A non-coding mutation implicates HCFC1 in non-syndromic intellectual disability. Homo sapiens

Human disease mutation discovery has so far been biased towards protein coding regions. Having excluded all annotated coding regions, we performed targeted massively parallel re-sequencing of the non-repetitive genomic linkage interval of the MRX3 family at Xq28. We identified a regulatory mutation in the YY1 transcription factor binding site, which leads to overexpression of the chromatin-associated transcriptional regulator, HCFC1. When tested on embryonic murine neural stem cells (NSCs) and embryonic hippocampal neurons, HCFC1 overexpression led to a significant increase of the production of astrocytes and considerable reduction in neurite growth. Two other non-synonymous, potentially deleterious changes have been identified by X-exome sequencing in individuals with intellectual disability, implicating HCFC1 in normal brain function. Overall design: Total RNA was extracted from LCL derived from four unrelated male controls, five unrelated female controls and two affected male cousins from the MRX3 family.