X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes
2016
X-linked intellectual disability(XLID) is a clinically and genetically
heterogeneous disorder. During the past two decades in excess of 100
X-chromosomeID genes have been identified. Yet, a large number of families mapping to the
X-chromosomeremained 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 sequencingof all
X-chromosomeexons in the index males. The majority of these males were previously tested negative for
copy number variationsand for mutations in a subset of known XLID genes by
Sanger sequencing. In total, 745
X-chromosomalgenes 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
CNKSR2variants 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-chromosomalgenes in a cohort of patients with genetic evidence for
X-chromosomelocus involvement may resolve up to 58% of Fragile X-negative cases.
Keywords:
-
Correction
-
Source
-
Cite
-
Save
140
References
183
Citations
NaN
KQI