Selection B- Gene function is consistent with phenotype.

GOterm: GO:0008191 (metalloendoproteinase inhibitor activity)

FunctionalEvidence: The functional evidence consists of an electrophoretic assay in which the 21-kDa chicken ortholog of human TIMP3 shows inhibitory activity towards a metalloproteinase.

FunctionalHPO: Abnormal extracellular matrix turnover in the inner aspect of Bruch's membrane

PhenotypeEvidence: This metalloproteinase inhibitor activity and ECM localization of the gene product indicate that it functions in ECM remodeling, balancing the activity of matrix metalloproteinases. This is consistent with the disease phenotype of abnormal thickening of the inner aspect of Bruch's membrane (PMID:11879143). The inhibitor evidence is shown in Figure 2B, where a 21-kDa band protects a gelatin substrate from enzymatic metalloproteinase activity. The purification of the gene product from the extracellular matrix is depicted in Figure 1. A later study showed that the human ortholog of this chicken gene is the TIMP3 gene, mapped to the region on chromosome 22 between q12.1-q13.2 (PMID:8188246).

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: NGS panel / WES / WGS

CaseMethod2: Sanger sequencing of RBP3

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

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

ClinVar ID: 1069291

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

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

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

CasePMIDs: N/A

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: SSCP

CaseMethod2: Sanger sequencing of PDE6A

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

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

ClinVar: 13110

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

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

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

CasePMIDs: N/A

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: whole exome sequencing

CaseMethod2: Sanger sequencing of the coding regions of PRPF4

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

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

ClinVar ID: 1395419

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

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

CaseAddInfo: The proband has apparently unaffected parents.

CasePMIDs: N/A

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: Sanger sequencing of NR2E3

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

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

ClinVarID: 191059, 1455685

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

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

CaseAddInfo: The proband has unaffected heterozygous carrier parents.

CasePMIDs: N/A

PMID: 16989765

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Sanger sequencing of NR2E3

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping was performed by Sanger sequencing of NR2E3.

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

ClinVarID: 5532

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

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

CaseAddInfo: The proband has two unaffected heterozygous parents.

CasePMIDs: N/A

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

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

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

CaseNotHPOs: Macular schisis HP:0011511

CaseNotHPOFreeText: N/A

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

CaseMethod1: Sanger sequencing of NR2E3

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping was performed by Sanger sequencing of NR2E3.

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

ClinVarID: 5534

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

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

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

CasePMIDs: N/A

ExperimentName: Patient iPSC-derived retinal organoids exhibit severe outer segment defects that can be rescued by CRISPR/Cas9-based editing.

RescuePatientCell: EFO:0004905 (induced pluripotent stem cell, differentiated into a retinal organoid)

GeneAlteration: The patient cells have inherited compound heterozygous variants in IMPG2, encoding either p.Tyr254Cys or a frameshift variant starting at codon 805.

RescuePhenotype: Patient iPSC-derived retinal organoids harboring these two variants exhibited almost complete failure to form an outer segment or an interphotoreceptor matrix during a 200-day period (Figure 2A), relative to control retinal organoids with CRISPR/Cas9-based editing / rescue of both variants (Figure 2D).

RescueMethod: CRISPR/Cas9-based editing was used to correct both variants.

RescueEvidence: Control retinal organoids with CRISPR/Cas9-based editing / rescue of both variants (Figure 2D) showed development of both the IPM and the outer segment, relative to the uncorrected retinal organoids (Figure 2A). This rescue argues for a role of IMPG2 in photoreceptor cell outer segment development / maintenance.

RescueVariants: NM_016247.4:c.761A>G (p.Tyr254Cys, CA353867908) and an undefined frameshift variant at codon 805, either NM_016247.4:c.2413del (p.Ala805LeufsTer8) or NM_016247.4:c.2414del (p.Ala805ValfsTer8).

