Supernumerary Marker Chromosomes Encompassing the 15q11q13 Region: About 6 New Tunisian Cases

Background: Supernumerary marker chromosomes (SMC) are additional abnormal chromosomes that can be derived from any chromosome. However, more than 50% of SMC are derived from acrocentric chromosomes, mainly chromosome15.

Objective: The aim of this study was to characterize six SMC detected in 6 children presenting heterogeneous phenotype ranging from mild to severe intellectual disability and/or developmental delay and dysmorphic features. Autism spectrum disorder, seizure and speech delay were noted in two patients.

Methods: R-Banding karyotypes of patients and their parents showed a de Novo SMC 15 in all cases except for one where the marker was maternally inherited, and one was in mosaic. In situ fluorescence hybridization (FISH) analysis using the SNRPN, GABRB3, IGF1R, Midi54, Sc15q, SE15 and WCP15 probes allowed us to determine the shape of these SMC and to delimit approximately the breakpoints.

Results: In three cases, the SMC was of inverted duplicated shape, encompassing the Prader-Willi/Angelman critical region (PW/ASCR). In two cases, the SMC had smaller size and did not contain the PW/ASCR. A disproportional subset of SMC is derived from chromosome 15 conferring a trisomy or tetrasomy of the 15q11-q13 region. In fact, this region is prone to unequal crossover responsible for the variable size of chromosomal rearrangements due to the existence of five known breakpoints. It is also a parentally imprinted region that undergoes differential phenotypic expression depending on the parental origin.

Conclusion: The presence of breakpoints, parental imprinting region and PW/ASCR, the content of euchromatic material and mosaicism are responsible for the morphological and clinical heterogeneity of the SMC15. The study of the extent of the duplicated region by array CGH would allow to identify the exact segmental gains and to delimit precisely the breakpoints.