De novo interstitial duplication of the 15q11.2‐q14 PWS/AS region of maternal origin: Clinical description, array CGH analysis, and review of the literature

Abstract

The 15q11-q13 PWS/AS critical region involves genes that are characterized by genomic imprinting. Multiple repeat elements within the region mediate rearrangements, including interstitial duplications, interstitial triplications, and supernumerary isodicentric marker chromosomes, as well as the deletions that cause Prader-Willi syndrome (PWS) and Angelman syndrome (AS). Recently, duplications of maternal origin concerning the same critical region have been implicated in autism spectrum disorders (ASD). We present a 6-month-old girl carrying a de novo duplication of maternal origin of the 15q11.2-q14 PWS/AS region (17.73 Mb in size) [46,XX,dup(15)(q11.2-q14)] detected with a high-resolution microarray-based comparative genomic hybridization (array-CGH). The patient is characterized by severe hypotonia, obesity, microstomia, long eyelashes, hirsutism, microretrognathia, short nose, severe psychomotor retardation, and multiple episodes of drug-resistant epileptic seizures, while her brain magnetic resonance imaging (MRI) documented partial corpus callosum dysplasia. In our patient the duplicated region is quite large extending beyond the Prader-Willi-Angelman critical region (PWACR), containing a number of genes that have been shown to be involved in ASD, exhibiting a severe phenotype, beyond the typical PWS/AS clinical manifestations. Reporting of similar well-characterized clinical cases with clearly delineated breakpoints of the duplicated region will clarify the contribution of specific genes to the phenotype.

Microdeletion and microduplication 17q21.31 plus an additional CNV, in patients with intellectual disability, identified by array-CGH

“…The methodology followed for aCGH hybridization and analysis was as previously described (Kitsiou-Tzeli et al, 2010). For the location of genes in the deleted/ duplicated genomic segments the UCSC (http://genome.ucsc.edu/) and the Database of Genomic Variants (http://projects.tcag.ca/variation/) (NCBI 36/ hg18) were used.…”

Array comparative genomic hybridization as a clinical diagnostic tool in syndromic and nonsyndromic congenital heart disease

“…Microdeletions or microduplications, which are clinically significant genomic rearrangements, have been identified in patients with intellectual disability/developmental delay and/or multiple congenital anomalies, with otherwise normal conventional karyotype (4). The main advantage of array CGH is its ability to detect any quantitative changes in DNA; it is 10-10,000-fold more detailed than conventional karyotype, depending on the size of the target and the coverage and density of probes in the array (5). This study describes the application of array CGH to detect submicroscopic genomic rearrangement in children with CHD and syndromic features.…”

Microstomia: A Rare but Serious Oral Manifestation of Inherited Disorders

“…Multiple repeat elements within the region mediate rearrangements, including interstitial duplications, interstitial triplications, and supernumerary isodicentric marker chromosomes, as well as the deletions that cause Prader-Willi syndrome and Angelman syndrome. Recently, duplications of maternal origin concerning the same critical region have been implicated in autism spectrum disorders (Kitsiou-Tzeli et al, 2010) presented a 6-month-old girl with a de novo duplication of maternal origin of the 15q11.2-q14 PWS/AS region (17.73Mb in size) [46,XX,dup(15)(q11.2-q14)] detected with a high-resolution microarray-based comparative genomic hybridization (array-CGH) Kitsiou-Tzeli et al, 2010 The features of the condition were described by the same authors as: severe hypotonia, obesity, microstomia, long eyelashes, hirsutism, microretrognathia, short nose, severe psychomotor retardation, and multiple episodes of drug-resistant epileptic seizures, partial corpus callosum dysplasia documented via magnetic resonance imaging. The duplicated region was quite large extending beyond the Prader-Willi-Angelman critical region, containing a number of genes that have been shown to be involved in autism spectrum disorders, exhibiting a severe phenotype, beyond the typical PWS/AS clinical manifestations.…”