ExperimentName: Mouse model of Trpm1 loss-of-function

NonHumanModel: Mus musculus

GeneAlteration: The mouse has homozygous disruption of the Trpm1 gene by targeted deletion of regions from exons 3, 4, and 5 (PMID: 19439586).

ModelPhenotype: HP:0007984 (Electronegative electroretinogram)

HumanPhenotype: HP:0000662 (Nyctalopia), HP:0000545 (Myopia), HP:0000572 (Visual loss), HP:0007984 (Electronegative electroretinogram)

ModelEvidence: The affected mice exhibit abnormal dark-adapted ERG with absent b-wave and normal a-wave (Figure 3), similar to the affected human patients. Retinal slices from these mice exhibit defects in chemically stimulated light responses (Figure 4), indicating that Trpm1 is required for generating the depolarizing light response in ON-bipolar cells.

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

PMID: 8673101

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.

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

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

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

CaseNotHPOs: HP:0000543 (Optic disc pallor)

CaseNotHPOFreeText: N/A

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

CaseMethod1: Linkage mapping using short tandem repeat markers

CaseMethod2: Sanger sequencing

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

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

ClinVar: 6876

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

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

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

CasePMIDs: PMID: 19409519

ExperimentName: Canine model of PDE6A loss-of-function

NonHumanModel: Canis lupus familiaris

GeneAlteration: Cardigan Welsh Corgi animals were found to develop retinal degeneration due to a homozygous 1-bp deletion variant at codon 616 that results in a frameshift and a premature stop codon (genotype previously reported in PMID: 10393029).

ModelPhenotype: HP:0030474 (Undetectable dark-adapted electroretinogram), HP:0000505 (Visual impairment), HP:0007843 (Attenuation of retinal blood vessels), HP:0030610 (Photoreceptor outer segment loss on macular OCT)

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

ModelEvidence: This mutation caused an Electronegative electroretinogram (HP:0007984) and Abnormal light-adapted electroretinogram (HP:0008275), (Figures 2, 3, and 4). Retinal degeneration (HP:0000546) was observed with outer nuclear photoreceptor layer thinning (HP:0030610, Figure 5). Photoreceptor outer segment loss is visible on macular OCT (Figure 6, Figure 7), particularly loss of rod photoreceptor cells.

ModelVariant: The model does not harbor a variant equivalent to one from the human patients, but rather has a naturally occurring frameshift variant disrupting Pde6a leading to full loss-of-function.

PMID: 31654038

Selection B- Gene function is consistent with phenotype.

Title: TRPM1 (MLSN) is a plasma membrane protein that mediates the cellular influx of calcium and other divalent cations, leading to depolarization, as part of the depolarizing photoresponse within ON-bipolar cells of the retina.

GOterm: GO:0005261 (cation channel activity), GO:0005262 (calcium channel activity)

FunctionalEvidence: Exogenous expression of TRPM1 (MLSN) in HEK293 cells conferred the ability to allow entry of calcium, barium, and strontium ions, unlike the pYFP or empty vector controls (Figures 4A, 4B, 3C). Confocal microscopy also showed localization to the plasma membrane (Figures 4C, 4D).

FunctionalHPO: HP:0000662 (Nyctalopia), HP:0000545 (Myopia), HP:0000572 (Visual loss), HP:0007984 (Electronegative electroretinogram)

PhenotypeEvidence: This evidence is consistent with the view of congenital stationary night blindness 1C as a channelopathy caused by a defect in divalent cation influx, signal transduction, and the polarization / depolarization of ON-bipolar cells.

ExperimentName: Rpe65 homozygous knockout triggers loss of cone response in certain mouse models.

NonHumanModel: Mus musculus

GeneAlteration: Rpe65 homozygous knockout was generated by replacing the 5' flanking region and the first three exons of Rpe65 with a PGK-Neo cassette (described in PMID: 9843205).

