1, female, age of onset 53 years old, country of origin France (northern)

DiseaseAssertion: Sorsby's fundus dystrophy

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

CasePresentingHPOs: HP:0011510 (Drusen), , HP:0000572 (Visual loss), HP:0007401 (Macular atrophy), HP:0007769 (Peripheral retinal degeneration), HP:0011506 (Choroidal neovascularization), HP:0007777 (Chorioretinal scar)

CaseHPOFreeText: Relatively late onset of phenotypes (at age 53, presenting with nyctalopia). Drusen was described as widespread and partially calcified. Macular atrophy was patchy, with round atrophic patches outside the vascular arcades.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: Pulmonary involvement

CasePreviousTesting: N/A

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

PreviouslyPublished: N/A

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

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

ClinVar: 843268

gnomAD: Variant is absent from gnomAD.

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

PMID: 11879143

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: 9295268

Gene: ABCA4

HGNC: 34

Disease: age related macular degeneration 2

MONDO: 0007932

InheritancePattern: autosomal dominant

Prevalence: The overall prevalence of age-related macular degeneration is estimated to be 9.9-19.5% (early-stage) or 1.1-3.9% (late-stage) among all people over age 50 years (PMID: 31712255).

Penetrance: The penetrance of proposed disease-causing alleles is not clear but is expected to be incomplete and age-dependent.

PMID: 2280973

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: Lebrun_2009_Family_1

Family#PresentingHPOs: HP:0001251 (Ataxia), HP:0001250 (Seizure), HP:0002463 (Language impairment), HP:0011463 (Childhood onset),

Family#PresentingHPOFreeText: Abnormalities on brain MRI scan

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: United Kingdom

Ethnicity: Family is of Pakistani ethnic origin.

Race: N/A

Family#PreviousTesting: 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.

Family#Method1: 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.

Family#Method2: N/A

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

Affected: 2

Unaffected: 1

Segregations: 1 segregation is reported in the family.

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Lebrun_2009_Patient_1

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

ClinVar: 56526

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

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

FamilyPMIDs: N/A

PMID: 18523664

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.

Case#: Zhou_2008_Patient_III:22, male, age of onset not reported, family origin reported to be from China

CasePresentingHPOs: HP:0000639 (Nystagmus), HP:0000646 (Amblyopia)

CaseHPOFreeText: The proband has been diagnosed with congenital nystagmus.

CaseNotHPOs: HP:0040030 (Chorioretinal hypopigmentation)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genotyping was initially performed by linkage mapping using 26 short tandem repeat markers on the X chromosome.

CaseMethod1: linkage analysis

CaseMethod2: Sanger sequencing

CaseGenotypingMethod: Genotyping was initially performed by linkage mapping using 26 short tandem repeat markers on the X chromosome, followed by Sanger sequencing of PCR products from each exon of the GPR143 gene.

Variant: The proband harbors the NM_000273.3(GPR143):c.162_198del (p.Ala55fs) variant in the hemizygous state.

ClinVar: 10524

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

VariantEvidence: NM_000273.3(GPR143):c.162_198del (p.Ala55fs) is a frameshift variant in exon 1, and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 87% of the protein product.

CaseAddInfo: The proband is from a family with at least seven other affected males who also harbor the variant.

CasePMIDs: N/A

Case#: Chang_2009_Family_CHRO572_Proband_II:1, male, age and family origin not described

CasePresentingHPOs: HP:0011516 (Achromatopsia)

CaseHPOFreeText: The proband was previously diagnosed with achromatopsia.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and his family members were initially subjected to genotyping of the CNGA3, GNGB3, and GNAT2 loci, confirming absence of causal variants in these known achromatopsia-related genes.

CaseMethod1: Sanger sequencing of CNGA3, GNGB3, and GNAT2

CaseMethod2: Sanger sequencing of the 22 exons and flanking regions of PDE6C

CaseGenotypingMethod: CNGA3, GNGB3, and GNAT2 were previously screened / known not to harbor causal variants for achromatopsia. The family members were then subjected to Sanger sequencing of the 22 exons and flanking regions of PDE6C.

Variant: The proband harbors the NM_006204.4(PDE6C):c.1682dup (p.Tyr561Ter) variant in the homozygous state.

ClinVar ID: 8775

gnomAD: The NM_006204.4(PDE6C):c.1682dup (p.Tyr561Ter) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_006204.4(PDE6C):c.1682dup (p.Tyr561Ter) is a nonsense variant in exon 13 of 22 and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 35% of the protein product.

CaseAddInfo: The patient's parents and sister are each unaffected heterozygous carriers of the variant.

CasePMIDs: N/A

Case#: Mykykyn_2002_Proband_PR5-1, gender not specified, age not described, family origin reported as from Puerto Rico

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: linkage mapping

CaseMethod2: Sanger sequencing of BBS1

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

Variant: The proband harbors the NM_024649.5(BBS1):c.1645G>T (p.Glu549Ter) and NM_024649.5(BBS1):c.432+1G>A variants in the compound heterozygous state.

ClinVar ID: 12144, 12145

gnomAD: The NM_024649.5(BBS1):c.1645G>T (p.Glu549Ter) variant is found in gnomAD v2.1.1 at a frequency of 0.00008675 (3 alleles out of 34584 total alleles, with 0 homozygotes) in the Admixed American population https://gnomad.broadinstitute.org/variant/11-66299163-G-T?dataset=gnomad_r2_1 The NM_024649.5(BBS1):c.432+1G>A variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_024649.5(BBS1):c.1645G>T (p.Glu549Ter) is a nonsense variant in exon 16 of 17 that is predicted to not to trigger nonsense-mediated decay but rather to truncate the C-terminal 8% of the protein product. NM_024649.5(BBS1):c.432+1G>A is a canonical splice site variant in intron 4 that does not have experimental evidence of impact on the gene product.

CaseAddInfo: The proband's family has not been described as consanguineous.

CasePMIDs: N/A

Case#: Mykykyn_2002_Proband_PR3-1, gender not specified, age not described, family origin reported as from Puerto Rico

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: linkage mapping

CaseMethod2: Sanger sequencing of BBS1

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

Variant: The proband harbors the NM_024649.5(BBS1):c.1645G>T (p.Glu549Ter) and NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) variants in the compound heterozygous state.

ClinVar ID: 12144, 12143

gnomAD: The NM_024649.5(BBS1):c.1645G>T (p.Glu549Ter) variant is found in gnomAD v2.1.1 at a frequency of 0.00008675 (3 alleles out of 34584 total alleles, with 0 homozygotes) in the Admixed American population https://gnomad.broadinstitute.org/variant/11-66299163-G-T?dataset=gnomad_r2_1 gnomAD: The NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) variant is found in gnomAD v2.1.1 at a frequency of 0.002773 in the European (non-Finnish) population, with 358 alleles / 129114 total alleles (0 homozygotes) https://gnomad.broadinstitute.org/variant/11-66293652-T-G?dataset=gnomad_r2_1

VariantEvidence: NM_024649.5(BBS1):c.1645G>T (p.Glu549Ter) is a nonsense variant in exon 16 of 17 that is predicted to not to trigger nonsense-mediated decay but rather to truncate the C-terminal 8% of the protein product. NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) is a missense variant with mouse knock-in evidence of a similar disease-causing effect in the homozygous state (PMID: 18032602). This has not been taken into account in scoring, as the mouse model has been scored separately. However, it has provided a rationale not to down-score for the relatively high gnomAD frequency of this variant.

CaseAddInfo: The proband's family has not been described as consanguineous.

CasePMIDs: N/A

Case#: Xin_Patient_6, sex not mentioned, age 8 at onset, Swedish nationality

CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0003621 (Juvenile onset), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material)

CaseHPOFreeText: Motor difficulty was the phenotype at presentation (age 8). Seizures (age 8), Visual loss (age 12), and Cognitive regression (age 11) subsequently developed. Curvilinear inclusions were observed in the skin specifically.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: as mentioned

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

Variant: The patient harbors the NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) and NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) variants, as well as the likely benign NM_006493.4(CLN5):c.381T>G (p.Thr127=) variant.

