Clinical and molecular characterization of a large family with an interstitial 15q11q13 duplication

Abstract

The clinical significance of an interstitial duplication of chromosome 15q11q13 is still not well documented. This abnormality has been associated with autistic spectrum disorders (ASD) and varying degrees of mental retardation. The clinical variability appears to be influenced by the parental origin of the duplication. We present here the clinical evaluation and psychological assessment of the largest reported family with 12 carriers on three generations. Patients exhibit mental retardation, motor and visuo-motor skills impairments and adaptive functioning deficit without formal diagnosis of autism. There appeared to be evidence in the family of reduced penetrance in duplication of paternal origin. This familial 15q11q13 duplication was precisely investigated by cytogenetic and molecular techniques including fluorescence in situ hybridization (FISH), PCR analysis of microsatellite markers, array-comparative genomic hybridization analysis (Array-CGH) and semi-quantitative methylation-sensitive PCR. Results showed an inherited 15q11q13 duplication of maternal origin in 10 patients and of paternal origin in the remaining two. The size of the duplicated area was around 6 Mb with breakpoints in accordance with those previously reported. This report extends the clinical spectrum of the 15q11q13 duplication, and we recommend the investigation of 15q11q13 duplication not only in subjects with autistic spectrum disorder but also in patients with low normal intelligence and dyspraxia.

Chromosomal microarray analysis in clinical evaluation of neurodevelopmental disorders-reporting a novel deletion of SETDB1 and illustration of counseling challenge

“…Five CNV [5 single CNV ( Table 1)] were “likely pathogenic” and 22 were “VUS”. Because there is evidence in literature supporting that the 15q11.2-q13.1 duplication, identified in #33, can cause mild ASD and ID [11,12], we classified it as pathogenic (see detail discussion below). However, the pathogenicity of this duplication is not certain in this family.…”

“…However, screening for a glycosylation disorder by carbohydrate-deficient transferring analysis was unremarkable. Maternal duplication of 15q11-q13 is strongly associated with ASD while the pathogenic role of the same duplication of paternal origin in ASD and ID has not been firmly established [11-12,23-24]. The deletion of 5q35.3 has not been reported in literature to be associated with any disease phenotype.…”

Epigenetic Impacts on Neurodevelopment: Pathophysiological Mechanisms and Genetic Modes of Action

“…Prader-Willi and Angelman syndrome both include MR/ID in their phenotypic spectrum and are caused by parent-of-origin-specific defects of 15q11q13 (33,34). Intriguingly, copy number variation of the 15q11q13 region is also associated with ASD (35)(36)(37), and there is emerging evidence for ASD symptomatology presenting with the imprinting disorder Prader-Willi Syndrome (36). Other MR/ID syndromes are also now being understood to include ASD phenotypes (e.g.…”

The neurobiology of mouse models syntenic to human chromosome 15q

“…This may cause difference between maternal and paternal duplication animals as well and should be investigated. At the very least, there is a significant variability and diversity of clinical phenotypes and gene expression in human chromosome 15q11–q13 duplication syndrome (Hogart et al 2009; Piard et al 2010). Further detailed epigenetic analyses both in humans and mice will provide an insight into the imprinting mechanisms.…”