ModelPhenotype: HP:0008275 (Abnormal light-adapted electroretinogram), HP:0030465 (Undetectable light-adapted electroretinogram)

HumanPhenotype: HP:0030479 (Abnormal amplitude of light-adapted flicker electroretinogram)

ModelEvidence: The human phenotype includes both dark-adapted (rod) and light-adapted (cone) ERG defects. The Rpe65 homozygous knockout mouse model was previously found to have dark-adapted but not light-adapted response defects (PMID: 9843205). This study shows that in mice harboring homozygous knockout of Nrl (homozygous knockout) , Rpe65 homozygous knockout triggers light-adapted (cone) ERG defects as well (Figures 6A and 6B).

ModelVariant: The model disrupts the entire Rpe65 locus rather than introducing a mutation equivalent to a human patient variant.

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

DiseaseAssertion: Sorsby's fundus dystrophy

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

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

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

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: Pulmonary involvement

CasePreviousTesting: N/A

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

PreviouslyPublished: N/A

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

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

ClinVar: 843268

gnomAD: Variant is absent from gnomAD.

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

Dog rescue RPGR.

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: next-generation sequencing

CaseMethod2: Sanger sequencing of PRPF4

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

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

ClinVar ID: 143057

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

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

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

CasePMIDs: N/A

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

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

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

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

CaseNotHPOFreeText: Fundus was described as largely normal.

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

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

CaseMethod2: N/A

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

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

ClinVar: 98563, 98576

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

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

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

CasePMIDs: N/A

PMID: 28532774

Gene: KCNQ1

HGNC: 6294

Selection B- Gene function is consistent with phenotype.

GOterm: GO:0016525 (negative regulation of angiogenesis)

FunctionalEvidence: The previously known ability of TIMP3 protein to block the binding of VEGF to the VEGFR-2 receptor (PMID:12652295, PMID:19478078) is mapped to the C-terminal region of TIMP3 consisting of amino acids 160-211 (Figures 1c, 2b). This region is relevant to disease in that nonsense variants (PMID:10854443) and splice site disrupting variants (PMID:9760202) of TIMP3 are predicted to remove most or all of this domain. This region is not only necessary and sufficient to block VEGF binding to VEGFR-2 in ELISA assays (Figure 2b), but also can block VEGF-stimulated endothelial migration (Figure 4) and proliferation (Figure 6). In an animal model of choroidal neovascularization (CNV) with lesions induced by laser, the injection of C-terminal TIMP3 peptides can limit CNV-based lesion size (Figure 7). This introduces the possibility that some phenotypes of Sorsby fundus dystrophy such as CNV may be mediated by loss of normal TIMP3 function rather than gain of an abnormal TIMP3 function.

FunctionalHPO: HP:0011506 (Choroidal neovascularization)

PMID: 28041994

Gene: RPE65

HGNC: 10294

Disease: Retinitis pigmentosa 87 with choroidal involvement

MONDO: 0032873

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 8,000 and 1 in 27,000). The prevalence of Retinitis pigmentosa 87 with choroidal involvement is considered to be much lower.

Penetrance: Incomplete penetrance, estimated at 80%

PMID: 23847139

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.

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

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

CaseHPOFreeText: This proband exhibited photophilia / staring at lights.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

Selection B Expression altered in patients

ExperimentName: Immunohistochemical localization of TIMP3 expression in eye sections from SFD and unaffected human patients

TissueExpression: In both unaffected and SFD patient tissues, strong TIMP3 expression was observed in Bruch's membrane (UBERON:0003957) and associated drusen (Figure 1).

ExpressionEvidence: As previously published (PMID:9006347), strong TIMP3 expression was observed in Bruch's membrane and drusen in both normal and SFD samples (Figure 1). In SFD patient tissues, thickened Bruch's membrane stained positively for TIMP3 as well, but only in areas where the retinal pigment epithelial cells were still intact (not in areas exhibiting RPE loss). Numerous extracellular deposits that stained positively with Periodic acid-Schiff (presumably drusen) were also TIMP3-positive. In some areas, retinal blood vessels were occluded by TIMP3-positive deposits as well. These findings clearly localize TIMP3 to the sites closely associated with pathogenesis within the SFD retina. Interestingly, SFD-like deposits in retinitis pigmentosa tissues were similarly TIMP3-positive (Figure 2).