ClinVar: 2565, 56543, 128783

gnomAD: Maximum allele frequency for NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) is 0.00005132 (in the European non-Finnish population, no homozygotes). https://gnomad.broadinstitute.org/variant/13-77566311-G-A Maximum allele frequency for NM_006493.4(CLN5):c.522dup (p.Trp175fs) is 0.00007033 (in the European non-Finnish population, no homozygotes). Maximum allele frequency for the NM_006493.4(CLN5):c.381T>G (p.Thr127=) variant is 0.06570 (in the East Asian population, 48 homozygotes) https://gnomad.broadinstitute.org/variant/13-77570078-T-G

VariantEvidence: The NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) nonsense variant is likely to be subject to nonsense mediated decay. The NM_006493.4(CLN5):c.522dup (p.Trp175fs) frameshift variant is predicted to truncate ~51% of the protein. On the other hand, the synonymous NM_006493.4(CLN5):c.381T>G (p.Thr127=) variant appears unlikely to have a gene impact.

CaseAddInfo: Parents do not appear to have been genotyped, so it is unclear whether the two variants with predicted gene impact have been shown or simply assumed to be in trans. The same is true for the benign, synonymous variant.

CasePMIDs: N/A

Case#: Brandl_2017_Family_13-501_Proband_#1, male, age 13 years at time of report, national origin reported as German

CasePresentingHPOs: HP:0007677 (Vitelliform-like macular lesions), HP:0007663 (Reduced visual acuity, 0.1 to 0.2 logMAR), HP:0007703 (Abnormality of retinal pigmentation, particularly in the center), HP:0000493 (Abnormal foveal morphology, specifically foveal detachment)

CaseHPOFreeText: The patient has been diagnosed with vitelliform macular dystrophy with onset in early childhood. The abnormal foveal morphology refers specifically to foveal detachment.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing appears to have been limited to Sanger sequencing of the BEST1 and PRPH2 loci.

CaseMethod1: Sanger sequencing of the exons and flanking intronic sequences of IMPG1 and IMPG2.

CaseMethod2: N/A

CaseGenotypingMethod: Previous testing appears to have been limited to Sanger sequencing of the BEST1 and PRPH2 loci, while subsequent genotyping included Sanger sequencing of the exons and flanking intronic sequences of IMPG1 and IMPG2.

Variant: The proband harbors the NM_001563.4(IMPG1):c.713T>C (p.Leu238Pro) variant in the heterozygous state.

ClinVar: 865770

gnomAD: The NM_001563.4(IMPG1):c.713T>C (p.Leu238Pro) variant was found in gnomAD v2.1.1 at a frequency of 0.00006598 (2/30310) in the South Asian population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/6-76728530-G-A?dataset=gnomad_r2_1

VariantEvidence: NM_001563.4(IMPG1):c.713T>C (p.Leu238Pro) is a missense variant that does not have evidence confirming an impact on the gene product. However, it has been reported by an independent group of researchers in multiple families with vitelliform macular dystrophy (PMID: 23993198).

CaseAddInfo: The proband is the only family member affected, with clinical and genetic testing data on the parents unavailable.

CasePMIDs: N/A

ExperimentName: LRP5 inhibition using a dominant negative construct blocks bone accrual in mouse calvarial explant culture.

NonPatientCell: CL:0001035 (bone cell, specifically mouse calvarial explant cultures)

GeneFunction: GO:0098868 (bone growth)

GeneAlteration: Calvarial explant cultures from mice were treated with conditioned media from cells exogenously secreting either wild-type LRP5 or dominant negative LRP5deltaTM.

FunctionalEvidence: Bone accrual / thickness decreases significantly at multiple points in mouse calvarial (skull) explants treated with LRP5deltaTM relative to LRP5-WT (Figure 7).

FAVariants: LRP5 function was attenuated using an artificial dominant negative mutant while a human variant was not introduced into the LRP5 gene.

PMID: 11719191

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.

PMID: 29525873

Gene: CABP4

HGNC: 1386

Disease: cone-rod synaptic disorder, congenital nonprogressive

MONDO: 0012490

InheritancePattern: autosomal recessive

Prevalence: The prevalence of the Åland eye disease or incomplete congenital stationary night blindness phenotype was estimated at 1 in 22,000 based on a Danish male cohort, with CABP4 variants specifically responsible for 1 out of 35 cases (PMID: 28002560).

Penetrance: Penetrance appears to be 100% among the reported individuals harboring biallelic disease-causing CABP4 variants.

FamilyLabel: Riazuddin_2006_Three_Families

Family#PresentingHPOs: HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000550 (Undetectable electroretinogram)

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: Pakistan

Ethnicity: Pakistani (reportedly with origin from remote parts of Punjab province)

Race: Not specifically described

Family#PreviousTesting: Genome-wide linkage analysis, with maximum LOD score associated with the D5S2015 microsatellite marker on chromosome 5q31-33.

Family#Method1: Genome-wide linkage analysis

Family#Method2: Sanger sequencing of the candidate gene PDE6A

Family#GenotypingMethod: Genome-wide linkage analysis was initially performed on all four families, with maximum LOD score associated with the D5S2015 microsatellite marker on chromosome 5q31-33. Sanger sequencing was then performed on PCR products of exons and flanking regions from the PDE6A candidate locus.

Affected: 12 genotyped

Unaffected: 7 genotyped

Segregations: 18 segregations are shown by the three pedigrees in Figure 3.

PublishedLOD: 7.4172

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Riazuddin_2006_Family_61019_Proband

Variant: The affected members of Family 61019 harbor the NM_000440.3(PDE6A):c.769C>T (p.Arg257Ter) variant in the homozygous state.

ClinVar: 437984

gnomAD: In gnomAD v2.1.1, NM_000440.3(PDE6A):c.769C>T (p.Arg257Ter) has a frequency of 0.0001633 (5/30612) in the South Asian population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/5-149310680-G-A

VariantEvidence: NM_000440.3(PDE6A):c.769C>T (p.Arg257Ter) is a nonsense variant in exon 4 of 22 that is predicted to trigger nonsense-mediated decay or at least to truncate ~70% of the protein product.

FamilyAddInfo: All three families are reportedly consanguineous.

FamilyPMIDs: N/A

Case: Lin_2006_Family_1_patient_IV-8, female, 62 years of age at presentation, Eastern European Jewish ancestry

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo: N/A

CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0012508 (Metamorphopsia), HP:0011510 (Drusen), HP:0025148 (Dark choroid), HP:0011506 (Choroidal neovascularization), HP:0025094 (Disciform macular scar), HP:0000662 (Nyctalopia), HP:0007703 (Abnormality of retinal pigmentation),

CaseHPOFreeText: Patient presented with central visual field loss and metamorphopsia in one eye, 10 years after a normal results from fundus and vision exam. Fluorescein angiography of the other eye revealed drusen and dark choroid. Choroidal neovascularization progressed to a central disc-shaped scar despite several treatments with argon laser thermal photocoagulation. The less affected eye initially showed mild nyctalopia only, but progressed within 2 years to fibrovascular pigment epithelial detachment, circular blocking lesion, choroidal neovascularization, and visual acuity loss.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: N/A

CasePreviousTesting: Complete ophthalmological exam to define clinical features.

CaseGenotypingMethod: Bidirectional Sanger sequencing of PCR products from exons 1 through 5.

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: NM_000362.5(TIMP3):c.542A>G, p.His181Arg is a missense variant predicted to replace a conserved histidine residue in exon 5 with arginine (conservative substitution).

CAID: CA411540357

gnomAD: Variant is absent from gnomAD.

VariantEvidence: p.His181Arg is a missense variant predicted to replace a conserved histidine residue in exon 5 with arginine (conservative substitution). Molecular modeling predicts that the affected amino acid is located on a protein-protein interaction interface.

Case#: Gu_1997_Family_PMK18_Patient_V-1, male, unknown age, Indian ethnicity

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Linkage analysis

CaseMethod2: PCR products were screened by restriction digest analysis using the Msel endonuclease.

CaseGenotypingMethod: The patient sample was subjected to PCR and Sanger sequencing of all RPE65 exons.

Variant: 4 out of 5 affected individuals are homozygous for the NM_000329.3(RPE65):c.858+1G>T variant.

ClinVar: 98893

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

VariantEvidence:

CaseAddInfo: The family pedigree shows consanguinity in the parents of all affected individuals. One of the affected individuals is a heterozygous carrier of the variant, rather than a homozygote.

CasePMIDs: N/A

PMID: 36440807

Gene: KCNJ13

HGNC: 6259

Disease: snowflake vitreoretinal degeneration

MONDO: 0008663

InheritancePattern: autosomal dominant

Prevalence: The overall prevalence of snowflake vitreoretinal degeneration is ~1 in 1,000,000 (https://www.orpha.net/en/disease/detail/91496).

