Whole exome sequencing reveals a mutation in ARMC9 as a cause of mental retardation, ptosis, and polydactyly

Am J Med Genet A. 2018 Jan;176(1):34-40. doi: 10.1002/ajmg.a.38537. Epub 2017 Nov 21.

Abstract

Intellectual disability (ID) refers to deficits in mental abilities, social behavior, and motor skills to perform activities of daily living as compared to peers. Numerous genetic and environmental factors may be responsible for ID. We report on elucidation of molecular basis for syndromic ID associated with ptosis, polydactyly, and MRI features suggestive of Joubert syndrome using homozygosity mapping followed by exome sequencing. The analysis revealed a novel synonymous variation p.T293T (c.879G>A) which leads to a splicing defect in ARMC9 gene. The variant is present in conserved region of ARM domain of ARMC9 protein, which is predicted to form a platform for protein interaction. This domain is likely to be altered in patient due to splicing defect caused by this synonymous variation. Our report of variant in ARMC9 Leading to Joubert syndrome phenotype (JS30), elucidates the genetic heterogeneity of Joubert syndrome, and expands the gene list for ciliopathies.

Keywords: ARMC9; exome sequencing; homozygosity mapping; intellectual disability; splice site assay.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Armadillo Domain Proteins / chemistry
  • Armadillo Domain Proteins / genetics*
  • Blepharoptosis / diagnosis
  • Blepharoptosis / genetics*
  • Brain / abnormalities
  • DNA Mutational Analysis
  • Exome Sequencing*
  • Exome*
  • Female
  • Genetic Association Studies
  • Genotype
  • Humans
  • Intellectual Disability / diagnosis
  • Intellectual Disability / genetics*
  • Magnetic Resonance Imaging
  • Male
  • Models, Molecular
  • Mutation*
  • Pedigree
  • Phenotype
  • Polydactyly / diagnosis
  • Polydactyly / genetics*
  • Protein Conformation
  • RNA Splice Sites
  • Structure-Activity Relationship
  • Syndrome

Substances

  • ARMC9 protein, human
  • Armadillo Domain Proteins
  • RNA Splice Sites