In a sibling pair from a consanguineous marriage (family B) and in a sibling pair from a nonconsanguineous family (family A), we identified large homozygous regions on chromosome 10 (11 Mb and 26 Mb, respectively) (Figure 1A). The common 26 Mb homozygous region in the sibs from family A was the largest homozygous region (SNP boundaries SNP_A-2260521 and SNP_A-1892358); the second, third, and fourth largest regions measured 8, 4.3, and 4.2 Mb. The overlapping 11 Mb homozygous region in the affected sibs of family B was the second largest homozygous region (SNP boundaries SNP_A-2003359 and SNP_A-1804692). The largest region in this family spanned 25 Mb; the third and fourth largest regions measured 10 and 6 Mb. The overlapping homozygous region in both families spanned the PDE6C gene but no other obvious candidate genes (Figure 1A; see also Table S1 available online). These regions were not found in other patients.
Case#: Thiadens_2009_Family_A_Proband_AII-2, male, age 6 years at onset and 51 years at the time of report, sites of treatment listed as the Netherlands, Belgium, U.K., or Canada
CasePresentingHPOs: HP:0030534 (Abnormal best corrected visual acuity test), HP:0000613 (Photophobia), HP:0000639 (Nystagmus), HP:0011003 (High myopia), HP:0000551 (Color vision defect, described as severe), HP:0030825 (Absent foveal reflex), HP:0007703 (Abnormality of retinal pigmentation, described as mild), HP:0030465 (Undetectable light-adapted electroretinogram)
CaseHPOFreeText: The proband and affected family member were previously diagnosed with early onset autosomal recessive cone dystrophy. The proband had onset by age 6 years.
CaseNotHPOs: HP:0007769 (Peripheral retinal degeneration)
CaseNotHPOFreeText: N/A
CasePreviousTesting: Affected and unaffected family members were initially subjected to homozygosity mapping based on Affymetrix GeneChIP SNP analysis, identifying an 11-Mb region of homozygosity shared with another unrelated family.
CaseMethod1: homozygosity mapping
CaseMethod2: screening of the 22 exons and flanking regions of PDE6C (the only strong candidate gene) using Sanger sequencing
CaseGenotypingMethod: Affected and unaffected family members were initially subjected to homozygosity mapping based on Affymetrix GeneChIP SNP analysis, identifying an 11-Mb region of homozygosity shared with another unrelated family. The clear candidate gene, PDE6C, was then subjected to Sanger sequencing-based screening of the 22 exons and flanking regions.
Variant: The proband harbors the NM_006204.4(PDE6C):c.85C>T (p.Arg29Trp) variant in the homozygous state.
ClinVar ID: 8763
gnomAD: The NM_006204.4(PDE6C):c.85C>T (p.Arg29Trp) variant is found in gnomAD v2.1.1 at a frequency of 0.00008009 (2/24972) in the African / African-American population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/10-95372567-C-T
VariantEvidence: NM_006204.4(PDE6C):c.85C>T (p.Arg29Trp) is a missense variant that does not have experimental evidence of a functional effect on the protein product. However, it has been reported in similarly affected individuals in other studies (PMID: 21127010, PMID: 30080950).
CaseAddInfo: The patient's affected sibling shares the same homozygous genotype, while the parents are unaffected and unrelated at least during the last 3 generations.
CasePMIDs: N/A