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Identification of a novel COL10A1: c.1952 G>T variant in a family with Schmid metaphyseal chondrodysplasia and development of a noninvasive prenatal testing method.

ABSTRACT:

Background

The collagen alpha-1(X) chain gene (COL10A1) is a known causative gene for Schmid metaphyseal chondrodysplasia (SMCD). This study clinically examined a Chinese family (n = 42) for SMCD and inheritance pattern. Fifteen individuals were diagnosed with SMCD based on characteristic skeletal phenotypes with autosomal dominant inheritance mode.

Methods

Four clinically diagnosed patients and three healthy relatives were selected for subsequent genetic tests. Trio-whole exome sequencing (Trio-WES) followed by Sanger sequencing and familial co-segregation analysis were performed to identify SMCD-associated variants.

Results

COL10A1 (NM_000493.4):c.1952 G>T(p.Trp651Leu) variant was detected only in the four patients and not in the three healthy relatives. The variant was evaluated as "likely pathogenic" according to the American College of Medical Genetics and Genomics variation classification guidelines with evidence of PM2, PM5, PP1, and PP3. To test the presence of the target variant in proband's fetal offspring, we developed a noninvasive prenatal testing method by extracting cell-free fetal DNA in maternal plasma followed by high-depth sequencing. The variant was also detected in the fetus and later confirmed by amniocentesis.

Conclusion

We identified a new disease-causing variant in COL10A1. Cell-free fetal DNA in maternal peripheral blood can be used as the rapid and noninvasive prenatal diagnostic method to detect the pathogenic/or likely pathogenic variant.

SUBMITTER: Ye Y

PROVIDER: S-EPMC8580095 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Characterization of a novel COL10A1 variant associated with Schmid-type metaphyseal chondrodysplasia and a literature review.

Project description:BackgroundSchmid-type metaphyseal chondrodysplasia (SMCD) is a rare autosomal dominant skeletal dysplasia caused by heterozygous mutations in COL10A1, the gene which encodes collagen type X alpha 1 chain. However, its genotype-phenotype relationship has not been fully determined. Subjects and Methods The proband is a 2-year-old boy, born of non-consanguineous Chinese parents. We conducted a systematic analysis of the clinical and radiological characteristics and a follow-up study of the proband. Whole-exome sequencing was applied for the genetic analysis, together with bioinformatic analysis of predicted consequences of the identified variant. A homotrimer model was built to visualize the affected region and predict possible outcomes of this variant. Furthermore, a literature review and genotype-phenotype analysis were performed by online searching all cases with SMCD.ResultsA novel heterozygous variant (NM_000493.4: c.1863_1866delAATG, NP_000484.2: p.(Met622 Thrfs*54)) was identified in COL10A1 gene in the affected child. And it was predicted to be pathogenic by in silico analysis. Protein modeling revealed that the variant was located in the NC1 domain, which was predicted to produce truncated collagen and impair the trimerization of collagen type X alpha 1 chain and combination with molecules in the matrix. Moreover, genotype-phenotype correlation analysis demonstrated that patients with truncating variants or variants in NC1 domain often presented earlier onset and severer symptoms compared with those with non-truncating or variants in non-NC1 domains.ConclusionThe NC1 domain of COL10A1 was proved to be the hotspot region underlying SMCD, patients with variants in NC1 domain were more likely to present severer manifestations at an earlier age.

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Identification of two novel COL10A1 heterozygous mutations in two Chinese pedigrees with Schmid-type metaphyseal chondrodysplasia.

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