Whole-exome sequencing identifies ALMS1, IQCB1, CNGA3, and MYO7A mutations in patients with Leber congenital amaurosis

Hum Mutat. 2011 Dec;32(12):1450-9. doi: 10.1002/humu.21587. Epub 2011 Sep 23.

Abstract

It has been well documented that mutations in the same retinal disease gene can result in different clinical phenotypes due to difference in the mutant allele and/or genetic background. To evaluate this, a set of consanguineous patient families with Leber congenital amaurosis (LCA) that do not carry mutations in known LCA disease genes was characterized through homozygosity mapping followed by targeted exon/whole-exome sequencing to identify genetic variations. Among these families, a total of five putative disease-causing mutations, including four novel alleles, were found for six families. These five mutations are located in four genes, ALMS1, IQCB1, CNGA3, and MYO7A. Therefore, in our LCA collection from Saudi Arabia, three of the 37 unassigned families carry mutations in retinal disease genes ALMS1, CNGA3, and MYO7A, which have not been previously associated with LCA, and 3 of the 37 carry novel mutations in IQCB1, which has been recently associated with LCA. Together with other reports, our results emphasize that the molecular heterogeneity underlying LCA, and likely other retinal diseases, may be highly complex. Thus, to obtain accurate diagnosis and gain a complete picture of the disease, it is essential to sequence a larger set of retinal disease genes and combine the clinical phenotype with molecular diagnosis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Calmodulin-Binding Proteins / genetics*
  • Cell Cycle Proteins
  • Child, Preschool
  • Chromosome Mapping
  • Consanguinity
  • Cyclic Nucleotide-Gated Cation Channels / genetics*
  • DNA Mutational Analysis
  • Exome / genetics*
  • Family
  • Homozygote
  • Humans
  • Leber Congenital Amaurosis / genetics*
  • Leber Congenital Amaurosis / pathology
  • Mutation*
  • Myosin VIIa
  • Myosins / genetics*
  • Pedigree
  • Proteins / genetics*
  • Saudi Arabia
  • Sequence Analysis, DNA

Substances

  • ALMS1 protein, human
  • CNGA3 protein, human
  • Calmodulin-Binding Proteins
  • Cell Cycle Proteins
  • Cyclic Nucleotide-Gated Cation Channels
  • IQCB1 protein, human
  • MYO7A protein, human
  • Myosin VIIa
  • Proteins
  • Myosins