Penetrance: Known disease-causing alleles appear to be completely penetrant (PMID: 14644728).

PMID: 32531858

Gene: IMPG1

HGNC: 6055

Disease: vitelliform macular dystrophy 4

MONDO: 0014508

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#: Weisschuh_2020_Patient_ARRP_339, male, age 32 years at diagnosis, age 34 years at report, national origin reported as German

CasePresentingHPOs: N/A

CaseHPOFreeText: The patient has been diagnosed with autosomal recessive retinitis pigmentosa.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of next generation sequencing-based RET.8 panel.

CaseMethod1: next generation sequencing-based RET.8 panel

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping was performed using a next-generation sequencing-based RET.8 panel.

Variant: The patient harbors the NM_001563.4(IMPG1):c.1291+1G>T variant in the homozygous state.

ClinVar: 547007

gnomAD: The NM_001563.4(IMPG1):c.1291+1G>T variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_001563.4(IMPG1):c.1291+1G>T is a canonical splice site variant in intron 12 of the 17-exon locus, and does not have evidence of impact on the protein product.

CaseAddInfo: Segregation confirmation in family members is not available.

CasePMIDs: N/A

FamilyLabel: Jiao_2004_Three_Families

Family#PresentingHPOs: N/A

FamilyPresentingHPOFreeText: The affected family members have been diagnosed with familial exudative vitreoretinopathy segregating with an autosomal recessive mode of inheritance.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: Although bone density measurements are not available, at least two of the affected individuals lack bone fractures in the first three decades of life, distinguishing their phenotype from osteoporosis-pseudoglioma syndrome.

CountryOrigin: The three families are reportedly of European descent.

Ethnicity: Not specifically described

Race: The three families are reportedly of European descent.

Family#PreviousTesting: Candidate-locus-directed linkage analysis focused on chromosome 11q, with maximum LOD score of 3.6 associated with the D11S987 microsatellite marker linked to a 311-Mb region.

Family#Method1: Genome-wide linkage analysis

Family#Method2: Sanger sequencing of the candidate gene LRP5

Family#GenotypingMethod: Candidate-locus-directed linkage analysis was initially performed on all three families, focused on chromosome 11q, with maximum LOD score of 3.6 associated with the D11S987 microsatellite marker linked to a 311-Mb region. Sanger sequencing of the candidate gene LRP5 locus was subsequently performed.

Affected: 6 genotyped

Unaffected: 0 genotyped (although 6 unaffected individuals are genotyped but ineligible because they are from previous generations that lack affected members.

Segregations: 3 segregations are shown by the three pedigrees in Figure 1.

PublishedLOD: 3.6

eLOD: N/A

AddSegregationInfo: While none 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: Jiao_2004_Family_68001_Proband, Jiao_2004_Family_68002_Proband, Jiao_2004_Family_68003_Proband

Variant: The affected family members harbor one of the following three variants in homozygous state; NM_002335.4(LRP5):c.2254C>G (p.Arg752Gly), NM_002335.4(LRP5):c.4099G>A (p.Glu1367Lys), or NM_002335.4(LRP5):c.1709G>A (p.Arg570Gln)

ClinVar: 6290, 6291, 6289

gnomAD: NM_002335.4(LRP5):c.2254C>G (p.Arg752Gly) was not found in gnomAD v2.1.1. NM_002335.4(LRP5):c.4099G>A (p.Glu1367Lys) is present in gnomAD v2.1.1. at a frequency of 0.00001760 (2/113626) in the European non-Finnish population https://gnomad.broadinstitute.org/variant/11-68204455-G-A?dataset=gnomad_r2_1 NM_002335.4(LRP5):c.1709G>A (p.Arg570Gln) was not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LRP5):c.2254C>G (p.Arg752Gly) is a missense variant in exon 10 of 23 that does not have experimental evidence of impact on the protein product. NM_002335.4(LRP5):c.4099G>A (p.Glu1367Lys) is a missense variant in exon 19 of 23 that does not have experimental evidence of impact on the protein product. NM_002335.4(LRP5):c.1709G>A (p.Arg570Gln) is a missense variant in exon 8 of 23 that does not have experimental evidence of impact on the protein product.

FamilyAddInfo: All three families are reportedly consanguineous.

FamilyPMIDs: N/A

Case#: Hull_2016_Patient_1.2, male, 18 years of age at onset, Irish ancestry

CasePresentingHPOs: HP:0003581 (Adult onset), HP:0007663 (Reduced visual acuity), HP:0000533 (Chorioretinal atrophy), HP:0000662 (Nyctalopia), HP:0007722 (Retinal pigment epithelial atrophy), HP:0000533 (Chorioretinal atrophy), HP:0030602 (Abnormal fundus autofluorescence imaging), HP:0000510 (Rod-cone dystrophy), HP:0008179 (Decreased Arden ratio of electrooculogram), HP:0000512 (Abnormal electroretinogram)

CaseHPOFreeText: The patient presented at age 18 with nyctalopia, progressed to central visual disturbance at age 33, and was limited to hand movement vision by age 48, with preserved peripheral vision.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: Variants in REP1 and PRPH2 were initially excluded.

CaseMethod1: Candidate gene sequencing

CaseMethod2: Bidirectional, targeted Sanger sequencing within the RPE65 locus

CaseGenotypingMethod: Bidirectional Sanger sequencing of exon 13 of the RPE65 gene and flanking sequences

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

ClinVar: 750796

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

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

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Yzer_2006_Patient_22597, female, diagnosed soon after birth, family origin not described

CasePresentingHPOs: HP:0003593 (Infantile onset), HP:0006934 (Congenital nystagmus), HP:0030532 (Visual acuity test abnormality), HP:0007843 (Attenuation of retinal blood vessels), HP:0000550 (Undetectable electroretinogram)

CaseHPOFreeText: The individual is described as having Leber congenital amaurosis. Diagnosis was made soon after birth, but an exact age is not described. Visual acuity was limited to light perception.

CaseNotHPOs: HP:0000543 (Optic disc pallor), HP:0007703 (Abnormality of retinal pigmentation)

CaseNotHPOFreeText: Most recent fundus examination was relatively normal at 25 years of age.

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

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

CaseMethod2: N/A

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

Variant: The individual is homozygous for the NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) variant.

ClinVar: 9350

gnomAD: The NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) 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

VariantEvidence: PMID: 9888789 provides evidence supporting the pathogenicity of the NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) variant by showing that the orthologous bovine F514S point mutation severely decreases the intrinsic cyclase activity of the protein and inactivates one of its calcium-responsive activating switches, CRM1.

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

CasePMIDs: N/A

FamilyLabel: Saihan_2009_Family

Family#PresentingHPOs: HP:0000662 (Nyctalopia), HP:0000529 (Progressive visual loss), HP:0000572 (Visual loss), HP:0011510 (Drusen), HP:0011506 (Choroidal neovascularization)

FamilyHPOFreeText: First presenting phenotypes were reduction of night vision and slow dark adaptation (with onset in fifth decade, 1 to 11 years prior to vision loss). Nyctalopia was progressive, with onset in the fifth decade of life (age 45-47). Vision loss was sudden, in some cases bilateral, and occurred in the fifth or sixth decade of life (age 48-56). Drusen-like deposits were present at the posterior pole in all three patients but varied in severity (possibly in proportion to age at examination). The degree of vision loss also varied in severity between patients and between the left and right eyes of each patient. Choroidal neovascularization was hemorrhagic and initiated loss of central vision.

FamilyNotHPOs: HP:0004328 (Abnormal anterior eye segment morphology), HP:0000518 (Cataract)

FamilyNotHPOFreeText: No history of renal disease or systemic disease was consistently observed among the affected family members.

CountryOrigin: British (of Welsh origin)

Family#PreviousTesting: Family history (indicating autosomal dominant inheritance of retinal degeneration) and ophthalmic exams (including LogMAR visual acuities, slit-lamp biomicroscopy, color fundus photography, optical coherence tomography scans of the fovea, and autofluorescent imaging of the fundus)

Family#GenotypingMethod: Mutational screening of TIMP3 by bidirectional Sanger sequencing

Affected: 3

Unaffected: 2

Segregations: 2

PublishedLOD: N/A

eLOD: Insufficient information available

AddSegregationInfo: N/A

ProbandLabel: Saihan_2009_Family_patient_III:4

Variant: Variant used was NM_000362.5(TIMP3):c.484G>A (p.Glu162Lys) (CAID:CA411540222). The variant is referred to in this publication as "Glu139Lys" (due to the removal of a 23-amino acid N-terminal signal peptide from the polypeptide sequence) but encodes Glu162Lys in the full/updated polypeptide sequence.