PMID: 1733835

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: 19074801

Gene: RBP3

HGNC: 9921

Disease: retinitis pigmentosa 66

MONDO: 0014093

InheritancePattern: autosomal recessive

Prevalence: RBP3-related cases are believed to be very rare (possibly with estimated prevalence of less than 1 in 1,000,000), however, it is believed that there may be under-diagnosis (PMID: 37806543).

Penetrance: RBP3 disease-causing variants appear to have complete penetrance.

PMID: 11062472

Gene: NYX

HGNC: 8082

Disease: Congenital stationary night blindness 1A

MONDO: 0010690

InheritancePattern: X-linked 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 1A specifically is unknown.

Penetrance: Penetrance is thought to be complete.

GroupName: Morimura_1998_Group_1

GroupPresentingHPOs: HP:0000546 (Retinal degeneration)

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

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

NumberMales: 8

NumberFemales: 9

CountryOrigin: Most residing within the United States or Canada

Ethnicity: Not mentioned

Race: Not mentioned

AgeRange: Not mentioned

TotalNumber: 17

FamilyInfo: 17

NoFamily: 0

VariantCount: 17

NonVariant: 0

OtherVariant: 0

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

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

GroupMethod2: Sanger sequencing of 14 RPE65 exons

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

GroupAddInfo: N/A

PMID: 20157620

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.

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

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

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

CaseMethod2: Sanger sequencing of the 29 coding exons of IFT140

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

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

ClinVar: 31679, 31680

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

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

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

CasePMIDs: N/A

PMID: 21671801

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

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: N/A

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

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

ClinVar: 56526

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

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

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

CasePMIDs: N/A

PMID: 1749427

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

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

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

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

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

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

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

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

ClinVar: 811743

gnomAD: The variant was not found in gnomAD.

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

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

CasePMIDs: N/A

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

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo:

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

CaseHPOFreeText: N/A

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: Normal rod and cone signals

CasePreviousTesting: N/A

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

PreviouslyPublished: N/A

SupplementalData: N/A

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

ClinVar: 12677

gnomAD: Variant is absent from gnomAD.

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

PMID: 25553308

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.

ExperimentName: Rescue of Nyx loss-of-function mouse by transgene expression in depolarizing bipolar cells of the retina

RescueModel: Mus musculus

GeneAlteration: This naturally occurring model, previously known to exhibit the absence of b-wave in ERG recordings, harbors an 85-bp deletion in the final exon of the Nyx gene that shifts the frame and replaces the C-terminal 61% of the protein product with 170 novel amino acids. The predicted effect is loss-of-function.

RescueVariant: Rescue was performed with a wild-type Nyx transgene, rather than a variant.

RescuePhenotype: HP:0007984 (Electronegative electroretinogram), HP:0000649 (Abnormality of visual evoked potentials), HP:0007663 (Reduced visual acuity)

RescueMethod: An EYFP-tagged mouse Nyx gene was placed under the control of the mouse GABAcp1 promoter for tissue-specific expression in bipolar cells of the retina, including rod and cone depolarizing and hyperpolarizing bipolar cells. The transgene was introduced by pronuclear injection to generate transgenic lines, then crossed to homozygous Nyx mice to yield transgenic male offspring with Nyx disruption.

RescueEvidence: The EYFP-Nyx transgene restores both the ERG b-wave (Figure 5B) and the spontaneous and light-evoked responses of retinal ganglion cells (Figure 6) in Nyx-deficient mice.

ModelVariant: The model is naturally occurring, and so the affected animals harbor a variant that does not have an exact human patient equivalent.

PMID: 37510153

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.

