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Recurrent missense mutation of GDF5 (p.R438L) causes proximal symphalangism in a British family.

ABSTRACT: Proximal symphalangism (SYM1B) (OMIM 615298) is an autosomal dominant developmental disorder affecting joint fusion. It is characterized by variable fusions of the proximal interphalangeal joints of the hands, typically of the ring and little finger, with the thumb typically being spared. SYM1 is frequently associated with coalition of tarsal bones and conductive hearing loss. Molecular studies have identified two possible genetic aetiologies for this syndrome, NOG and GDF5. We herein present a British caucasian family with SYM1B caused by a mutation of the GDF5 gene. A mother and her three children presented to the orthopaedic outpatient department predominantly for feet related problems. All patients had multiple tarsal coalitions and hand involvement in the form of either brachydactyly or symphalangism of the proximal and middle phalanx of the little fingers. Genetic testing in the eldest child and his mother identified a heterozygous missense mutation in GDF5 c.1313G>T (p.R438L), thereby establishing SYM1B as the cause of the orthopaedic problems in this family. There were no mutations identified in the NOG gene. This report highlights the importance of thorough history taking, including a three generation family history, and detailed clinical examination of children with fixed planovalgus feet and other family members to detect rare skeletal dysplasia conditions causing pain and deformity, and provides details of the spectrum of problems associated with SYM1B.

SUBMITTER: Leonidou A

PROVIDER: S-EPMC5155261 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Recurrent missense mutation of GDF5 (p.R438L) causes proximal symphalangism in a British family.

Leonidou Andreas A Irving Melita M Holden Simon S Katchburian Marcos M

World journal of orthopedics 20161218 12

Proximal symphalangism (SYM1B) (OMIM 615298) is an autosomal dominant developmental disorder affecting joint fusion. It is characterized by variable fusions of the proximal interphalangeal joints of the hands, typically of the ring and little finger, with the thumb typically being spared. SYM1 is frequently associated with coalition of tarsal bones and conductive hearing loss. Molecular studies have identified two possible genetic aetiologies for this syndrome, NOG and GDF5. We her ...[more]

PMID: 28032038

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Project description:BackgroundProximal 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 reportIn 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.ConclusionOur 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.

Project description:Pathogenic variants in aminoacyl-tRNA synthetases (ARS1) cause a diverse spectrum of autosomal recessive disorders. Tyrosyl tRNA synthetase (TyrRS) is encoded by YARS1 (cytosolic, OMIM*603,623) and is responsible of coupling tyrosine to its specific tRNA. Next to the enzymatic domain, TyrRS has two additional functional domains (N-Terminal TyrRSMini and C-terminal EMAP-II-like domain) which confer cytokine-like functions. Mutations in YARS1 have been associated with autosomal-dominant Charcot-Marie-Tooth (CMT) neuropathy type C and a heterogenous group of autosomal recessive, multisystem diseases. We identified 12 individuals from 6 families with the recurrent homozygous missense variant c.1099C > T;p.(Arg367Trp) (NM_003680.3) in YARS1. This variant causes a multisystem disorder with developmental delay, microcephaly, failure to thrive, short stature, muscular hypotonia, ataxia, brain anomalies, microcytic anemia, hepatomegaly, and hypothyroidism. In silico analyses show that the p.(Arg367Trp) does not affect the catalytic domain responsible of enzymatic coupling, but destabilizes the cytokine-like C-terminal domain. The phenotype associated with p.(Arg367Trp) is distinct from the other biallelic pathogenic variants that reside in different functional domains of TyrRS which all show some common, but also divergent clinical signs [(e.g., p.(Phe269Ser)-retinal anomalies, p.(Pro213Leu)/p.(Gly525Arg)-mild ID, p.(Pro167Thr)-high fatality)]. The diverse clinical spectrum of ARS1-associated disorders is related to mutations affecting the various non-canonical domains of ARS1, and impaired protein translation is likely not the exclusive disease-causing mechanism of YARS1- and ARS1-associated neurodevelopmental disorders. KEY MESSAGES: The missense variant p.(Arg367Trp) in YARS1 causes a distinct multisystem disorder. p.(Arg367Trp) affects a non-canonical domain with cytokine-like functions. Phenotypic heterogeneity associates with the different affected YARS1 domains. Impaired protein translation is likely not the exclusive mechanism of ARS1-associated disorders.

Dataset Information

Recurrent missense mutation of GDF5 (p.R438L) causes proximal symphalangism in a British family.

Publications

Recurrent missense mutation of <i>GDF5</i> (<i>p.R438L</i>) causes proximal symphalangism in a British family.

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