CAID: CA411540222

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: The mother of the proband and affected siblings was unaffected and negative for the variant, while the father was affected but not genotyped.

FamilyPMIDs: N/A

Selection B- Gene function is consistent with phenotype.

Title: GPR143 binds heterotrimeric G proteins and shows subcellular localization to melanosomes.

GOterm: GO:0032402 (melanosome transport)

FunctionalEvidence: Exogenously expressed GPR143 in COS-7 cells forms protein-protein interactions with heterotrimeric G-proteins that can be co-immunoprecipitated (Figure 2). This was validated with endogenous GPR143 (Figure 3). GPR143 shows subcellular localization not to the plasma membrane but to melanosomes (Figures 4, 6).

FunctionalHPO: HP:0005592 (Giant melanosomes in melanocytes), severely reduced microtubule-based motility in melanosomes

HumanPhenotype: HP:0005592 (Giant melanosomes in melanocytes), HP:0007894 (Hypopigmentation of the fundus), severely reduced microtubule-based motility in melanosomes, Giant melanosomes in retinal pigment epithelial cells

PhenotypeEvidence: This evidence is consistent with the melanocyte trafficking defects characteristic of human patients.

PMID: 25690007

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:34743040

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.

PMID: 19402160

Gene: BBS7

HGNC: 18758

Disease: Bardet-Biedl syndrome 7

MONDO: 0014435

InheritancePattern: autosomal recessive

Prevalence: The prevalence of BBS7 variants among Bardet-Biedl syndrome cohorts has been reported at 4.2% (PMID: 19402160), while the prevalence of Bardet-Biedl syndrome overall has been estimated between 1 in 13,500 and 1 in 160,000 live births, depending on the population (PMID: 22713813).

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

Case#: Bin_2009_Family_04-01_Case_26, female, age 11.6 years at time of report, national origin reported as from Peru

CasePresentingHPOs: HP:0001513 (Obesity), HP:0010442 (Polydactyly), HP:0100543 (Cognitive impairment), HP:0012758 (Neurodevelopmental delay), HP:0003077 (Hyperlipidemia), HP:0034685 (Abnormal liver enzyme activity or concentration), HP:0000077 (Abnormality of the kidney), HP:0410042 (Abnormal liver morphology), HP:0030515 (Moderately reduced visual acuity), HP:0000548 (Cone/cone-rod dystrophy), HP:0001133 (Constriction of peripheral visual field)

CaseHPOFreeText: The patient has been diagnosed with Bardet-Biedl syndrome.

CaseNotHPOs: HP:0000639 (Nystagmus), HP:0000518 (Cataract)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of Sanger sequencing of the TTC8 locus.

CaseMethod1: Sanger sequencing of the TTC8 locus

CaseMethod2: Sanger sequencing of the BBS7 locus

CaseGenotypingMethod: Genotyping consisted of Sanger sequencing of the TTC8 and BBS7 loci.

Variant: The patient harbors the NM_176824.3:c.712_715del (p.Arg238GlufsTer?) and NM_176824.3:c.1121C>G (Ser374Ter) variants in the compound heterozygous state.

CAID: CA3064432, CA358062298

gnomAD: The NM_176824.3:c.1121C>G (Ser374Ter) variant is found in gnomAD v2.1.1 at a maximum allele frequency of 0.0001633 (1/6124 in the Other population), with 0 homozygotes. https://gnomad.broadinstitute.org/variant/4-122766768-G-C The NM_176824.3:c.712_715del (p.Arg238GlufsTer?) variant is found in gnomAD v2.1.1 at a maximum allele frequency of 0.0001146 (13/113390) in the European non-FInnish population), with 0 homozygotes.

VariantEvidence: NM_176824.3:c.1121C>G (Ser374Ter) is a nonsense variant in exon 11 of 18 that is predicted to trigger nonsense-mediated decay or at least truncation of the C-terminal 48% of the protein product. NM_176824.3:c.712_715del (p.Arg238GlufsTer?)is a frameshift variant in exon 7 of 18 that is predicted to trigger nonsense-mediated decay or at least truncation of the C-terminal 67% of the protein product.

CaseAddInfo: Consanguinity in the proband's family has not been reported. The carrier status of her unaffected parents and an unaffected sibling have been confirmed by genotyping.

CasePMIDs: N/A

Case#: Chatterjee_2022_proband_II:4, female, age 16 years at time of report, onset in second decade of life, geographic origin reported as north Indian

CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0000613 (Photophobia), HP:0000662 (Nyctalopia), HP:0030564 (Best corrected visual acuity 1.1 LogMAR), HP:0025147 (Beaten bronze macular sheen), HP:0011507 (Macular flecks), HP:0030619 (Reduced OCT-measured foveal thickness), HP:0025010 (Foveal atrophy)

CaseHPOFreeText: The patient and siblings have been diagnosed with Stargardt-like juvenile macular dystrophy.

CaseNotHPOs: HP:0007737 (Bone spicule pigmentation of the retina)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of whole-exome sequencing.

CaseMethod1: whole-exome sequencing

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

CaseGenotypingMethod: Genotyping consisted of whole-exome sequencing followed by Sanger sequencing of the 19 exons of the IMPG2 gene.

Variant: The patient harbors the NM_016247.4:c.1239+1G>T variant in the homozygous state.

CAID: CA353864391

gnomAD: The variant was found in gnomAD v2.1.1.

VariantEvidence: NM_016247.4:c.1239+1G>T is a canonical splice site variant in intron 11 of the 19-exon locus that has been shown by mini-gene assay to trigger a splicing defect that leads to complete skipping of exon 11. Because this would lead to a shift of frame, the variant is predicted to lead to a premature stop after codon 385 and either NMD or truncation of 69% of the C-terminus of the protein product.

CaseAddInfo: The family is consanguineous, with the parents being first cousins and heterozygous carriers of the variant. The patient has two affected siblings who share the same genotype.

CasePMIDs: N/A

ExperimentName: CRISPR/Cas9-based disruption of mouse Impg1

NonHumanModel: Mus musculus

GeneAlteration: Model animals were subjected to CRISPR/Cas9-based deletion of 10bp from exon 2 of Impg1, and analyzed in the homozygous state. Absence of Impg1 signal was confirmed by immunofluorescent staining. Mice were studied at ages 5 months and 8 months.

ModelPhenotype: HP:0030612 (Abnormal retinal morphology, specifically mislocalization of chondroitin sulfate in the IPM, with none in the outer segment and more in the inner segment)

HumanPhenotype: HP:0007754 (Macular dystrophy), HP:0007769 (Peripheral retinal degeneration), HP:0032037 (Mildly reduced visual acuity, progressive), HP:0008179 (Decreased Arden ratio of electrooculogram)

ModelEvidence: This is the first mouse model of Impg1 disruption, with confirmed absence of Impg1 in the homozygous animals. The only observed abnormality is mislocalization of chondroitin sulfate in the IPM, with none in the outer segment and more in the inner segment (Figure 7). A mild disruption was observed in the localization of PNA, a cone-specific marker, to the outer segment (Fig. 2F). Impg2 appears to be normally localized (Figure 2C). ERG responses were normal (data not shown). Please note that an independent study generating a different model of homozygous Impg1 disruption reported different findings (PMID: 36140676).

ModelVariant: The model does not introduce a variant previously observed in human patients, but rather disrupts the expression of the Impg1 ortholog.

PMID: 26216056

Gene: IFT140

HGNC: 29077

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

MONDO: 0009964

InheritancePattern: autosomal recessive

Prevalence: Within the lumped disease entity for this curation, the most prevalent form may be retinitis pigmentosa. The prevalence of Saldino-Mainzer syndrome (one of the synonyms of Short-rib thoracic dysplasia 9) is less than 1 in 1,000,000. The prevalence of Leber congenital amaurosis cases caused by IFT140 variants (PMID: 26216056) is calculated to be less than 1 in 3,000,000. Although IFT140 variants are estimated to be responsible for less than 2% of RP, the prevalence of the overall disorder at 1 in 3,000 or 1 in 4,000 means the frequency of these cases could potentially be higher than 1 in 1,000,000.

Penetrance: Known variants for this lumped disease entity appear to be completely penetrant, with highly variable phenotypes and age of onset. On the other hand, the split disease entity caused by monoallelic IFT140 variants appears to have incomplete penetrance.