FamilyLabel: Gliem_2015_Family_1

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

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

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: Germany

Family#PreviousTesting: N/A

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

Affected: 7

Unaffected: 1

Segregations: 7

PublishedLOD: N/A

eLOD: 2.1

AddSegregationInfo: N/A

ProbandLabel: Gliem_2000_Family_1_patient_II.1

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

CAID: CA411540328

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: N/A

FamilyPMIDs: N/A

PMID: 25091951

Gene: ADAM9

HGNC: 216

Disease: cone-rod dystrophy 9

MONDO: MONDO:0013002

InheritancePattern: autosomal recessive

Prevalence: The prevalence of cone-rod dystrophy in general is estimated to be 1 in 40,000 (PMID: 17270046), however, the specific prevalence of cone-rod dystrophy 9 is unknown.

Penetrance: Penetrance appears to be complete in reported families, but it is possible that incomplete penetrance may be associated with some variants.

NonPatientCell*: ARPE-19 (human retinal pigment epithelial) cell line (CLO:0001749, CL:0009004)

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 "Ser181Cys", "Ser156Cys", and "Glu139X" variants (officially referred to as the Ser204Cys, Ser179Cys, and Glu162X variants) were generated by PCR-based mutagenesis of the wild-type TIMP-3-pCI.neo construct (previously described in PMID:10854443).

FunctionalEvidence: TIMP3 variants were exogenously expressed in ARPE-19 cells alongside wild-type and empty vector controls. The percentage of exogenously expressed wild-type TIMP3 protein remaining associated with the extracellular matrix after separation of transfected cells from ECM was 20% (after 1 day) or <1% (after 4 days). All three variants were turned over at a slower rate, with 35-50% remaining after 1 day, and 20-25% remaining after 4 days (Figure 2). On the other hand, while the Ser179Cys and Glu162X variants showed reduced ability to inhibit cell surface activation of Pro-MMP2, Ser204Cys did not (Figure 3). As a result, the key, consistent function of TIMP3 variants in SFD may be (toxic) aggregation rather than loss of inhibitory activity.

FAVariants: Variants used were equivalent to NM_000362.5(TIMP3):c.610A>T (p.Ser204Cys) (ClinVarID:12676), NM_000362.5(TIMP3):c.536C>G, (p.Ser179Cys) (ClinVarID:12678), and NM_000362.5(TIMP3):c.484G>T (p.Glu162X) (ClinVarID:12680).

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: as mentioned

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

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

ClinVar: 56544 and 56529

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

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

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

CasePMIDs: N/A

PMID: 29559409

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: 22282595

Gene: IFT140

HGNC: 29077

Disease: polycystic kidney disease

MONDO: 0020642

InheritancePattern: autosomal dominant

Prevalence: The overall prevalence of polycystic kidney disease is between 1 in 400 and 1 in 1,000 individuals (PMID: 30523303).

Penetrance: Disease caused by monoallelic IFT140 variants is incompletely penetrant.

FamilyLabel: Pineda-Trujillo_Family_1

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

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

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

FamilyNotHPOFreeText: N/A

CountryOrigin: Colombia

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

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

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

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

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

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

Affected: 2

Unaffected: 9

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

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Pineda-Trujillo_Patient_NCL-22

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

ClinVar: 2567

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

FamilyAddInfo: N/A

FamilyPMIDs: N/A

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

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

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

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

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: N/A

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

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

ClinVar: 1459979

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

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

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

CasePMIDs: N/A

Case#:Table II, MPS-I, Enzyme activity=1.15

DiseaseAssertion: MPS1

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: 1.15 umol/hr/L blood (newborn blood spot)

CaseUrineGAGs:

CaseERT:

CaseBMT:

Variant1:c.246C>G (p.His82Gln)

Variant1ClinVarID: 92637

Variant1CAID: CA220506

Variant2: c.246C>G (p.His82Gln)

Variant2ClinVarID: 92637

Variant2CAID: CA220506

AdditionalVariants:

ParentalGenotype:

PreviouslyPublished

Case#:Table II, MPS-1, Enzyme activity=1.05

DiseaseAssertion: MPS1

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: 1.05 umol/hr/L blood, newborn blood spot

