Abstract
BackgroundDefining the phenotype-genotype correlation of small supernumerary marker chromosomes (sSMCs) remains a challenge in prenatal diagnosis. We karyotyped 20,481 amniotic fluid samples from pregnant women and explored the molecular characteristics of sSMCs using a single nucleotide polymorphism (SNP) array.ResultsOut of the 20,481 samples, 15 abnormal karyotypes with sSMC were detected (frequency: 0.073%) and the chromosomal origin was successfully identified by SNP array in 14 of them. The origin of sSMCs were mainly acrocentric-derived chromosomes and the Y chromosome. Two cases of sSMC combined with uniparental disomy (UPD) were detected, UPD(1) and UPD(22). More than half of the cases of sSMC involved mosaicism (8/15) and pathogenicity (9/15) in prenatal diagnosis. A higher prevalence of mosaicism for non-acrocentric chromosomes than acrocentric chromosomes was also revealed. One sSMC derived from chromosome 3 with a neocentromere revealed a 24.99-Mb pathogenic gain of the 3q26.31q29 region on the SNP array, which presented as an abnormal ultrasound indicating nasal bone hypoplasia.ConclusionThe clinical phenotypes of sSMCs are variable and so further genetic testing and parental karyotype analysis are needed to confirm the characteristics of sSMCs. The SNP array used here allows a detailed characterisation of the sSMC and establishes a stronger genotype-phenotype correlation, thus allowing detailed genetic counselling for prenatal diagnosis.
Highlights
Defining the phenotype-genotype correlation of small supernumerary marker chromosomes remains a challenge in prenatal diagnosis
One-third of Small supernumerary marker chromosome (sSMC) cases are associated with specific clinical symptoms, (e.g. i(12p) and Pallister–Killian syndrome, sSMC(15) and Prader–Willi Syndrome/Angelman Syndrome (PWS/AS), and inv. dup(22) and cat-eye syndrome) while two-thirds of sSMC cases have not been associated with clinical syndromes [3]
Zhou et al Molecular Cytogenetics (2020) 13:19 mental and growth retardation, craniofacial and urogenital abnormalities, and cardiac anomalies, which are associated with the size of the sSMCs, gene content, mosaicism percentage, uniparental disomy, and other concomitant imbalances [6]
Summary
Defining the phenotype-genotype correlation of small supernumerary marker chromosomes (sSMCs) remains a challenge in prenatal diagnosis. Small supernumerary marker chromosomes (sSMCs) are structurally abnormal chromosome fragments that cannot be clearly determined by conventional banding cytogenetics alone and are equal in size or smaller than a chromosome 20 of the same metaphase spread [1]. Dup(22) and cat-eye syndrome) while two-thirds of sSMC cases have not been associated with clinical syndromes [3]. Defining the phenotypegenotype correlation of sSMCs remains a challenge due to their complex origins and genetic materials. Zhou et al Molecular Cytogenetics (2020) 13:19 mental and growth retardation, craniofacial and urogenital abnormalities, and cardiac anomalies, which are associated with the size of the sSMCs, gene content, mosaicism percentage, uniparental disomy, and other concomitant imbalances [6]. Chromosomal microarray analysis is a sensitive technique for characterising sSMCs and can detect genomic copy number changes and define breakpoints and the genes involved [7,8,9]
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