CDHR1 variants in a Japanese family with inherited retinal dystrophy and intrafamilial phenotypic variability

Introduction To report a Japanese family with inherited retinal dystrophy (IRD) in which CDHR1 variants were identified, and to characterize the marked intrafamilial phenotypic variability. Methods This retrospective case series included three brothers diagnosed with retinal dystrophy at Juntendo University Hospital. Comprehensive ophthalmic evaluations were performed, including best-corrected visual acuity (BCVA), Goldmann perimetry, fundus photography, fundus autofluorescence (FAF), optical coherence tomography (OCT), and full-field electroretinogram (ERG). Genetic testing was conducted using next-generation sequencing with an IRD gene panel. Results All three patients exhibited progressive visual decline with onset in their 40s–50s. Fundus examination revealed severe macular atrophy in two brothers (Cases 1 and 2), consistent with cone–rod dystrophy, whereas the youngest (Case 3) showed diffuse retinal degeneration with bone-spicule pigmentation resembling retinitis pigmentosa. FAF demonstrated hypoautofluorescence in the macula and hyperautofluorescence at the borders of atrophic areas in Cases 1 and 2, but widespread hypoautofluorescence in Case 3. ERG revealed rod–cone dysfunction in Cases 1 and 2 and non-recordable responses in Case 3. Genetic analysis identified a single heterozygous CDHR1 c.748C>A (p.Pro250Thr) variant in Case 1. In Cases 2 and 3, two heterozygous CDHR1 variants—c.748C>A (p.Pro250Thr) and c.2027T>A (p.Ile676Asn)—were detected. Case 1 as having a single heterozygous CDHR1 variant with a phenotype overlapping that of Cases 2 and 3, and explicitly note that the genetic diagnosis in Case 1 remains inconclusive. Conclusions This study describes a Japanese family with IRD showing substantial intrafamilial phenotypic heterogeneity, ranging from macular-predominant cone–rod dystrophy to generalized rod–cone dystrophy, in the context of identified CDHR1 variants. These findings highlight the complexity of genotype–phenotype correlations in CDHR1 -related retinal disease and underscore the importance of cautious interpretation of genetic results, particularly when variants of uncertain significance are identified.