FamilyLabel: Felbor_1995_Family_1

Family#PresentingHPOs: HP:0030666 (Retinal neovascularization), HP:0007777 (Chorioretinal scar), HP:0000603 (Central scotoma), HP:0000556 (Retinal dystrophy), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000630 (Abnormal retinal artery morphology), HP:0030491 (Choriocapillaris atrophy), HP:0007994 (Peripheral visual field loss), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0008275 (Abnormal light-adapted electroretinogram),

FamilyHPOFreeText: Patients were considered to exhibit early-onset SFD with a mean age of 25. The presenting symptom was central subretinal neovascularisation, which preceded extensive scarring. Second eye involvement generally occurred months later, indicating rapid progression. Retinal dystrophy was reported to be tapetal. Intraretinal arteries were attenuated. Dark adaptation was decreased.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: The family is described as German-Czech.

Family#PreviousTesting: Genetic linkage testing / genotyping of affected and unaffected family members with three microsatellite markers that were previously associated with SFD and that flank the TIMP3 locus. This was followed by single-stranded conformational polymorphism (SSCP) of all five TIMP3 exons, detecting a mobility shift in exon 5.

Family#GenotypingMethod: Bidirectional Sanger sequencing of exon 5 PCR products from two affected individuals.

Affected: 2 (Sanger sequenced)

Unaffected: 1 (Sanger sequenced)

Segregations: N/A

PublishedLOD: Maximum two-point LOD score of 4.75 was reported for marker D22S280 at a recombination fraction of 0.001. D22S280 is also tightly associated with the TIMP3 locus.

eLOD: Insufficient information available

AddSegregationInfo: Family pedigree (from microsatellite-based linkage testing) mapping the disease locus to chr22q13-qter is shown in Figure 1.

ProbandLabel: Felbor_1995_Family_1_patient_1

Variant: NM_000362.5(TIMP3):c.536C>G, (p.Ser179Cys) is a missense variant predicted to substitute a new cysteine residue into exon 5.

ClinVar: 12678

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: N/A

FamilyPMIDs: N/A

ExperimentName: Mouse model of homozygous Cln5 loss

NonHumanModel: Mus musculus

GeneAlteration: Mice are homozygous for Cln5 loss of function, caused by Insertion of a neomycin resistance cassette eliminating exon 3, resulting in a premature stop codon in exon 4. The presence or absence of a truncated gene product was not assessed.

ModelPhenotype: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0000572 (Visual loss)

HumanPhenotype: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0000572 (Visual loss)

ModelEvidence: The model phenotypes closely match the human patient phenotypes at the microscopic level (characteristic autofluorescent inclusion bodies ) as well as the loss of vision, but do not reproduce neurological features such as seizures, ataxia, loss of motor coordination, mental regression, and behavioral changes.

ModelVariant: While it is unclear whether the mice express a truncated form of Cln5 or whether this form is degraded, the predicted protein product does not represent a particular human variant. The authors speculate that it may be most similar to the NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) variant (PMID:10953198).

FamilyLabel: Farrar_1991_Family, family national origin reported as Irish

Family#PresentingHPOs: Nyctalopia HP:0000662, Peripheral visual field loss HP:0007994, Undetectable dark-adapted electroretinogram HP:0030474, Abnormal light-adapted electroretinogram HP:0008275, Pigmentary retinopathy HP:0000580, Optic disc pallor HP:0000543, Retinal arteriolar constriction HP:0008043, Bone spicule pigmentation of the retina HP:0007737

FamilyHPOFreeText: The patient and affected family members have been diagnosed with retinitis pigmentosa, with onset noted as late. Nyctalopia generally presented in the early third decade, while rod ERG responses showed reduced amplitudes in the teens.

Family#PresentingNotHPOs: N/A

Family#PresentingNotHPOFreeText: N/A

CountryOrigin: Ireland

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: Previous testing did not occur in this family, although linkage mapping had previously identified PRPH2 as a candidate locus for variants causing RP.

Family#Method1: Single strand conformation polymorphism analysis of PCR-amplified cDNA products from the PRPH2 gene, followed by Sanger sequencing of the relevant PCR product to identify the variant

Family#Method2: allele-specific PCR to genotype family members

Family#GenotypingMethod: Previous testing of this family did not include linkage mapping, although this technique had previously identified PRPH2 as a candidate locus for variants causing RP. Genotyping started with single strand conformation polymorphism analysis of PCR-amplified cDNA products from the PRPH2 gene, followed by Sanger sequencing of the relevant PCR product to identify the variant. Allele-specific PCR was subsequently performed to genotype family members.

Affected: 9

Unaffected: 6

Segregations: Nine segregations are reported in the family, with none inconsistent. The family is not reported to be consanguineous. The pedigree is shown in Figure 2.

PublishedLOD: N/A

eLOD: 2.70

AddSegregationInfo: N/A

ProbandLabel: Farrar_1991_Proband

Variant: The affected family members harbor the NM_000322.5:c.356_358del (p.Cys119del) variant in the heterozygous state.

CAID: CA226222

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

FamilyAddInfo: The family has not been reported as consanguineous.

FamilyPMIDs: N/A

Case#: Bessa_Patient_1, female, age 3 at onset, Portuguese nationality

CasePresentingHPOs: HP:0000736 (Short attention span), HP:0002463 (Language impairment), HP:0002312 (Clumsiness), HP:0033044 (Motor regression), HP:0002376 (Developmental regression), HP:0000572 (Visual loss), HP:0002066 (Gait ataxia), HP:0001336 (Myoclonus), HP:0010819 (Atonic seizure), HP:0032794 (Myoclonic HP:0000648 (Optic atrophy), HP:0000546 (Retinal degeneration), HP:0012011 (EEG with occipital focal spike waves), HP:0002059 (Cerebral atrophy), HP:0001272 (Cerebellar atrophy), HP:0030891 (Periventricular white matter hyperdensities), HP:0001268 (Mental deterioration), HP:0031058 (Impairment of activities of daily living), HP:0011463 (Childhood onset), HP:0000712 (Emotional lability), HP:0002015 (Dysphagia), HP:0010864 (Intellectual disability, severe), HP:0001332 (Dystonia), HP:0007256 HP:0025357 (Erratic myoclonus), HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material)

CaseHPOFreeText: Progressive attention deficits and regression of language ability were the phenotypes at presentation (age 3). Motor clumsiness presented at age 4, initiating a larger pattern of developmental regression. Phenotypes with onset at age 7 included visual deterioration, gait ataxia, distal and axial myoclonus, atonic and myoclonic generalized epileptic seizures, bilateral optic atrophy, retinal degeneration, abnormal EEG showing diffuse slowing of background rhythm and occipital spike-wave activity, and abnormal brain MRI with cerebral and cerebellar atrophy as well as increased signal intensity of both the posterior limb of the capsula interna and the periventricular white matter. At age 8, any independence in daily activities was lost, as well as any language abilities. Ataxic gait was marked, and EEG activity showed slowing and disorganization, frequent multifocal high-voltage polyspike-slow wave complexes, and epileptic activity corresponding to myoclonus. At 15 years (time of study), the patient was bedridden and showed amaurotic behavior, emotional lability, marked dysphagia, severe mental retardation, dystonic postures of the limbs and trunk, pyramidal signs in the limbs, bilateral optic atrophy, and frequent myoclonus (both erratic and stimulus-induced). Intracellular accumulation of autofluorescent lipopigment storage material was also detected at age 15.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotype testing was not performed. While the PPT1 and TPP1 loci were not sequenced, their enzymatic activity in extracts from leucocyte and fibroblast cells was confirmed to be within the normal range.

CaseGenotypingMethod: Based on detailed clinical phenotypes consistent with variant NCL with late-infantile onset, coding regions and intron boundaries of the CLN3, CLN5, and CLN6 loci were PCR-amplified and subjected to Sanger sequencing. Genome-wide analysis methods were not used. Parents (and patient) were subsequently genotyped using single strand conformational polymorphisms and restriction digest of PCR products, to identify variants in cis and in trans with one another.

Variant: The patient is a compound heterozygote with a paternally inherited NM_006493.4(CLN5):c.418C>T (p.Gln140Ter) variant and maternally inherited NM_006493.4(CLN5):c.688G>A (p.Asp230Asn) and NM_006493.4(CLN5):c.188G>C (p.Arg63Pro) variants.