CaseUrineGAGs:

CaseERT:

CaseBMT:

Variant1:c.208C>T (p.Gln70X)

Variant1ClinVarID: 11909

Variant1CAID: CA204563

Variant2: c.208C>T (p.Gln70X)

Variant2ClinVarID: 11909

Variant2CAID: CA204563

AdditionalVariants:

ParentalGenotype:

PreviouslyPublished

Case#: 3 (19 y, male - cousin of Cases 1 and 2, symptom onset/pain+movement limittion 12y, diagnosis 19y))

DiseaseAssertion: Scheie syndrome

FamilyInfo: Male patient born to consanguineous parents

CasePresentingHPOs:

CaseHPOFreeText: electroneurology showed bilateral signs of mild median nerve suffering.

CaseNotHPOs: 0034337;HP:0001510; HP:0000943

CaseNotHPOFreeText: no coarse face, growth failure, other joint involvement, evidence of dysostosis multiplex of other bones. Normal intelligence, ophthalmologic, hearing and echocardiography, brain MRI

CaseEnzymeAssay: 0.57 (umol/g/h)

CaseUrineGAGs:

CaseERT: Yes, after diagnosis at 19y

CaseBMT:

Variant1:c.1189+4A>T

Variant1ClinVarID:

Variant1CAID: CA2586965965

Variant2: 1189+4A>T

Variant2ClinVarID:

Variant2CAID: CA2586965965

AdditionalVariants:

ParentalGenotype:

PreviouslyPublished

PMID: 31064749

Gene: VWF

HGNC: 12726

Disease: von Willebrand Disease Type 2

MONDO: 0013304

InheritancePattern: Autosomal Dominant (for Types 2A, 2B and 2M) or Autosomal Recessive (for Type 2N)

Prevalence: Overall VWD prevalence is estimated to be as high as 1 in 100 in the general population, with 1 in 10,000 pursuing tertiary care referral ((PMID: 28847738).

Penetrance: Fully penetrant / nearly fully penetrant for most pathogenic variants

PMID: 9723578

Gene: VWF

HGNC: 12726

Disease: von Willebrand disease type 2B

MONDO: 0015629

InheritancePattern: Autosomal Dominant

Prevalence: Overall VWD prevalence is estimated to be as high as 1 in 100 in the general population, with 1 in 10,000 pursuing tertiary care referral ((PMID: 28847738).

Penetrance: Fully penetrant / nearly fully penetrant for most pathogenic type 2 variants

PMID: 32664776

Gene: VWF

HGNC: 12726

Case: Moreno-Castano_2021_Case_1, female, age 21 at time of study

DiseaseAssertion: VWD2A

FamilyInfo: The phenotypes of the affected propositus, the two unaffected parents, and the unaffected sibling are documented in Table I and Figure 1, while the family relationsihps and genotypes are not shown but described.

ParentalGenotype(s): The parental genotypes are negative for the variant, indicating that the variant is likely de novo in the proband.

CasePresentingHPOs: HP:0030129 (Impaired ristocetin cofactor assay activity), HP:0011871 (Impaired ristocetin-induced platelet aggregation), HP:0040225 (Decrease in high molecular weight von Willebrand factor Multimers), HP:0000978 (Bruising susceptibility), HP:0000421 (Epistaxis)

CaseHPOFreeText: Low VWF:RCo/VWF:Ag ratio

CaseNOTHPOs: HP:0030976 (Abnormal factor VIII activity)

CaseNOTHPOFreeText: Normal / slightly higher VWF antigen level

CasePreviousTesting: Because of the detailed clinical phenotype, genotyping was limited to the VWF locus alone.

GenotypingMethod: Genotyping consisted of PCR amplification and Sanger sequencing of the 52 exons of the VWF gene, as well as linkage analysis using four STRs located within the VWF locus.

PreviouslyPublished: The case appears to have been first published in PMID: 28971901.

