X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes

Mol Psychiatry. 2016 Jan;21(1):133-48. doi: 10.1038/mp.2014.193. Epub 2015 Feb 3.


X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4(-/-) mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adolescent
  • Adult
  • Animals
  • Cells, Cultured
  • Chloride Channels / genetics
  • Chloride Channels / metabolism
  • Cohort Studies
  • Cyclin-Dependent Kinases / genetics
  • Genetic Variation*
  • High-Throughput Nucleotide Sequencing
  • Histone Acetyltransferases / genetics
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Male
  • Mental Retardation, X-Linked / genetics*
  • Mice, Knockout
  • Microfilament Proteins / genetics
  • Neurons / metabolism
  • Neurons / pathology
  • Nuclear Proteins / genetics
  • RNA, Messenger / metabolism
  • TATA-Binding Protein Associated Factors / genetics
  • Transcription Factor TFIID / genetics
  • Ubiquitin-Protein Ligases / genetics


  • Adaptor Proteins, Signal Transducing
  • CLC-5 chloride channel
  • CLCN4 protein, human
  • CNKSR2 protein, human
  • Chloride Channels
  • FRMPD4 protein, human
  • Intracellular Signaling Peptides and Proteins
  • KLHL15 protein, human
  • Las1L protein, human
  • Microfilament Proteins
  • Nuclear Proteins
  • RNA, Messenger
  • TATA-Binding Protein Associated Factors
  • Transcription Factor TFIID
  • Histone Acetyltransferases
  • RLIM protein, human
  • Ubiquitin-Protein Ligases
  • TATA-binding protein associated factor 250 kDa
  • Cyclin-Dependent Kinases
  • PCTAIRE-1 protein kinase