Complex de novo chromosomal rearrangement at 15q11–q13 involving an intrachromosomal triplication in a patient with a severe neuropsychological phenotype: Clinical report and review of the literature

Abstract

Interstitial triplications of 15q11-q13, leading to tetrasomy of the involved region, are very rare, with only 11 cases reported to date. Their pathogenicity is independent of the parental origin of the rearranged chromosome. The associated phenotype resembles, but is less severe, than that of patients bearing inv dup(15) marker chromosomes. Here, we describe a boy of 3 years and 9 months of age who exhibited very mild craniofacial dysmorphism (arched eyebrows, hypertelorism, and a wide mouth), developmental delay, generalized hypotonia, ataxic gait, severe intellectual disability, and autism. Array comparative genomic hybridization (CGH) analysis identified a heterozygous duplication of 1.1 Mb at 15q11.2 (between low-copy repeats BP1 and BP2), and a heterozygous triplication of 6.8 Mb at 15q11.2-q13.1 (BP2-BP4). Both acquisitions were de novo and contiguous. Microsatellite polymorphism analysis revealed the maternal origin of the triplication and the involvement of both maternal chromosomes 15. Furthermore, fluorescence in situ hybridization (FISH) analysis using BAC clones revealed that the rearrangement was complex, containing three differently sized tandem repeats of which the middle one was inverted. Our study confirms and extends the model proposed to explain the formation of intrachromosomal triplications through recombination events between non-allelic duplicons. The comparison of the proband's clinical presentation with those of previously described cases attests the existence of endophenotypes due to the parental origin of the 15q11-q13 triplicated segment and suggests a timetable for achievement of developmental milestones, thereby contributing to improved genotype-phenotype correlations.

Testing single/combined clinical categories on 5110 Italian patients with developmental phenotypes to improve array‐based detection rate

“…In the processed cohort, we found that 20% of CNVs were associated to a known syndrome, a value lower than the one obtained for the CNVs identified by CMA studies (Ahn et al, ; Castronovo et al, ; Kaminsky et al, ; Mc Cormack et al, ). In compliance with the literature, the most common microdeletion syndromes are the 22q11.2 and the 16p11.2 microdeletion, while the most common microduplication syndromes are the 15q11.2, the 16p13.11, and the 16p11.2 microduplications (Ahn et al, ; Kaminsky et al, ).…”

Detection of copy number variations in epilepsy using exome data

“…Prior to WES, 42 patients took one or more genetic tests (33 patients underwent karyotype analysis, 10 microarray analysis, and 13 took another genetic test such as mutation screening for a few epilepsy genes). 15q11-q13 interstitial triplication (Case732), 19 Terminal 14q deletion syndrome (Case 741), 20 Pelizaeus-Merzbacher disease (Case 751), 21 Potocki-Lupski syndrome (Case 760), 22 1p36 deletion syndrome (Case 811), 23 Williams-Beuren syndrome (Case 815), 24 1q44 deletion syndrome (Case 919), 25 and 1q43-q44 deletion syndrome (Case 944). 26 35 and FOXG1 (Case 995).…”

Rare partial trisomy and tetrasomy of 15q11-q13 associated with developmental delay and autism spectrum disorder

“…It's reported that people with 15q11-q13 dup syndrome or inv dup (15) are pathogenic only when the extra parts inherited form mother, and the level of effect on brain function and development have much to do with the maternal gene dosage [25,26]. Though CNV-Seq can be used in detecting dup15q syndrome accurately, but it cann't determine whether the extra fragment is paternal or maternal without other technologies such as FISH or quantitative fluorescent polymerase chain reaction (QF-PCR).…”