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Novel NOG (p.P42S) mutation causes proximal symphalangism in a four-generation Chinese family.

ABSTRACT: BACKGROUND:Proximal symphalangism (SYM1; OMIM 185800), also called Cushing's symphalangism, is an infrequent autosomal dominant disease. An SYM1 patient typically features variable fusion of proximal interphalangeal joints in the hands and feet. METHODS:We recruited a four-generation Chinese non-consanguineous family with SYM1. We examined their hands and feet using X-rays to confirm fusion of proximal interphalangeal joints. We evaluated their audiology using standard audiometric procedures and equipment. Then, we identified genetic variants using whole exome sequencing and validated mutations using Sanger sequencing. Mutation pathogenicity was analyzed with bioinformatics. RESULTS:Radiographs revealed proximal-joint fusion of fingers and toes in the patients. Two elderly individuals (II:1 and II:4) exhibited slight hearing loss. Additionally, we detected a novel heterozygous missense mutation in exon 1 of NOG (NM_005450) c.124C?>?T, p.(Pro42Ser) in all patients. This c.124C?>?T mutation is highly conserved across multiple species and the p.(Pro42Ser) variation is potentially highly pathogenic. CONCLUSION:Our results suggest that heterozygous c.124C?>?T, p.(Pro42Ser) in NOG is a novel mutation that causes human SYM1 phenotype.

SUBMITTER: Sha Y

PROVIDER: S-EPMC6670124 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Novel NOG (p.P42S) mutation causes proximal symphalangism in a four-generation Chinese family.

Sha Yanwei Y Ma Ding D Zhang Ning N Wei Xiaoli X Liu Wensheng W Wang Xiong X

BMC medical genetics 20190801 1

<h4>Background</h4>Proximal symphalangism (SYM1; OMIM 185800), also called Cushing's symphalangism, is an infrequent autosomal dominant disease. An SYM1 patient typically features variable fusion of proximal interphalangeal joints in the hands and feet.<h4>Methods</h4>We recruited a four-generation Chinese non-consanguineous family with SYM1. We examined their hands and feet using X-rays to confirm fusion of proximal interphalangeal joints. We evaluated their audiology using standard audiometric ...[more]

PMID: 31370824

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Project description:Background:Proximal symphalangism (SYM1) is a rare genetic bone disorder characterized by the fusion of proximal interphalangeal joints in the hands and feet. Genetic studies have identified two genes underlying SYM1 as the noggin (NOG) and the growth differentiation factor 5 (GDF5). Case Report:In the present report, a 43-year-old gravida at 11 weeks of gestation was referred for evaluation of abnormal fusions of the joints. In the initial diagnosis, physical examination was undertaken. However, traditional radiological examination was not applied due to the need to protect the fetus, making diagnosis results inefficient to determine the exact disease affecting the proband. To acquire alternative clinical evidences, we conducted radiological examinations on two other affected family members. The radiological examination revealed that they carried the symphalangism accompanied with tarsal coalition, a very rare manifestation of SYM1. A combination of whole exome sequencing (WES) and Sanger sequencing revealed a novel heterozygous missense mutation (c.163G > T; p.Asp55Tyr) in the NOG gene, which could be associated with the observed pathogenic SYM1 in the studied family. The p.Asp55Tyr mutation co-segregated with SYM1 through the affected and unaffected family members. In silico structural modeling of the p.Asp55Tyr mutation showed that it abolishes the interaction with the Arg167 residue and causes a change in the electrostatic potential profile of the type II binding site of the noggin protein. Conclusion:Our findings indicate that the genetic test based on WES can be useful in diagnosing SYM1 patients, with particular advantages in preventing the fetus from contacting harmful X-ray through the traditional radiography. The novel pathogenic mutation identified would further expand our understanding of the mutation spectrum of NOG in association with SYM1 disease and provide a guidance on how to determine whether the fetus is affected by SYM1 through the prenatal diagnosis.

Dataset Information

Novel NOG (p.P42S) mutation causes proximal symphalangism in a four-generation Chinese family.

Publications

Novel NOG (p.P42S) mutation causes proximal symphalangism in a four-generation Chinese family.

Similar Datasets

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