6q22.1 microdeletion and susceptibility to pediatric epilepsy

Abstract

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 molecular field of pediatric neurodevelopmental disorders. In a previous study, a novel epilepsy locus was identified on 6q16.3q22.31 by linkage analysis in a large pedigree. Subsequent array comparative genomic hybridization (array CGH) analysis of four unrelated cases narrowed this region to B5 Mb 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-time qPCR was used to estimate relative expression in the brain of the candidate genes. We identified six unrelated patients with overlapping microdeletions within 6q22.1q22.31 region, three of whom manifested seizures. Deletions were found to be de novo in 5/6 cases, including all subjects presenting with seizures. We sequenced the deletion breakpoints in four patients and 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 that dosage alteration in particular, of NUS1, EST AI858607, or SLC35F1 are important contributors to the neurodevelopmental phenotype associated with 6q22 deletion, including epilepsy and tremors.

cis-Prenyltransferase: New Insights into Protein Glycosylation, Rubber Synthesis, and Human Diseases

“…In both instances, mutations in NgBR or hCIT show altered ratios of dolichol chain lengths when measured in urine and plasma from affected carriers (47,80). Finally, chromosomal deletion within NgBR locus may play a role in driving susceptibility to pediatric epilepsy and congenital anomalies (81,82). Because epilepsy is commonly observed in congenital disorders of glycosylation (83), observed symptoms may be consistent with defects in dolichol synthesis and hypoglycosylation.…”

Moderating effect of mode of delivery on the genetics of intelligence: Explorative genome‐wide analyses in ALSPAC

“…Other notable interaction signals observed in this study are rs705670 on chromosome 9 for PIQ and rs1276529 on chromosome 6 for VIQ ( (Ripke et al, 2014;Vondervoort et al, 2013;Wapinski & Chang, 2011;Zayats et al, 2015), while RFPL4B gene has been linked to language delay (Szafranski et al, 2015) and neuropsychiatric conditions where IQ is also affected (Hudson et al, 2014;Sun, Cheng, Zhang, & Xu, 2015).…”

“…The first SNP (rs705670) is an intronic variant within a long non‐protein‐coding RNA (lncRNA) gene, LINC01502 , while rs1276529 is an intergenic SNP located 141,817 bp to RFPL4B (Ret Finger Protein‐Like 4B) gene. lncRNAs have recently been implicated in a number of neuropsychiatric disorders where IQ is affected, such as schizophrenia, fragile X syndrome, and attention‐deficit/hyperactivity disorder (Ripke et al, ; Vondervoort et al, ; Wapinski & Chang, ; Zayats et al, ), while RFPL4B gene has been linked to language delay (Szafranski et al, ) and neuropsychiatric conditions where IQ is also affected (Hudson et al, ; Sun, Cheng, Zhang, & Xu, ).…”

Phenotypic variability in patients with interstitial 6q21‐q22 microdeletion and Acro–Cardio–Facial syndrome

“…To date, interstitial microdeletions in the 6q21‐q22 region have been identified by molecular karyotyping in 15 cases including four entries in the Decipher database (https://decipher.sanger.ac.uk/) [Zherebtsov et al, ; Rosenfeld et al, ; Toschi et al, ; Hudson et al, ; Szafranski et al, ; Tassano et al, ]. We compared the clinical findings of our patient with the previously reported patients including two cases with clinical findings of ACFS harboring 6q21‐q22 microdeletion [Toschi et al, ; Hudson et al, ] (Fig.…”