ClinVar: 56538, 2566, 56533

gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.688G>A (p.Asp230Asn) variant is 0.00005437 (within the East Asian population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77574715-G-A The NM_006493.4(CLN5):c.418C>T (p.Gln140Ter) and NM_006493.4(CLN5):c.188G>C (p.Arg63Pro) variants are absent from gnomAD.

VariantEvidence: Reduced CLN5 expression by 45% at the mRNA level indicates that one of the two alleles may be subject to nonsense mediated decay and likely absence of the corresponding protein product. This may confirm the prediction that the nonsense variant NM_006493.4(CLN5):c.418C>T (p.Gln140Ter) is likely subject to nonsense mediated decay. One of the two maternally inherited variants, NM_006493.4(CLN5):c.688G>A (p.Asp230Asn), has been previously shown to introduce an additional N-glycosylation site within the C-terminal region of CLN5 (PMID:20052765) and to disturb its localization to the lysosome (PMID:20052765).

CaseAddInfo: Parents are healthy and non-consanguineous.

CasePMIDs: N/A

Case#: Morimura_1998_Family_9145_Patient_II-1, female, age and family origin not specified

CasePresentingHPOs: HP:0000546 (Retinal degeneration)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA

CaseMethod2: Sanger sequencing of all 14 exons of RPE65

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

Variant: The proband is a homozygote within the RPE65 locus, harboring the NM_000329.3(RPE65):c.1418T>A (p.Val473Asp) variant.

ClinVar: 98846 (homozygous)

gnomAD: The NM_000329.3(RPE65):c.1418T>A (p.Val473Asp) variant is not found within gnomAD.

VariantEvidence: NM_000329.3(RPE65):c.1418T>A (p.Val473Asp) is a missense variant with unknown impact on gene function.

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

CasePMIDs: N/A

Case#: Morimura_1998_Family_7828_Patient_III-4, male, age not specified, from family originating in the Dominican Republic

CasePresentingHPOs: HP:0000546 (Retinal degeneration)

CaseHPOFreeText: 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.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA

CaseMethod2: Sanger sequencing of all 14 exons of RPE65

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

Variant: The proband is a compound heterozygote harboring the NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser) and NM_000329.3(RPE65):c.1207_1210dup (p.Glu404fs) variants.

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.

VariantEvidence: The paternal frameshift variant is predicted to either trigger NMD or disrupt 24% of the protein product. The maternal missense variant does not have evidence of gene impact.

CaseAddInfo: 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.

CasePMIDs: N/A

PMID: 33328889

Case#: Li_2025_Proband_XXXVII, age 8 years at time of report, male, seen at a medical center in Beijing

CasePresentingHPOs: Abnormal morphology of the choroidal vasculature HP:0025568, High myopia HP:0011003, Best corrected visual acuity 0.1 LogMAR HP:0030554

CaseHPOFreeText: The choroidal vascular abnormality referred to in the text was described as a tesselated fundus. The patient's refractive error was reported as -14.00 and -12.88 in the two eyes, with, axial lengths of 27.01 and 26.64.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genotyping of the proband was performed by whole genome sequencing.

CaseMethod1: whole genome sequencing

CaseMethod2: possibly Sanger sequencing of OPN1LW

CaseGenotypingMethod: Genotyping of the proband was performed by whole genome sequencing, possibly followed by Sanger sequencing of OPN1LW.

Variant: The individual harbors the NM_020061.6(OPN1LW):c.843G>A (p.Trp281Ter) variant in the hemizygous state.

CAID: CA415308527

gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.00002111 (1 / 47,376) in the Remaining population. https://gnomad.broadinstitute.org/variant/chrX-154156392-G-A?dataset=gnomad_r4

VariantEvidence: NM_020061.6(OPN1LW):c.843G>A (p.Trp281Ter) is a nonsense variant in exon 5 of 6 that is predicted to undergo nonsense-mediated decay.

CaseAddInfo: The proband was seen at a medical center in Beijing.

CasePMIDs: N/A

Case#: Family_22142_Proband_II-1, onset before age 7 years, male, seen at a medical center in Guangzhou

CasePresentingHPOs: High myopia HP:0011003, Blurred vision HP:0000622, Childhood onset HP:0011463, Protanopia HP:0011522

CaseHPOFreeText: The proband is part of a cohort in which all patients had a diagnosis of early onset high myopia, with onset in early childhood and either high myopia or axial length >25 mm before age 7, or refractive errors <-10 as an adult.

CaseNotHPOs: Nystagmus HP:0000639, Photophobia HP:0000613, Nyctalopia HP:0000662

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genotyping of the proband was performed by either targeted exome sequencing or whole exome sequencing.

CaseMethod1: targeted exome or whole exome sequencing

CaseMethod2: Sanger sequencing of OPN1LW

CaseGenotypingMethod: Genotyping of the proband was performed by either targeted exome sequencing or whole exome sequencing, followed by Sanger sequencing of OPN1LW.

Variant: The individual harbors the NM_020061.6(OPN1LW):c.739C>T (p.Arg247Ter) variant in the hemizygous state.

ClinVarID: 10503

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

VariantEvidence: NM_020061.6(OPN1LW):c.739C>T (p.Arg247Ter) is a nonsense variant in exon 3 of 6 that is predicted to undergo nonsense-mediated decay.

CaseAddInfo: The proband was seen at a medical center in Guangzhou. The variant was inherited from the proband's unaffected mother.

CasePMIDs: N/A

PMID: 24849935

Gene: BBS7

HGNC: 18758

Disease: Bardet-Biedl syndrome 7

MONDO: 0014435

InheritancePattern: autosomal recessive

Prevalence: The prevalence of BBS7 variants among Bardet-Biedl syndrome cohorts has been reported at 4.2% (PMID: 19402160), while the prevalence of Bardet-Biedl syndrome overall has been estimated between 1 in 13,500 and 1 in 160,000 live births, depending on the population (PMID: 22713813).

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

PMID: 8944027

Gene: GUCY2D

HGNC: 4689

Disease: Leber congenital amaurosis 1

MONDO: 0008764

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by GUCY2D variants is between 10% and 20% (PMID: 10951519). Thus, the prevalence of Leber congenital amaurosis 1 is between 1 in 165,000 and 1 in 1,000,000.

Penetrance: Fully penetrant, with onset in neonates or in infancy

PMID: 15981244

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.

PMID: 19717472

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: GUCY2D protein-protein interaction with RD3

InteractingGene: HGNC:19689 (implicated in LCA12)

InteractionType: Physical (protein-protein) interaction

InteractionMethod: Interaction was established by coimmunoprecipitation followed by mass spectrometry (Table S1), confirmed by western blotting (Figure 2A).

InteractionEvidence: Mouse Rd3 was immunoprecipitated by monoclonal antibody and co-purifying proteins were identified by LC-MS/MS. The highest-scoring interacting partner was Gucy2e, the mouse ortholog of GUCY2D (Table S1). This was confirmed by western blotting (Figure 2A) and found to be dependent on the C-terminus of Gucy2e (Figure 5).

PMID: 21078983

Gene: GUCY2D

HGNC: 4689

Disease: Leber congenital amaurosis 1

MONDO: 0008764

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by GUCY2D variants is between 10% and 20% (PMID: 10951519). Thus, the prevalence of Leber congenital amaurosis 1 is between 1 in 165,000 and 1 in 1,000,000.

Penetrance: Fully penetrant, with onset in neonates or in infancy

PMID: 19759534

Gene: OPN1LW

HGNC: 9936

Disease: protan color blindness

MONDO: 0010565

InheritancePattern: X-linked

Prevalence: The overall prevalence of protan color blindness is approximately 1% in males, which is higher than that of blue cone monochromacy (~1 in 100,000, PMID: 35759666).

Penetrance: Known disease-causing alleles appear to be almost completely penetrant in males (PMID: 21167193).

Case#: van_Dorp_1992_Family_P9145_patient_IV-20, male, age not reported, family origin reported to be Dutch

CasePresentingHPOs: HP:0012263 (Immotile cilia), HP:0002205 (Recurrent respiratory infections), HP:0012261 (Abnormal respiratory motile cilium physiology), HP:0012255 (Dynein arm defect of respiratory motile cilia), HP:0012260 (Abnormal central microtubular pair morphology of respiratory motile cilia), HP:0012864 (Abnormal sperm morphology),

CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa in combination with recurrent respiratory infections. The family exhibits an X-linked pattern of inheritance. Inner dynein arms of respiratory cilia were described as deficient. Cilia were described as disoriented.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The patient and his family members were subjected to linkage analysis using X chromosomal markers, followed by a chromosomal analysis of the patient that revealed no abnormalities (such as a translocation involving the X chromosome).

