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Genotype-phenotype correlation in 75 patients with small supernumerary marker chromosomes.

ABSTRACT: Background:Small supernumerary marker chromosomes (sSMCs) are rare structural abnormalities in the population; however, they are frequently found in children or fetuses with hypoevolutism and infertile adults. sSMCs are usually observed first by karyotyping, and further analysis of their molecular origin is important in clinical practice. Next-generation sequencing (NGS) combined with Sanger sequencing helps to identify the chromosomal origins of sSMCs and correlate certain sSMCs with a specific clinical picture. Results:Karyotyping identified 75 sSMCs in 74,266 samples (0.1% incidence). The chromosomal origins of 27 of these sSMCs were detected by sequencing-related techniques (NGS, MLPA and STR). Eight of these sSMCs are being reported for the first time. sSMCs mainly derived from chromosomal X, Y, 15, and 18, and some sSMC chromosomal origins could be correlated with clinical phenotypes. However, the chromosomal origins of the remaining 48 sSMC cases are unknown. Thus, we will develop a set of economical and efficient methods for clinical sSMC diagnosis. Conclusions:This study details the comprehensive characterization of 27 sSMCs. Eight of these sSMCs are being reported here for the first time, providing additional information to sSMC research. Identifying sSMCs may reveal genotype-phenotype correlations and integrate genomic data into clinical care.

SUBMITTER: Li T

PROVIDER: S-EPMC7362453 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Genotype-phenotype correlation in 75 patients with small supernumerary marker chromosomes.

Li Tingting T Sang Haiquan H Chu Guoming G Zhang Yuanyuan Y Qi Manlong M Liu Xiaoliang X Cui Wanting W Zhao Yanyan Y

Molecular cytogenetics 20200714

<h4>Background</h4>Small supernumerary marker chromosomes (sSMCs) are rare structural abnormalities in the population; however, they are frequently found in children or fetuses with hypoevolutism and infertile adults. sSMCs are usually observed first by karyotyping, and further analysis of their molecular origin is important in clinical practice. Next-generation sequencing (NGS) combined with Sanger sequencing helps to identify the chromosomal origins of sSMCs and correlate certain sSMCs with a ...[more]

PMID: 32684981

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Project description:BackgroundSmall supernumerary marker chromosomes (sSMCs) are additional, structurally abnormal chromosomes, generally smaller than chromosome 20 of the same metaphase spread. Due to their small size, they are difficult to characterize by conventional cytogenetics alone. In regard to their clinical effects, sSMCs are a heterogeneous group: in particular, sSMCs containing pericentromeric euchromatin are likely to be associated with abnormal outcomes, although exceptions have been reported. To improve characterization of the genetic content of sSMCs, several approaches might be applied based on different molecular and molecular-cytogenetic assays, e.g., fluorescent in situ hybridization (FISH), array-based comparative genomic hybridization (array CGH), and multiplex ligation-dependent probe amplification (MLPA).To provide a complementary tool for the characterization of sSMCs, we constructed and validated a new, FISH-based, pericentromeric Bacterial Artificial Chromosome (BAC) clone set that with a high resolution spans the most proximal euchromatic sequences of all human chromosome arms, excluding the acrocentric short arms.ResultsBy FISH analysis, we assayed 561 pericentromeric BAC probes and excluded 75 that showed a wrong chromosomal localization. The remaining 486 probes were used to establish 43 BAC-based pericentromeric panels. Each panel consists of a core, which with a high resolution covers the most proximal euchromatic ~0.7 Mb (on average) of each chromosome arm and generally bridges the heterochromatin/euchromatin junction, as well as clones located proximally and distally to the core. The pericentromeric clone set was subsequently validated by the characterization of 19 sSMCs. Using the core probes, we could rapidly distinguish between heterochromatic (1/19) and euchromatic (11/19) sSMCs, and estimate the euchromatic DNA content, which ranged from approximately 0.13 to more than 10 Mb. The characterization was not completed for seven sSMCs due to a lack of information about the covered region in the reference sequence (1/19) or sample insufficiency (6/19).ConclusionsOur results demonstrate that this pericentromeric clone set is useful as an alternative tool for sSMC characterization, primarily in cases of very small SMCs that contain either heterochromatin exclusively or a tiny amount of euchromatic sequence, and also in cases of low-level or cryptic mosaicism. The resulting data will foster knowledge of human proximal euchromatic regions involved in chromosomal imbalances, thereby improving genotype-phenotype correlations.

Dataset Information

Genotype-phenotype correlation in 75 patients with small supernumerary marker chromosomes.

Publications

Genotype-phenotype correlation in 75 patients with small supernumerary marker chromosomes.

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