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Cadherin-related family member 1 (CDHR1) is a photoreceptor-specific cadherin critical for outer segment morphogenesis. Biallelic CDHR1 variants cause autosomal recessive cone-rod dystrophy (MONDO:0015993), characterized by early cone dysfunction followed by rod involvement. Genetic and experimental evidence support a strong gene–disease relationship enabling diagnostic testing and therapeutic development.
Three siblings from a consanguineous pedigree presented at ages 16–24 years with blurred central vision, dyschromatopsia (HP:0007641), photoaversion, and myopia. Fundoscopy showed macular pigmentary changes and subfoveal lesions; full-field electroretinography revealed severe cone-rod dysfunction. All three were homozygous for c.1463del (p.Gly488AlafsTer20) (PMID:24265541).
An independent case report described a 49-year-old man with progressive visual loss, granular macular hyperfluorescence, and diminished photopic ERG. Genetic testing confirmed homozygosity for the pathogenic c.783G>A (p.Pro261=) variant, defining CRD15. This expands the allelic and phenotypic spectrum of CDHR1-related dystrophy (PMID:36837600).
Targeted exome sequencing in 43 Japanese patients with cone and cone-rod dystrophies identified causative CDHR1 c.386A>G (p.Asn129Ser) in one individual, highlighting locus heterogeneity and confirming CDHR1 involvement in diverse populations (PMID:26957898).
In a cohort of seven sporadic and six familial cases, eleven novel CDHR1 variants were discovered in nine index patients with CRD or CD. Minigene assays for two non-canonical splice site changes demonstrated aberrant splicing, further validating variant pathogenicity (PMID:28765526).
Autosomal recessive inheritance is supported by segregation of biallelic variants in multiple families, including two additional affected siblings beyond the proband trio. The variant spectrum comprises loss-of-function frameshifts (e.g., c.1463del), missense substitutions, and splice site mutations, consistent with a haploinsufficiency mechanism.
Functional studies in zebrafish showed that Cdhr1a loss phenocopies cone and rod depletion, while overexpression of E3 ligase Siah1 reduces photoreceptor numbers in a proteasome-dependent manner. Rescue by cdhr1a mRNA and a Siah1-insensitive cdhr1a variant confirmed the critical role of CDHR1 in photoreceptor survival (PMID:33330480).
Together, strong genetic segregation, a broad allelic series, and concordant in vivo models establish CDHR1 as a definitive cause of autosomal recessive cone-rod dystrophy. Early molecular diagnosis via CDHR1 variant screening enables accurate prognosis, genetic counseling, and positions patients for emerging gene replacement therapies. Key take-home: CDHR1 testing is essential for clinical management of cone-rod dystrophy.
Gene–Disease AssociationStrong14 probands from 13 unrelated cases, segregation in three siblings, concordant functional data Genetic EvidenceStrong14 individuals with biallelic CDHR1 variants across multiple studies, autosomal recessive inheritance, diverse LoF and missense mutations Functional EvidenceModerateZebrafish Cdhr1a knock-out replicates photoreceptor loss; rescue experiments and splice assays confirm pathogenic mechanisms |