CaseMethod1: Linkage analysis (PMID: 1733835)

CaseMethod2: Sanger sequencing of PCR products from the RPGR locus (PMID: 10094550)

CaseGenotypingMethod: The patient and family members were subjected to linkage analysis using X chromosomal markers, and then the patient DNA underwent chromosomal analysis that revealed no abnormalities (such as a translocation involving the X chromosome). The family members were then genotyped by Sanger sequencing of PCR products from the RPGR locus (PMID: 10094550).

Variant: The patient harbors the NM_001034853.2(RPGR):c.469+1G>T variant in the hemizygous state.

ClinVar: 9912

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

VariantEvidence: NM_001034853.2(RPGR):c.469+1G>T is a canonical splice site variant in the final exon (exon 15) that disrupts the 5' splice site of intron 5. Functional evidence confirming the expected effect on splicing is not available.

CaseAddInfo: The proband is a member of Family P9145 (shown in Figure 1), which includes four other affected genotype-positive males and as well as three carrier females who showed no detectable abnormality. The detailed genotype for the affected and carrier individuals was later published in PMID: 10094550.

CasePMIDs: PMID: 10094550

ExperimentName: Interaction with TPP1 and CLN3

InteractingGene: TPP1 (formerly known as CLN2) and CLN3

InteractionType: Physical (protein-protein) interaction

InteractionMethod: Co-immunoprecipitation

InteractionEvidence: PPT1 (aka CLN1), CLN3, and CLN5 were exogenously expressed in COS-1 cells. Immunoprecipitation of endogenous TPP1 (Fig. 5A) or exogenously expressed CLN3 (Fig. 5B) successfully co-immunoprecipitated CLN5 (demonstrated by western blotting). Immunoprecipitation of GST-CLN5 successfully co-immunoprecipitated TPP1 and CLN3 (Fig. 5C). This evidence helps validate the link between CLN5 variants and neuronal ceroid lipofuscinosis, as both TPP1 and CLN3 have also been linked with this disease state.

PMID: 25383878

Gene: PRPF4

HGNC: 17349

Disease: retinitis pigmentosa 70

MONDO: 0014400

InheritancePattern: autosomal dominant

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 dominant mode of inheritance is estimated to be 15-35% (between 1 in 8,500 and 1 in 27,000). The proportion of that incidence made up by the specific form caused by variants in PRPF4 is not clear.

Penetrance: Known disease-causing alleles appear to be incompletely penetrant (PMID: 25383878).

PMID: 9618177

Gene: GUCY2D

HGNC: 4689

Disease: Cone-rod dystrophy 6

MONDO: 0011143

InheritancePattern: Autosomal Dominant

Prevalence: The overall prevalence of cone-rod dystrophy is between 1 in 30,000 and 1 in 40,000 (PMID: 17270046), while the proportion of cone-rod dystrophy caused by GUCY2D variants is between 19% and 23% (PMID: 22183351, PMID: 25515582). Thus, the prevalence of cone-rod dystrophy 6 is between 1 in 130,000 and 1 in 215,000.

Penetrance: Penetrance is age-dependent, with onset between the 1st and 6th decades of life.

ExperimentName: Rescue of Rpgr-deficient mice with human RPGR

RescueModel: Mus musculus

GeneAlteration: The Rpgr−/y mouse model was constructed with targeted hemizygous (male) disruption of the mouse Rpgr gene by insertion of a neomycin resistance cassette to replace exons 4 through 6 and generate a null variant (PMID: 10725384).

RescueVariant: Rescue was performed with wild-type human RPGR.

RescuePhenotype: HP:0030612 (Abnormal retinal morphology on macular OCT), partial mislocalization of blue and green cone opsins to the inner segment, reduced rhodopsin content in the outer segment, HP:0000546 (Retinal degeneration), HP:0030609 (Photoreceptor layer loss on macular OCT), HP:0030610 (Photoreceptor outer segment loss on macular OCT), disorganization of disk membranes, normal connecting cilia morphology, HP:0030483 (Reduced amplitude of dark-adapted bright flash electroretinogram a-wave), HP:0008275 (Abnormal light-adapted electroretinogram)

RescueMethod: Rescue was performed by subretinal injection of AAV8 particles delivering wild-type human RPGR (Figure 5).

RescueEvidence: ERG analyses show significant rescue of rod function and a rescue of cone function that is trending towards statistical significance (Figures 5B and 5C).

ModelVariant: The model does not harbor a variant equivalent to one from the human patients, but rather has targeted disruption of Rpgr leading to full loss-of-function.

PMID: 9924344

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: 9400791

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: 35608844

Case#: Preising_2001_Patient_IV.1, male, age 3 months at time of diagnosis, family ethnicity described as White

CasePresentingHPOs: HP:0006934 (Congenital nystagmus), HP:0012805 (Iris transillumination defect), HP:0007894 (Hypopigmentation of the fundus), HP:0001104 (Macular hypoplasia), HP:0007663 (Reduced visual acuity), HP:0030463 (Asymmetrical distribution of flash visual evoked potentials), HP:0025551 (Optic nerve misrouting)

CaseHPOFreeText: The proband and his family members have been diagnosed with congenital nystagmus.

CaseNotHPOs: HP:0009887 (Abnormality of hair pigmentation), HP:0001000 (Abnormality of skin pigmentation)

CaseNotHPOFreeText: N/A

CasePreviousTesting: The patients were initially genotyped by SSCP of PCR products from each exon, revealing an abnormality in exon 6.

CaseMethod1: SSCP

CaseMethod2: Sanger sequencing

CaseGenotypingMethod: The proband was initially genotyped by SSCP of PCR products from each exon, revealing an abnormality in exon 6, followed by Sanger sequencing and restriction enzyme analysis by Tsp509I digest of PCR products from all family members.

Variant: The proband harbors the NM_000273.3(GPR143):c.756_767+2del variant in the hemizygous state.

ClinVar: 98643

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

VariantEvidence: NM_000273.3(GPR143):c.756_767+2del is a 14-bp deletion variant removing the 3' end of exon 6 and the canonical splice donor site, and has been shown to trigger aberrant splicing that leads to frameshift at codon 252 and premature termination at codon 259 (Figure 4C).

CaseAddInfo: The proband is part of a family with at least 3 affected generations showing a pattern of X-linked inheritance, including a similarly affected maternal uncle.

CasePMIDs: N/A

PMID: 8919688

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: 20034086

PMID: 27703005

Gene: GUCY2D

HGNC: 4689

Disease: Cone-rod dystrophy 6

MONDO: 0011143

InheritancePattern: Autosomal Dominant

Prevalence: The overall prevalence of cone-rod dystrophy is between 1 in 30,000 and 1 in 40,000 (PMID: 17270046), while the proportion of cone-rod dystrophy caused by GUCY2D variants is between 19% and 23% (PMID: 22183351, PMID: 25515582). Thus, the prevalence of cone-rod dystrophy 6 is between 1 in 130,000 and 1 in 215,000.

Penetrance: Penetrance is age-dependent, with onset between the 1st and 6th decades of life.

ExperimentName: Higher GUCY2D activity in the R838S variant

NonPatientCell: HEK293 cells (EFO:0001182)

GeneFunction: GO:0006182 (cGMP biosynthetic process)

GeneAlteration: Site-directed mutagenesis was used to introduce the substitution encoding the R838S substitution into the gene expression construct (PMID: 15504042).

FunctionalEvidence: The variant exhibits higher activity than the wild-type in HEK293 cells, with enhanced Ca2+ sensitivity (Figure 1A), higher GCAP1 affinity, (Figure 1B), and reduced sensitivity to RD3 inhibition (Figure 1C).

FAVariants: NM_000180.4(GUCY2D):c.2512C>A (p.Arg838Ser) (ClinVar: 98568)

PMID: 31589838

Gene: BBS7

HGNC: 18758

Disease: Bardet-Biedl syndrome 7

MONDO: 0014435

InheritancePattern: autosomal recessive

Prevalence: The prevalence of BBS7 variants among Bardet-Biedl syndrome cohorts has been reported at 4.2% (PMID: 19402160), while the prevalence of Bardet-Biedl syndrome overall has been estimated between 1 in 13,500 and 1 in 160,000 live births, depending on the population (PMID: 22713813).

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

PMID: 419532

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).

