PatientID: V1

KindredID: 1

Case: M, 24Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: This patient’s brother also had this germline mutation and at least one brainstem hemangioblastoma at 30 years old.

CasePresentingHPOs: HP:0006880 (Cerebellar hemangioblastoma)

CaseHPOFreeText: Study reports 2 cerebellar hemangioblastomas at the ages of 22 and 24. Other phenotype information not provided.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table 2

Variant: p.Q73Rfs*86 (c.216del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432536422, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA432536422

gnomAD: N/A

VariantEvidence: The c.216delC variant was not genetically confirmed to be germline but was found in tumor samples from both the siblings.

MutationType: minus_1_frameshift_variant

CivicName: S72fs (c.216delC)

MultipleGeneVariants: N/A

FamilyLabel: Danciger_2001_Family

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

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

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: Brazil

Ethnicity: Brazilian

Race: Not described

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

Family#Method1: Linkage mapping using short tandem repeat markers

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

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

Affected: 5

Unaffected: 7

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

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

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Danciger_2001_Family_Patient_A

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

ClinVar: 6876

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

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

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

FamilyPMIDs: PMID: 19409519

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

PMID: 11581183

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.

Case#: Parry_2009_Family_MOL0277_patient_IV:2, male, age not specified, family origin reported to be Arab Muslim

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

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

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

CaseNotHPOFreeText: N/A

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

CaseMethod1: Autozygosity mapping

CaseMethod2: Sanger sequencing

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

Variant: The proband harbors the NM_003816.3(ADAM9):c.411-8A>G variant in the homozygous state.

ClinVar: 6879

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

VariantEvidence: NM_003816.3(ADAM9):c.411-8A>G is a variant in intron 5 that has been shown to trigger aberrant splicing and abolish normal splicing by activating use of a cryptic splice acceptor site (Figure 2B). The predicted result is to add 7 bp to the 5' end of exon 6 and introduce a frameshift causing premature termination. Since this affects exon 6 of 21, the predicted result is nonsense-mediated decay or truncation of the C-terminal 83% of the protein product (p.Arg137SerfsX16).

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

CasePMIDs: N/A

PMID: 19409519

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.

ExperimentName: Mouse model of Adam9 loss-of-function

NonHumanModel: Mus musculus

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

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

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

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

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

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

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

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

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

CaseNotHPOFreeText: N/A

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

CaseMethod1: Autozygosity mapping

CaseMethod2: Sanger sequencing

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

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

ClinVar: 6877

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

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

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

CasePMIDs: N/A

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

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

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

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

CaseNotHPOFreeText: N/A

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

CaseMethod1: Autozygosity mapping

CaseMethod2: Sanger sequencing

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

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

ClinVar: 6878

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

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

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

CasePMIDs: N/A

PMID: 23661369

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.

Case#: Fu_2013_Patient_4263_1, male, age 9 at time of report, family origin reported to be Chinese

CasePresentingHPOs: HP:0030534 (Abnormal best corrected visual acuity test), HP:0000662 (Nyctalopia), HP:0007663 (Reduced visual acuity), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude), HP:0007984 (Electronegative electroretinogram), HP:0410280 (Pediatric onset)

CaseHPOFreeText: The proband was initially diagnosed with retinitis pigmentosa with an autosomal recessive pattern of inheritance, and subsequently re-diagnosed with cone-rod dystrophy with early-onset retinal dystrophy.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was initially genotyped by next-generation sequencing focusing on a panel of 163 known retinal disease genes.

CaseMethod1: Next-generation sequencing panel (163 genes)

CaseMethod2: Sanger sequencing of ADAM9

CaseGenotypingMethod: The proband was initially genotyped by next-generation sequencing focusing on a panel of 163 known retinal disease genes, followed by Sanger sequencing of ADAM9.

Variant: The proband harbors the NM_003816.3(ADAM9):c.1786C>T (p.Arg596Ter) variant in the homozygous state.

CAID: CA370746588

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

VariantEvidence: NM_003816.3(ADAM9):c.1786C>T (p.Arg596Ter) is a nonsense variant in exon 16 of 21, which is predicted to trigger NMD or to truncate the C-terminal ~27% of the protein product.

CaseAddInfo: The proband's parents are consanguineous and are each heterozygous for the variant, while his unaffected sister does not carry the variant.

CasePMIDs: N/A

PMID: 11162558

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.

Selection B- Gene function is consistent with phenotype.

Title: ADAM9 (MDC-9) functions as an adhesion molecule by interacting with integrins.