Gene: VWF

Variant: NM_000552.5(VWF):c.8318G>C (p.Cys2773Ser)

ClinVarID: 100503

gnomAD: This variant is absent from gnomAD v2.1.1 and v3.1.2.

PMID: 25431025

Gene: VWF

HGNC: 12726

Disease: von Willebrand disease type 2B

MONDO: 0015629

InheritancePattern: Autosomal Dominant

Prevalence: Overall VWD prevalence is estimated to be as high as 1 in 100 in the general population, with 1 in 10,000 pursuing tertiary care referral ((PMID: 28847738).

Penetrance: Fully penetrant / nearly fully penetrant for most pathogenic type 2 variants

PMID: 9473222

Gene: VWF

HGNC: 12726

Disease: von Willebrand disease type 2M

MONDO: 0015630

InheritancePattern: Autosomal Dominant

Prevalence: Overall VWD prevalence is estimated to be as high as 1 in 100 in the general population, with 1 in 10,000 pursuing tertiary care referral (PMID: 28847738).

Penetrance: Fully penetrant / nearly fully penetrant for most pathogenic type 2 variants

FamilyLabel: Hillery_1998_Family_A

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

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

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

PMID: 22197721

Gene: VWF

HGNC: 12726

Disease: von Willebrand Disease Type 2N

MONDO: 0015631

InheritancePattern: Autosomal Recessive

Prevalence: Various sources (PMID: 28847738, PMID:19809303, PMID:29115006) can be combined to estimate the prevalence of VWD Type 2N between 1:15,000 and 1:80,000.

Penetrance: VWD type 2 is fully penetrant / nearly fully penetrant for most pathogenic variants.

PMID: 17139364

Gene: VWF

HGNC: 12726

PMID: 23636243

Gene: VWF

HGNC: 12726

Disease: von Willebrand Disease Type 2N

MONDO: 0015631

InheritancePattern: Autosomal Recessive

Prevalence: Various sources (PMID: 28847738, PMID:19809303, PMID:29115006) can be combined to estimate the prevalence of VWD Type 2N between 1:15,000 and 1:80,000.

Penetrance: VWD type 2 is fully penetrant / nearly fully penetrant for most pathogenic variants.

PMID: 25851809

Gene: VWF

HGNC: 12726

Disease: von Willebrand disease type 2B

MONDO: 0015629

InheritancePattern: Autosomal Dominant

Prevalence: Overall VWD prevalence is estimated to be as high as 1 in 100 in the general population, with 1 in 10,000 pursuing tertiary care referral ((PMID: 28847738).

Penetrance: Fully penetrant / nearly fully penetrant for most pathogenic type 2 variants

PMID: 6426499

Gene: VWF

HGNC: 12726

Disease: von Willebrand disease type 2M

MONDO: 0015630

InheritancePattern: Autosomal Dominant

Prevalence: Overall VWD prevalence is estimated to be as high as 1 in 100 in the general population, with 1 in 10,000 pursuing tertiary care referral ((PMID: 28847738).

Penetrance: Fully penetrant / nearly fully penetrant for most pathogenic type 2 variants

PMID: 40298995

Gene: VWF

HGNCID: HGNC:12726

ExperimentName: Factor VIII binding assays for variants exogenously expressed in COS-7 cells

NonPatientCell: COS-7 cell line (CLO:0002597, EFO:0002009)

GeneFunction: GO:0005515 (protein binding, specifically to Factor VIII)

GeneAlteration: Site-directed mutagenesis was used to introduce a mutation encoding "His54Gln" (corresponding to the p.His817Gln substitution from the variant) into the mature (cleaved) VWF protein.

FunctionalEvidence: The variant did not disrupt multimer formation (Figure 5) but reduced Factor VIII binding to 75% of wild-type levels (Figure 6). In combination with another missense mutation in cis that reduced Factor VIII binding by an additional 21-23%, and a frameshift mutation in trans predicted to cause the absence of a gene product, the variant appears likely to be contributing to pathogenicity.

