Nonsyndromic Early-Onset Cone-Rod Dystrophy and Limb-Girdle Muscular Dystrophy in a Consanguineous Israeli Family are Caused by Two Independent yet Linked Mutations inALMS1andDYSF

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Genetic analysis of clinical phenotypes in consanguineous families is complicated by coinheritance of large DNA regions carrying independent variants. Here, we characterized a family with early onset cone-rod dystrophy (CRD) and muscular dystrophy. Homozygosity mapping (HM) followed by whole exome sequencing revealed a nonsense mutation, p.R270*, inALMS1and two novel potentially disease-causing missense variants, p.R1581C and p.Y2070C, inDYSF.ALMS1andDYSFare genetically and physically linked on chromosome 2 in a genomic region suggested by HM and associated with Alström syndrome, which includes CRD, and with limb girdle muscular dystrophy, respectively. Affected family members lack additional systemic manifestations of Alström syndrome but exhibit mild muscular dystrophy. RNA-seq data did not reveal any significant variations inALMS1transcripts in the human retina. Our study thus implicatesALMS1as a nonsyndromic retinal disease gene and suggests a potential role of variants in interacting cilia genes in modifying clinical phenotypes.Cone-rod dystrophy and limb-girdle muscular dystrophy phenotypes in a consanguineous Arab family are caused by mutations in two linked genes – ALMS1 and DYSF – on chromosome 2.

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