GOterm: GO:0033630 (positive regulation of cell adhesion mediated by integrin)

FunctionalEvidence: Melanoma cells bind to they the immobilized recombinant ADAM9 disintegrin domain in a manner that is dependent on divalent cations (Mn2+ or Ca2+). The interaction can also be disrupted by an antibody to the alpha(v)beta(5) integrin, indicating that the cell-cell adhesion function of ADAM9 is mediated by an interaction with this molecule.

FunctionalHPO: HP:0000546 (Retinal degeneration), HP:0007703 (Abnormality of retinal pigmentation), HP:0030610 (Photoreceptor outer segment loss on macular OCT

PhenotypeEvidence: This evidence is consistent with evidence that Adam9 knockout mice exhibit a gap between the photoreceptor outer nuclear segment and the retinal pigment epithelium, indicating that loss of this adhesion molecule may impair the integrity of retinal organization.

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.

Case#: El-Haig_2014_Proband, female, age not specified, family origin reported to be Egyptian

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000548 (Cone/cone-rod dystrophy), HP:0007787 (Posterior subcapsular cataract), HP:0010923 (Anterior subcapsular cataract), HP:0000505 (Visual impairment), HP:0007703 (Abnormality of retinal pigmentation), HP:0007843 (Attenuation of retinal blood vessels), HP:0000543 (Optic disc pallor)

CaseHPOFreeText: The proband and her affected family members have been diagnosed with cone-rod dystrophy, with the family showing an autosomal recessive mode of inheritance.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and her family were initially genotyped by IROme, which generates a hybridization-based DNA library of the 64 most frequently mutated genes in retinal dystrophy, then analyzes it by high-throughput sequencing.

CaseMethod1: Next-generation sequencing panel

CaseMethod2: Sanger sequencing of ADAM9 exon 14 and flanking exon-intron junctions

CaseGenotypingMethod: The proband and her family were initially genotyped by IROme, which generates a hybridization-based DNA library of the 64 most frequently mutated genes in retinal dystrophy, then analyzes it by high-throughput sequencing. Sanger sequencing of ADAM9 exon 14 and flanking exon-intron junctions was then performed.

Variant: The proband harbors the NM_003816.3(ADAM9):c.1396-2A>G variant in the homozygous state.

ClinVar: 189795

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

VariantEvidence: NM_003816.3(ADAM9):c.1396-2A>G is a variant disrupting a canonical splice site in intron 13, which is predicted but not confirmed to disrupt mRNA splicing.

CaseAddInfo: The proband is from a consanguineous family and has two affected sons who are also homozygous for the variant, as well as five unaffected heterozygous family members.

CasePMIDs: N/A

PMID: 19273593

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.

Selection B- Gene function is consistent with phenotype.

Title: ADAM9 enhances protelytic shedding of membrane protein ectodomains.

GOterm: GO:0006509 (membrane protein ectodomain proteolysis), GO:0045765 (regulation of angiogenesis)

FunctionalEvidence: ADAM9 over-expression in COS-7 cells enhances proteolytic shedding of membrane proteins involved in angiogenesis (Figure 5). This effect is further enhanced by reactive oxygen species (Figures 6, 7).

FunctionalHPO: HP:0007843 (Attenuation of retinal blood vessels), HP:0000546 (Retinal degeneration)

PhenotypeEvidence: This evidence is consistent with attenuation of retinal blood vessels observed in human patients as well as the finding from this same paper that Adam9 knockout mice exhibit reduced ocular neovascularization (Figures 1, 3).

ExperimentName: Canine model of Adam9 loss-of-function

NonHumanModel: Canis lupus familiaris

GeneAlteration: The affected dogs have homozygous disruption of the Adam9 gene by a deletion of regions from exons 15 and 16.

ModelPhenotype: HP:0001105 (Retinal atrophy), HP:0000529 (Progressive visual loss), HP:0000580 (Pigmentary retinopathy), HP:0000662 (Nyctalopia)

HumanPhenotype: HP:0011463 (Childhood onset), HP:0000548 (Cone/cone-rod dystrophy), HP:0007663 (Reduced visual acuity), HP:0001141 (Severely reduced visual acuity), HP:0007994 (Peripheral visual field loss), HP:0000545 (Myopia), HP:0000483 (Astigmatism), HP:0000523 (Subcapsular cataract)

ModelEvidence: The affected dogs have been described as having generalized progressive retinal atrophy. Complete loss of all retinal layers was observed in affected animals (Figures 1H-1P). This matches the mode of inheritance and progressive nature of the human disease state, as well as the retinal abnormalities and visual defects.

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

PMID: 20691256

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.