FAVariants: A construct equivalent to the c.2451T>A (p.His817Gln) variant was used (ClinVar:100224), although it expressed the proteolytically processed version of the protein product and referred to the variant as "His54Gln".

PMID: 20409624

Gene: VWF

HGNC: 12726

Disease: von Willebrand disease type 2B

MONDO: 0015629

InheritancePattern: Autosomal Dominant

Prevalence: Overall VWD prevalence is estimated to be as high as 1 in 100 in the general population, with 1 in 10,000 pursuing tertiary care referral ((PMID: 28847738).

Penetrance: Fully penetrant / nearly fully penetrant for most pathogenic type 2 variants

PMID: 28491642

Gene: ACTC1

HGNC ID: 143

PMID: 28491642

Gene: ACTC1

HGNC ID: 143

PMID: 28491642

Gene: ACTC1

HGNC ID: 143

PMID: 32370479

Gene: MYH7

HGNC: 7577

PMID: 23707328

Gene: MYH7

HGNC: 7577

PMID: 32461996

Gene: MYH7

HGNC: 7577

PMID: 23674365

Gene: MYH7

HGNC: 7577

PMID: 20301725

Gene: MYH7

HGNC: 7577

"The purpose of this overview is to increase clinician awareness of the genetic basis of hypertrophic cardiomyopathy (HCM) and the benefits of early diagnosis and management to individuals with genetic HCM."

PMID: 32830170

Gene: MYH7

HGNC: 7577

PMID: 32380038

Gene: MYH7

HGNC: 7577

Case2: female, 16 years old

DiseaseAssertion: Myopathy

FamilyInfo:

CasePresentingHPOs: HP:0040083, HP:0002650, HP:0003722, HP:0001371, HP:0009027, HP:0012515

"Toe walking, Scoliosis, Neck flexor weakness, Flexion contractures, Foot dorsiflexor weakness, Hip flexor weakness"

CaseHPOFreeText: Presented with toe-walking at age 5 years and required bilateral tendo-Achilles releases at ages 7 and 13 years. A progressive scoliosis required surgical stabilization at age 12 years. At age 13 years neck movements were markedly restricted in all directions except extension, and there were mild flexion contractures at the hips, knees and ankles. There was marked neck flexion weakness, moderate weakness of hip extension and ankle dorsiflexion, and mild weakness of shoulder abduction, hip flexion and knee flexion/extension. While walking her upper body was angled forward, there was external rotation of the feet and mild foot-drop. The axial involvement in this case largely spares the lumbar musculature and is restricted to the upper thoracic and neck regions.

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: Serum creatine kinase was 308 iu/l (24–215). There was moderate restrictive lung disease (as determined by formal pulmonary function testing) at age 12 years (FVC 55% of predicted). Electromyography, sural nerve biopsy and cardiac investigations (EKG and echocardiogram) were normal. A quadriceps muscle biopsy taken at age 13 years demonstrated congenital fiber type disproportion. There was type 1 fiber predominance (82%), marked type 1 hypotrophy and type 2 fiber hypertrophy. Muscle MRI scan at age 12 years showed selective fatty infiltration of spinalis muscles in the upper thoracic and cervical regions. Unreported heterozygous variants in RYR1 (p.Asn4200Ser), COL6A3 (p.Ser2829Pro) and TTN (p.Gly4604Glu) were detected, but were all present in a healthy parent. In addition, Sanger sequencing was normal for ACTA1, SEPN1, LMNA, TPM3, TPM2, TNNT1 and MYOZ2.

GenotypingMethod: A heterozygous MYH7 p.Leu1597Arg (c.4790T>G) missense change was found by whole exome sequencing studies, and confirmed by Sanger sequencing. This change was absent in parental DNA samples.

Variant: NM_000257.4:c.4790T>G (MYH7)

ClinVar: not found

CAID: CA389037627

gnomAD: not found

PMCID: 6447666

Gene: MYH7

HGNC: 7577

PMID: 23711808