CRB1-related retinopathy overlapping the ocular phenotype of S-adenosylhomocysteine hydrolase deficiency

BACKGROUND: S-adenosylhomocysteine hydrolase deficiency due to pathologic variants in AHCY gene is a rare neurometabolic disease for which no eye phenotype has been documented. Pathologic variants in CRB1 gene are known to cause a wide spectrum of autosomal recessive retinal diseases with Leber's congenital amaurosis as a most common. The aim of this study is to report co-inheritance of neurometabolic disease and eye disease in a pedigree. MATERIALS AND METHODS: Comprehensive eye examination was performed in available family members together with color vision test, visual fields, fundus images, OCT, electroretinogram and visual evoked potentials. Genetic testing included whole-exome sequencing (WES), retinal dystrophy gene panel and segregation analysis. RESULTS: Two children from a family not known to be consanguineous were affected with neurometabolic disease and one of them presented with reduced vision due to maculopathy. The mother had symptoms of retinal degeneration of unspecified cause. Clinical WES revealed homozygous missense pathologic variants in AHCY gene c.148G>A, p.(Ala50Thr) as a cause of S-adenosylhomocysteine hydrolase deficiency. Retinal dystrophy gene panel sequencing revealed two heterozygous missense pathologic variants in CRB1 gene c.1831T>C, p.(Ser611Pro) and c.3955T>C, p.(Phe1319Leu) in the proband and her mother. These variants segregated with disease phenotype in family members. CONCLUSIONS: Establishing an ocular genetic diagnosis may be challenging with the co-existence of a rare systemic genetic disease with previously unknown eye involvement. Extensive phenotyping and genotyping of available family members showed that the proband and her mother shared a CRB1-related retinopathy at different stages while the brother did not.