Novel X-Linked Intellectual Disability Genes Identified

A novel group of genes on the X-chromosome that when mutated lead to the mental disorder X-linked intellectual disability (XLID) have been added to list of more than a 100 such genes that had been identified previously.

XLID is a generalized neurodevelopmental disorder characterized by significantly impaired intellectual and adaptive functioning. It is defined by an IQ score below 70 in addition to deficits in two or more adaptive behaviors that affect everyday general living. The syndrome is caused by mutations on the X-chromosome. Since males have only one X-chromosome and the syndrome is passed on in a recessive manner, the disorder mainly occurs in boys. Over the past 20 years more than 100 X-chromosome genes linked to XLID have been found. Nonetheless, intellectual disabilities that map to the X-chromosome remain unresolved in a large number of families, which suggests that more XLID genes or loci are yet to be identified.

To identify more XLID-linked genes investigators at the Max Planck Institute for Molecular Genetics (Berlin, Germany) employed massively parallel sequencing of all X-chromosome exons in the index males of 405 families with XLID of unknown origin. In total, 745 X-chromosomal genes were screened.

Results revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, the investigators detected likely causative protein truncating and missense variants in seven novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM, and USP27X) and potentially deleterious variants in two novel candidate XLID genes (CDK16 and TAF1). Furthermore, they showed that the CLCN4 and CNKSR2 variants impaired protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from mice lacking CLCN4 or after mRNA knock-down.

"In addition to known disease-related genes, we have discovered seven novel genes as the cause of X-linked intellectual disability and analyzed what signaling pathways in the cells each protein is involved in," said senior author Dr. Vera Kalscheuer, professor of human molecular genetics at the Max Planck Institute for Molecular Genetics. "The clinical presentation and severity of the disorder depend on the responsible gene and the nature of the mutation."

The study was published in the February 3, 2015, online edition of the journal Molecular Psychiatry.

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Max Planck Institute for Molecular Genetics