Case#: Fang_2008_Family_1_Patient_IV16, male, age 8 at time of report, family national origin reported to be from China

CasePresentingHPOs: HP:0000639 (Nystagmus), HP:0030534 (Abnormal best corrected visual acuity test), HP:0007750 (Hypoplasia of the fovea)

CaseHPOFreeText: The proband and his affected family members have been diagnosed with ocular albinism 1.

CaseNotHPOs: HP:0007730 (Iris hypopigmentation), HP:0007894 (Hypopigmentation of the fundus)

CaseNotHPOFreeText: albinotic fundus

CasePreviousTesting: N/A

CaseMethod1: Sanger sequencing

CaseMethod2: N/A

CaseGenotypingMethod: The proband was genotyped by Sanger sequencing of PCR products from the 9 exons of the GPR143 gene.

Variant: The proband harbors the NM_000273.3(GPR143):c.849del (p.Val284SerfsTer15) variant in the hemizygous state.

CAID: CA2573320706

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

VariantEvidence: NM_000273.3(GPR143):c.849del (p.Val284SerfsTer15) is a frameshift variant in exon 7 of 9, predicted to trigger nonsense-mediated decay or to at least truncate 30% of the protein product.

CaseAddInfo: The family of the proband includes at least 7 other affected males and 4 unaffected female carriers.

CasePMIDs: N/A

ExperimentName: OPN1LW variants identified in myopic patients were expressed exogenously in HEK293T cells and exhibited reduced expression at the mRNA level.

NonPatientCell: HEK293T cells (EFO:0001184)

GeneFunction: GO:0007602 (phototransduction)

GeneAlteration: Site-directed mutagenesis was used to introduce the variants into minigenes encoding portions of the wlid-type OPN1LW gene.

FunctionalEvidence: Three OPN1LW variants identified in myopic patients were expressed exogenously in HEK293T cells and two out of three exhibited reduced expression at the mRNA level (Figures 1A and 1B).

FAVariants: NM_020061.6(OPN1LW):c.973A>G (p.Met325Val), CA415309107, NM_020061.6(OPN1LW):c.970T>A (p.Phe324Ile), CA415309100, NM_020061.6(OPN1LW):c.971T>A (p.Phe324Tyr), CA415309101

Case#: Savukoski_Fin_Minor_Patient_1, no demographic details, Finnish origin

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing relied on linkage analysis using PCR-amplifiable polymorphisms, including microsatellite markers. The marker D13S160 was found to co-segregate with disease with a LOD score of 4.78 across 14 Finnish pedigrees, mapping the disease locus to chromosome 13q21.1-q32 (PMID:7942847). A follow-up study used two additional microsatellite markers to map the locus to a 200-kb region (PMID:8661106), which was then analyzed in the present study and found to contain a single coding gene.

CaseMethod1: Linkage analysis using PCR-amplifiable polymorphisms, including microsatellite markers, followed by more detailed linkage analysis using two additional microsatellite markers to map the locus to a smaller 200-kb region (PMID:8661106).

CaseMethod2: N/A

CaseGenotypingMethod: PCR products from the four exons of CLN5 were generated from the affected individual and a control individual and subjected to Sanger sequencing. Genome-wide analysis methods were not used.

Variant: Patient is homozygous for NM_006493.4(CLN5):c.78G>A (p.Trp26Ter), although this variant is referred to in the article as c.G1517A or p.Trp75Stop.

ClinVar: 2565

gnomAD: The variant is reported to have a maximum allele frequency of 0.00005132 (in the European non-Finnish population, with no homozygous individuals). https://gnomad.broadinstitute.org/variant/13-77566311-G-A

VariantEvidence: This nonsense variant is predicted to introduce a stop codon near the N-terminus of the encoded protein, likely triggering NMD and the absence of a protein product (loss of function).

CaseAddInfo: N/A

CasePMIDs: PMID:7942847, PMID:8661106

PMID: 27737822

Gene: EYS

HGNC: 21555

Disease: Retinitis pigmentosa 25

MONDO: MONDO:0011272

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 caused by homozygous or compound heterozygous EYS variants is estimated to be 12% in the French population (PMID: 20333770), implying in an overall prevalence between 1 in 25,000 and 1 in 33,000.

Penetrance: The disease appears to be completely penetrant among published families.

PMID: 18824093

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.

PMID: 17848510

Gene: RPE65

HGNC: 10294

Disease: Leber congenital amaurosis 2

MONDO: 0008765

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by RPE65 variants is between 1% and 16.7%. Thus, the prevalence of Leber congenital amaurosis 2 is between 1 in 200,000 and 1 in 10,000,000.

Penetrance: Fully penetrant, with onset typically by 1 year of age

ExperimentName: Functional testing of Ser179Cys, Gly190Cys, Tyr191Cys and Ser204Cys variants of TIMP3 in baby hamster kidney (BHK) cells

NonPatientCell: Baby hamster kidney (BHK) cells, EFO:0001643 (kidney-derived cell line), CLO:0000696 (immortal hamster kidney-derived cell line), CLO:0001965 (BHK-21 cell line)

GeneFunction: GO:0008191 (metalloendopeptidase inhibitor activity), GO:0046872 (metal ion binding), GO:0002020 (protease binding), GO:0005615 (active in extracellular space), GO:0031012 (active in extracellular matrix)

GeneAlteration: TIMP3 expression constructs encoding the Ser179Cys, Gly190Cys, Tyr191Cys, and Ser204Cys variants (referred to in the paper as "Ser156Cys", "Gly167Cys", "Tyr166Cys", and "Ser181Cys") were generated by PCR-based mutagenesis of wild-type TIMP3 and cloned into the pNUT expression vector.

FunctionalEvidence: BHK cells were stably transfected with each of four variants or wild-type TIMP3. All variants expressed and localized successfully to the extracellular matrix (western blotting), Both variants tested exhibited intact metalloproteinase inhibitor activity in ECM fractions (reverse zymography). All four of the variants accumulated as higher molecular weight species (Figure 1A, Figure 2), with Ser179Cys and Ser204Cys in particular accumulating to a much greater degree than the other variants or the wild-type control (Figure 2). Cell morphology and adherence were affected within the variant-expressing cells. While wild-type-transfected cells were more adherent to the ECM than the untransfected controls were, both variant-transfected cells (Ser179Cys, Ser204Cys) were even more ECM-adherent (Figure 5). Association constants were measured for TIMP3 interaction with a series of metalloproteinases, calculating their values for wild-type TIMP3 and for the Ser156Cys variant, which exhibited a 2- or 3-fold loss of reduction, depending on the substrate (Table 2).

FAVariants: The four variants used were NM_000362.5(TIMP3):c.536C>G, p.Ser179Cys (ClinVar:12678), NM_000362.5(TIMP3):c.568G>T, p.Gly190Cys (CA411540415), NM_000362.5(TIMP3):c.572A>G, p.Tyr191Cys (ClinVar:12677), and NM_000362.5(TIMP3):c.610A>T, p.Ser204Cys (ClinVar:12676).

FamilyLabel: Langton_2000_Family_1

Family#PresentingHPOs: HP:0031609 (Geographic atrophy), HP:0007663 (Reduced visual acuity), HP:0007703 (Abnormality of retinal pigmentation), HP:0000512 (Abnormal electroretinogram)

FamilyHPOFreeText: First presentation of symptoms was in the 3rd or 4th decade of life. Geographic macular atrophy was the cause of central vision loss. Retinal pigmentary disturbances were peripheral. Scotopic ERGs were abnormal. Other common SFD phenotypes were seen in some affected individuals but not uniformly across all affected family members.

FamilyNotHPOs: N/A

CountryOrigin: British (PMID:11734514)

Family#PreviousTesting: Family previously diagnosed with SFD, with details provided in PMID:11734514.

Family#GenotypingMethod: Sanger sequencing of PCR product from Exon 5 of the TIMP3 gene.

Affected: 3

Unaffected: 2

Segregations: N/A

PublishedLOD: N/A

eLOD: Insufficient information available

AddSegregationInfo: N/A

ProbandLabel: Langton_2000_Family_1_patient_II2

Variant: The NM_000362.5(TIMP3):c.484G>T, p.Glu139X variant converts the GAG codon to a TAG, resulting in early termination of the transcript. This nonsense substitution affects the final exon 5, so that truncation of the protein product is predicted but not nonsense-mediated decay of the transcript.

ClinVar: 12680

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: Variant is referred to in the paper as "Glu139X" but encodes Glu162X in the updated polypeptide sequence (which includes the 23-amino acid N-terminal signal peptide).

FamilyPMIDs: PMID:11734514