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Nonsyndromic Early‐Onset Cone‐Rod Dystrophy and Limb‐Girdle Muscular Dystrophy in a Consanguineous Israeli Family are Caused by Two Independent yet Linked Mutations in ALMS1 and DYSF
Author(s) -
Lazar Csilla H.,
Kimchi Adva,
Namburi Prasanthi,
Mutsuddi Mousumi,
Zelinger Lina,
Beryozkin Avigail,
BenSimhon Shiran,
Obolensky Alexey,
BenNeriah Ziva,
Argov Zohar,
Pikarsky Eli,
Fellig Yakov,
MarksOhana Devorah,
Ratnapriya Rinki,
Banin Eyal,
Sharon Dror,
Swaroop Anand
Publication year - 2015
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22822
Subject(s) - genetics , biology , disease gene identification , muscular dystrophy , missense mutation , dystrophy , exome sequencing , facioscapulohumeral muscular dystrophy , phenotype , gene
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*, in ALMS1 and two novel potentially disease‐causing missense variants, p.R1581C and p.Y2070C, in DYSF . ALMS1 and DYSF are 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 in ALMS1 transcripts in the human retina. Our study thus implicates ALMS1 as a nonsyndromic retinal disease gene and suggests a potential role of variants in interacting cilia genes in modifying clinical phenotypes.