Molecular characterization of a complex small supernumerary marker chromosome derived from chromosome 18p: an addition to the literature

Abstract

Background Small supernumerary marker chromosomes (sSMC) are a heterogeneous group of structurally abnormal chromosomes, with an incidence of 0,044% in newborns that increases up to almost 7 times in developmentally retarded patients. sSMC from all 24 chromosome have been described, most of them originate from the group of the acrocentric, with around half deriving from the chromosome 15. Non-acrocentric sSMC are less common and, in the 30 percent of the cases, are associated with phenotypic effect. Complex sSMC consist of chromosomal material derived from more than one chromosome. Genotype–phenotype correlations in patients with sSMC are difficult to assess. Clinical features depend on factors such as its size, genetic content, the involvement of imprinted genes which may be influenced by uniparental disomy and the level of mosaicism. Trisomy of the short arm of chromosome 18 (18p) is an infrequent finding and does not appear to be associated with a specific syndrome. However, mild intellectual disability with or without other anomalies is reported in almost one-third of the patients. Case presentation Here we present clinical and molecular characterization of a new case of de novo complex sSMC consisting of the entire short arm of chromosome 18p associated with a centromere of either chromosome 13 or 21, evidenced in a 5-year-old boy during diagnostic workup for moderate intellectual disability and dysmorphisms. To date, only seven cases of isolated trisomy 18p due to a sSMC have been reported, three of which have been characterized by array CGH. In two of them the breakpoints and the size of the duplication have been described. In the manuscript we also reviewed cases reported in the DECIPHER database carrying similar duplication and also considered smaller duplications within the region of interest, in order to evaluate the presence of critical regions implicated in the pathological phenotype. Conclusions Our case provides additional information about phenotypic effects of pure trisomy 18p, confirms chromosomal microarray analysis as gold standard to characterize complex sSMC, and supplies additional elements for genetic counselling.

Cytogenomic characterization of small supernumerary marker chromosomes in patients with pigmentary mosaicism

“…Small supernumerary marker chromosomes (sSMCs) are defined as structurally abnormal chromosomes equal to or smaller than chromosome 20 of the same metaphase spread ( Matsubara et al, 2020 ), with an incidence of 0.072%–0.075% in prenatal cases and 0.044% in newborns ( Reddy et al, 2013 ; Sun et al, 2017 ; Pinto et al, 2018 ; Zhou et al, 2020 ; Marchina et al, 2021 ) . Notably, in patients with intellectual disabilities, the incidence may increase to 0.288% ( Reddy et al, 2013 ; Zhou et al, 2020 ).…”

“…In addition, the genotype-phenotype correlation in patients with sSMC is challenging. The combination of gene content (presence of heterochromatin or euchromatin) on the marker chromosome, its chromosomal origin, level of mosaicism, origin mechanism (chromothripsis), and the presence of uniparental disomy can influence the final characterization of sSMC ( Murthy et al, 2008 ; Liehr, 2013 ; Liehr, 2021 ; Marchina et al, 2021 ). The exceptions are a few syndromes with well-defined sSMC: isochromosomes (5p), (9p), (12p)/Pallister-Killian-syndrome, (18p), der (22)t(11; 22)/Emanuel syndrome, sSMC(15) containing the Prader-Willi/Angelman syndrome critical region, and sSMC(22), which contains the critical region for cat eye syndrome ( Liehr T, 2013 ; Sun et al, 2017 ).…”

Familial microdeletion 18p11.32 to 18p11.31 in a Chinese family with normal phenotype

“…For short arm of chromosome 18 it is known that partial tetrasomy 18p (iso-chromosome 18p syndrome; OMIM # 614,290) leads to a severe phenotype, while trisomy of the same region only impairs such carriers comparatively mild [5]. On the other hand there is a 18psyndrome (OMIM # 146,390), which impairs the carriers when the shortened 18p-arm can be clearly identified in GTG-banding.…”