2q24 deletions: Further characterization of clinical findings and their relation to the SCN cluster

Abstract

As the resolution of molecular cytogenetic methods continues to improve, it has become increasingly possible to refine genotype-phenotype correlations based upon gene involvement. We report three new patients with nonrecurrent deletions involving subbands of 2q24. These patients were referred for evaluation of developmental delay, but were found to have unique, nonoverlapping clinical features. Patient 1 presented with infantile seizures, microcephaly, and brain anomalies, along with facial dysmorphism, growth retardation, neuromuscular scoliosis, and later with developmental regression. Array comparative genomic hybridization (aCGH) detected an 8 Mb interstitial deletion encompassing the neuronal sodium channel (SCN) gene cluster. Patient 2 presented with growth retardation, congenital heart defect, and hypotonia. Patient 3 presented with developmental delay and behavioral problems. Patients 2 and 3 had no history of seizures, microcephaly, or brain anomalies and were found to have deletions of 2q24, ∼8 Mb and <500 kb respectively, centromeric to and outside the SCN cluster. It has been demonstrated that mutations and copy number variants (CNVs) affecting the SCN gene cluster result in severe, early-onset seizures. It is however, less clear whether haploinsufficiency of regions outside the SCN cluster may result in phenotypically recognizable and clinically significant features. We discuss additional dosage sensitive genes that may exist outside the SCN cluster. Our and published data indicate that 2q24 deletions not involving the SCN cluster are associated with fewer neurobehavioral problems, but may predispose to congenital malformations.

Critical Roles of Xirp Proteins in Cardiac Conduction and Their Rare Variants Identified in Sudden Unexplained Nocturnal Death Syndrome and Brugada Syndrome in Chinese Han Population

“…XIRP2-containing locus has not been linked to cardiac arrhythmia, but deletion of chromosome band 2q24 has been associated with congenital heart defects. 41 We hypothesized that XIRP variants may contribute to the pathogenesis of human cardiac arrhythmia disorders. In this study, genetic screens for 134 sporadic SUNDS cases and for 22 BrS patients were aimed to determine whether variants of XIRP are present and responsible for a proportion of SUNDS.…”

“…The XIRP1 ‐containing locus also harbors the SCN5A and SCN10A genes that encode cardiac sodium channels and are known to be associated with BrS, long QT syndrome, and SUNDS . On the other hand, XIRP2 ‐containing locus has not been linked to cardiac arrhythmia, but deletion of chromosome band 2q24 has been associated with congenital heart defects …”

Epilepsies in Children with 2q24.3 Deletion/Duplication

“…We identified 18 patients with deletion of at least one gene in the 2q24.3 region, determined by array CGH (►Table 1). [10][11][12][13][14][15][16][17][18][19][20][21][22] Patients with chromosomal aberrations, indicating 2q24.3 deletion, but without array CGH analysis results, were not included. The patients comprised nine females and nine males.…”