Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes

Retinal dystrophy (RD) is a heterogeneous group of hereditary diseases caused by loss of photoreceptor function and contributes significantly to the etiology of blindness globally but especially in the industrialized world. The extreme locus and allelic heterogeneity of these disorders poses a major diagnostic challenge and often impedes the ability to provide a molecular diagnosis that can inform counseling and gene-specific treatment strategies. In a large cohort of nearly 150 RD families, we used genomic approaches in the form of autozygome-guided mutation analysis and exome sequencing to identify the likely causative genetic lesion in the majority of cases. Additionally, our study revealed six novel candidate disease genes (C21orf2, EMC1, KIAA1549, GPR125, ACBD5, and DTHD1), two of which (ACBD5 and DTHD1) were observed in the context of syndromic forms of RD that are described for the first time

Molecular Genetic Basis of Recessively Inherited Retinal Dystrophies in the Saudi Population

Inherited retinal dystrophies (IRD) are a remarkably genetically and phenotypically heterogeneous group of inherited eye diseases, with over 190 causative genes identified to date. In the highly consanguineous Saudi population, autosomal recessive forms of IRD are thought to account for the overwhelming majority of cases. Consanguinity is known to increase the frequency of recessive disorders since it increases the coefficient of inbreeding, which is a measure of the percentage of the genome that is identical by descent. Homozygosity mapping, targeted candidate gene analysis and whole exome sequencing were used to identify the causes of IRD in the Saudi population. Retinitis pigmentosa (RP) is the most common form of IRD, and mutations in the RP1 gene cause both recessive and dominant RP. Mutations in RP1 were found to be a common cause of recessive RP in the Saudi population. Novel and previously identified homozygous mutations in the KCNV2 gene were identified in a cohort of patients with a distinct recessive retinal disorder, ‘cone dystrophy with supranormal rod response,’ demonstrating phenotype/genotype correlation. In addition, a founder homozygous CABP4 mutation was identified in four consanguineous Saudi families with clinical features including congenital nystagmus, stable low vision, photophobia and a normal or near-normal fundus appearance, and no symptom of night blindness. Causative homozygous mutations were also found in the IRD genes RBP3, RDH12, CRB1, BBS4, CNGA3, CNGB1, EYS, RLBP1, ABCA4 and PCDH12 in Saudi patients. Four novel candidate genes for retinal degeneration were identified in this study. Potentially pathogenic homozygous variants were identified in EMC1 (c.G430A, p.A144T), KIAA1549 (c.2399_2400insAA, p.T800fs809X), GPR125 (c.C2504G, p.S835C) and DHX29 (c.C2738T, p.A913V). In the majority of cases (31 families) the genetic cause of IRD was identified, demonstrating the power of homozygosity mapping and whole exome sequencing. In four families (3 multiplex and 1 simplex case), however, no potentially pathogenic homozygous variants were identified, indicating that other novel loci and genes may be implicated as causing IRD in the Saudi population