6q22.1 microdeletion and susceptibility to pediatric epilepsy

Genomic copy-number variations (CNVs) constitute an important cause of epilepsies and other human neurological disorders.Recent advancement of technologies integrating genome-wide CNV mapping and sequencing is rapidly expanding the molecularfield of pediatric neurodevelopmental disorders. In a previous study, a novel epilepsy locus was identified on 6q16.3q22.31 bylinkage analysis in a large pedigree. Subsequent array comparative genomic hybridization (array CGH) analysis of four unrelatedcases narrowed this region to B5Mb on 6q22.1q22.31. We sought to further narrow the critical region on chromosome 6q22.Array CGH analysis was used in genome-wide screen for CNVs of a large cohort of patients with neurological abnormalities.Long-range PCR and DNA sequencing were applied to precisely map chromosomal deletion breakpoints. Finally, real-timeqPCR was used to estimate relative expression in the brain of the candidate genes. We identified six unrelated patients withoverlapping microdeletions within 6q22.1q22.31 region, three of whom manifested seizures. Deletions were found to be denovo in 5/6 cases, including all subjects presenting with seizures. We sequenced the deletion breakpoints in four patientsand narrowed the critical region to a B250-kb segment at 6q22.1 that includes NUS1, several expressed sequence tags(ESTs) that are highly expressed in the brain, and putative regulatory sequences of SLC35F1. Our findings indicate thatdosage alteration in particular, of NUS1, EST AI858607, or SLC35F1 are important contributors to the neurodevelopmentalphenotype associated with 6q22 deletion, including epilepsy and tremors.European Journal of Human Genetics advance online publication, 14 May 2014; doi:10.1038/ejhg.2014.75INTRODUCTIONDespite a wealth of information on the developmental pathways thatoperate during neurogenesis, only a limited number of epileptogenicgenes were identified before the advent of high-throughput techno-logies for studies of structural genomic variations. It has now becomeclear that copy-number variations (CNVs) frequently cause epilepsyand contribute to other neurodevelopmental disorders, includingintellectual disability, neuropsychiatric disorders, autism spectrumdisorder (ASD), and behavior abnormalities. Undoubtedly, the impactof recurrent genomic CNVs involving 14q12, 7q11.23, 15q13.3,16p11.2, and 16p13.11 loci on pediatric epilepsy and other neurode-velopmental problems is substantial.