Molecular and phenotypic investigation of a New Zealand cohort of childhood-onset retinal dystrophy

Inherited retinal diseases are clinically heterogeneous and are associated with nearly 300 different genes. In this retrospective, observational study of a consecutive cohort of 159 patients (134 families) with childhood-onset (<16 years of age) retinal dystrophy, molecular investigations, and in-depth phenotyping were performed to determine key clinical and molecular characteristics. The most common ocular phenotype was rod-cone dystrophy in 40 patients. Leber Congenital Amaurosis, the most severe form of retinal dystrophy, was present in 10 patients, and early onset severe retinal dystrophy in 22 patients. Analysis has so far identified 131 pathogenic or likely pathogenic variants including 22 novel variants. Molecular diagnosis was achieved in 112 of 134 families (83.6%) by NGS gene panel investigation in 60 families, Sanger sequencing in 27 families, and Asper microarray in 25 families. An additional nine variants of uncertain significance were also found including three novel variants. Variants in 36 genes have been identified with the most common beingABCA4retinopathy in 36 families. Five sporadic retinal dystrophy patients were found to have variants in dominant and X-linked genes (CRX,RHO,RP2, andRPGR) resulting in more accurate genetic counseling of inheritance for these families. Variants in syndromic associated genes includingALMS1,SDCCAG8, andPPT1were identified in eight families enabling directed systemic care.