Molecular characterization of 39 de novosSMC: contribution to prognosis and genetic counselling, a prospective study

Abstract

Small supernumerary marker chromosomes (sSMCs) are structurally abnormal chromosomes that cannot be characterized by karyotype. In many prenatal cases of de novo sSMC, the outcome of pregnancy is difficult to predict because the euchromatin content is unclear. This study aimed to determine the presence or absence of euchromatin material of 39 de novo prenatally ascertained sSMC by array-comparative genomic hybridization (array-CGH) or single nucleotide polymorphism (SNP) array. Cases were prospectively ascertained from the study of 65,000 prenatal samples [0.060%; 95% confidence interval (CI), 0.042-0.082]. Array-CGH showed that 22 markers were derived from non-acrocentric markers (56.4%) and 7 from acrocentic markers (18%). The 10 additional cases remained unidentified (25.6%), but 7 of 10 could be further identified using fluorescence in situ hybridization; 69% of de novo sSMC contained euchromatin material, 95.4% of which for non-acrocentric markers. Some sSMC containing euchromatin had a normal phenotype (31% for non-acrocentric and 75% for acrocentric markers). Statistical differences between normal and abnormal phenotypes were shown for the size of the euchromatin material (more or less than 1 Mb, p = 0.0006) and number of genes (more or less than 10, p = 0.0009). This study is the largest to date and shows the utility of array-CGH or SNP array in the detection and characterization of de novo sSMC in a prenatal context.

Three-Year Follow-Up of a Prenatally Ascertained Apparently Non-Mosaic sSMC(10): Delineation of a Non-Critical Region

“…To our knowledge, only 10 cases of sSMC(10) have been reported in normal carriers, including the present case, and 11 cases of patients with clinical findings [Marle et al, 2014]. A non-critical region, ranging from 34.72 to 44.51 Mb (UCSC hg19, 2009) has been proposed based on cases with mosaic sSMC(10) [Liehr et al, 2009].…”

“…In recent years, chromosomal microarray analysis (array comparative genomic hybridization, array-CGH) has been increasingly used to characterize the genetic content of sSMC and has been found very helpful in defining genotype-phenotype correlations [Ballif et al, 2007;Marle et al, 2014]. Chromosome 10 is rarely involved in the formation of marker chromosomes as only 2 prenatal cases have been reported with a de novo sSMC present in 100% of the cells [Liehr, 2014].…”

Molecular Cytogenetic Diagnostics of Marker Chromosomes: Analysis in Four Prenatal Cases and Long-Term Clinical Evaluation of Carriers

“…FISH is very important despite the recent boom of array techniques. Array comparative genome hybridization (aCGH) can also determine the origin and size of the sSMCs [Gruchy et al, 2008;Marle et al, 2014]. However, it may fail in sSMCs formed exclusively of heterochromatin and in mosaic cases, and as a stand-alone test it can identify only about 75% of prenatal sSMC cases.…”

“…However, it may fail in sSMCs formed exclusively of heterochromatin and in mosaic cases, and as a stand-alone test it can identify only about 75% of prenatal sSMC cases. These unidentified sSMCs are of a better prognosis because of the lack of euchromatin and because of a low level of mosaicism [Marle et al, 2014]. Nevertheless, such sSMCs could still alter meiosis and lead to fertility problems.…”

Characterization of a de novo Supernumerary Neocentric Ring Chromosome Derived from Chromosome 7

“…Prior to the development of array-comparative genomic hybridization (array-CGH) or single nucleotide polymorphism (SNP) technology, sSMC characterization was time-consuming and sometimes unsuccessful. Array-CGH and SNP array have proved to be powerful tools to characterize sSMC [Ballif et al, 2007;Marle et al, 2014]. Nevertheless, the origin of sSMC still remains difficult to establish in the case of low mosaicism, since the mosaic detection threshold of array-CGH is 10%.…”