A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures

Abstract

We report a recurrent microdeletion syndrome causing mental retardation, epilepsy and variable facial and digital dysmorphisms. We describe nine affected individuals, including six probands: two with de novo deletions, two who inherited the deletion from an affected parent and two with unknown inheritance. The proximal breakpoint of the largest deletion is contiguous with breakpoint 3 (BP3) of the Prader-Willi and Angelman syndrome region, extending 3.95 Mb distally to BP5. A smaller 1.5-Mb deletion has a proximal breakpoint within the larger deletion (BP4) and shares the same distal BP5. This recurrent 1.5-Mb deletion contains six genes, including a candidate gene for epilepsy (CHRNA7) that is probably responsible for the observed seizure phenotype. The BP4-BP5 region undergoes frequent inversion, suggesting a possible link between this inversion polymorphism and recurrent deletion. The frequency of these microdeletions in mental retardation cases is approximately 0.3% (6/2,082 tested), a prevalence comparable to that of Williams, Angelman and Prader-Willi syndromes.

Genome-wide gene expression in a patient with 15q13.3 homozygous microdeletion syndrome

“…[1][2][3][4][5][6][7][8] The phenotype varies in spectrum and severity owing to incomplete penetrance or variable expressivity. The 15q13.3 deletion is typically 1.6 Mb, harboring at least seven genes, ARHGAP11B, MTMR15, MTMR10, TRPM1, KLF13, OTUD7A, and CHRNA7.…”

“…9 Alterations in a7nAChR are reported to cause seizures and neuropsychiatric disturbances in the affected individuals with an incomplete dominant inheritance pattern. [4][5][6]8,[10][11][12] One large genomic database survey identified 19 individuals with isolated heterozygous CHRNA7 gene deletions and 1 with an isolated homozygous deletion. 13 The neurological symptoms in individuals with isolated CHRNA7 deletions implicate CHRNA7 as the major candidate gene responsible for the predominant manifestations of 15q13.3 microdeletion syndrome.…”

CHRNA7 triplication associated with cognitive impairment and neuropsychiatric phenotypes in a three-generation pedigree

“…23 Remarkably, LCRs BP4 and BP5, which mediate most of the rearrangements involving CHRNA7, are constituted by a complex set of large duplicated segments with 499% identity, lying in an inverted orientation relative to each other (Figure 3a). 24 Polymorphic inversions mediated by BP4 and BP5 are frequently found in individuals from various populations 24 and have been hypothesized to predispose to microdeletions and microduplications of the region by NAHR. In fact, at least six classes of microduplications, varying in size from 350 kb to 1.6 Mb, were shown to arise involving pre-existing heterogeneous inverted BP4 and BP5 chromosomes.…”

The effects of aging vs. α7 nAChR subunit deficiency on the mouse brain transcriptome: aging beats the deficiency

“…This subunit has important roles in brain development and neuron differentiation and migration (Gotti et al 2009;Taly et al 2009), and its chromosomal locus was associated in humans with developmental and neurological disorders (Ben-Shachar et al 2009;Consortium 2008;Helbig et al 2009;Miller et al 2009;Sharp et al 2008;Shinawi et al 2009;Stefansson et al 2008). Despite the importance of the α7 nAChR subunit, its deficiency results in viable, anatomically normal α7-null mice (Orr-Urtreger et al 1997;Paylor et al 1998).…”

“…The nAChRs have been implicated in complex diseases affecting the nervous system, including epilepsy, schizophrenia, developmental disorders, and aging-associated neurodegenerative diseases such as AD and PD (Freedman et al 2001;Steinlein et al 1995). Several recent genome-wide association studies identified genomic alterations in the human α7 nAChR subunit gene locus in patients with schizophrenia, bipolar disorder, autism, developmental delay, and seizures (Ben-Shachar et al 2009;Consortium 2008;Helbig et al 2009;Miller et al 2009;Sharp et al 2008;Shinawi et al 2009;Stefansson et al 2008). α7 subunits can form homopentameric receptor channels, which are activated by acetylcholine (ACh) and blocked by α-bungarotoxin (αBgtx).…”