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

Csilla H. Lazar, Adva Kimchi, Prasanthi Namburi, Mousumi Mutsuddi, Lina Zelinger, Avigail Beryozkin, Shiran Ben-Simhon, Alexey Obolensky, Ziva Ben-Neriah, Zohar Argov, Eli Pikarsky, Yakov Fellig, Devorah Marks-Ohana, Rinki Ratnapriya, Eyal Banin, Dror Sharon, Anand Swaroop*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

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. 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.

Original languageAmerican English
Pages (from-to)836-841
Number of pages6
JournalHuman Mutation
Volume36
Issue number9
DOIs
StatePublished - 1 Sep 2015
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2015 WILEY PERIODICALS, INC..

Keywords

  • ALMS1
  • DYSF
  • Photoreceptor
  • Pleiotropic phenotypes
  • Retinal degeneration
  • Vision loss

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