Dataset Information

Identification of pathogenic mutations in 6 Chinese families with multiple exostoses by whole-exome sequencing and multiplex ligation-dependent probe amplification: Case series.

ABSTRACT:

Rationale

Hereditary multiple exostoses (HMEs) is an autosomal dominant skeletal disorder.

Patient concerns

Six probands of the 6 unrelated Han Chinese families were identified as having HME. These patients had exostoses at multiple sites and significantly affected joints malformation and movement.

Diagnoses

Hereditary multiple exostoses.

Interventions

To detect the genetic mechanism of HME in 6 unrelated Chinese families, whole-exome sequencing (WES) and multiplex ligation-dependent probe amplification (MLPA) were used after genomic DNA was isolated from peripheral blood leucocytes. Point mutations identified by these methods were verified by Sanger sequencing after PCR amplification.

Outcomes

Six mutations in the EXT1 and EXT2 genes were identified, including a heterozygous deletion mutation from exon 2 to exon 8 (Family 1), a c.448C>T, p.(Gln150X) heterozygous nonsense mutation (Family 4), a c.1057-2A>T heterozygous splicing substitution (Family 5), and a c.1468dupC, p.(Leu490fs519X) (Family 6) heterozygous duplication mutation in the EXT1 gene in addition to a heterozygous deletion mutation from exon 2 to exon 3 (Family 2) and a c.1197C>G, p.(Tyr399X) heterozygous nonsense mutation (Family 3) in the EXT2 gene.

Lessons

Overall, we identified 5 novel mutations and 1 recurrent mutation in the EXT1 and EXT2 genes in 6 Chinese families with HME. Our findings expand the mutational spectrum of the EXT1 and EXT2 genes and are useful for genetic counseling and prenatal diagnosis.

SUBMITTER: Long X

PROVIDER: S-EPMC6531242 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Publications

Identification of pathogenic mutations in 6 Chinese families with multiple exostoses by whole-exome sequencing and multiplex ligation-dependent probe amplification: Case series.

Long Xigui X Li Zhuo Z Huang Yanru Y Zhang Li L Lv Weigang W Teng Yanling Y Linpeng Siyuan S Liang Desheng D Wu Lingqian L

Medicine 20190501 20

<h4>Rationale</h4>Hereditary multiple exostoses (HMEs) is an autosomal dominant skeletal disorder.<h4>Patient concerns</h4>Six probands of the 6 unrelated Han Chinese families were identified as having HME. These patients had exostoses at multiple sites and significantly affected joints malformation and movement.<h4>Diagnoses</h4>Hereditary multiple exostoses.<h4>Interventions</h4>To detect the genetic mechanism of HME in 6 unrelated Chinese families, whole-exome sequencing (WES) and multiplex l ...[more]

PMID: 31096510

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Project description:Background: Muscular dystrophy (MD) includes multiple types, of which dystrophinopathies caused by dystrophin (DMD) mutations are the most common types in children. An accurate identification of the causative mutation at the genomic level is critical for genetic counseling of the family, and analysis of genotype-phenotype correlations, as well as a reference for the development of gene therapy. Methods: Totally, 70 Chinese families with suspected MD probands were enrolled in the study. The multiplex ligation-dependent probe amplification (MLPA) was first performed to screen large deletions/duplications of DMD exons in the patients, and then, next-generation sequencing (NGS) was carried out to detect small mutations in the MLPA-negative patients. Results: Totally, 62 mutations of DMD were found in 62 probands with DMD/BMD, and two compound heterozygous mutations in LAMA2 were identified in two probands with MDC1A (a type of congenital MD), indicating that the diagnostic yield was 91.4% by MLPA plus NGS for MD diagnosis in this cohort. Out of the mutations, 51 large mutations encompassing 47 (75.8%) deletions and four duplications (6.5%) were identified by MLPA; 11 small mutations including six (9.7%) nonsense, two (3.2%) small deletions, two splice-site mutations (3.2%), and one small insertion (1.6%) were found by NGS. Large mutations were found most frequently in the hotspot region between exons 45 and 55 (70.6%). Out of the 11 patients harboring point mutations in DMD, 8 were novel mutations. Additionally, one novel mutation in LAMA2 was identified. All the novel mutations were analyzed and predicted as pathogenic according to American College of Medical Genetics and Genomics (ACMG) guideline. Finally, 34 DMD, 4 BMD, 24 BMD/DMD, and 2 MDC1A were diagnosed in the cohort. Conclusion: Our data indicated that the MLPA plus NGS can be a comprehensive and effective tool for precision diagnosis and potential treatment of MD and is particularly necessary for the patients at very young age with only two clinical indicators (persistent hyperCKemia and typical myopathy performance on electromyogram) but no definite clinical manifestations.

Dataset Information

Identification of pathogenic mutations in 6 Chinese families with multiple exostoses by whole-exome sequencing and multiplex ligation-dependent probe amplification: Case series.

Rationale

Patient concerns

Diagnoses

Interventions

Outcomes

Lessons

Publications

Identification of pathogenic mutations in 6 Chinese families with multiple exostoses by whole-exome sequencing and multiplex ligation-dependent probe amplification: Case series.

Similar Datasets

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