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Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5.

ABSTRACT: Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83%] individuals), and nine families had an identical c.8057G>A (p.Arg2686His) mutation. The phenotype of GS overlaps with distal arthrogryposis type 5 (DA5) and Marden-Walker syndrome (MWS). Using molecular inversion probes for targeted sequencing to screen PIEZO2, we found mutations in 24/29 (82%) DA5-affected families and one of two MWS-affected families. The presence of cleft palate was significantly associated with c.8057G>A (Fisher's exact test, adjusted p value < 0.0001). Collectively, although GS, DA5, and MWS have traditionally been considered separate disorders, our findings indicate that they are etiologically related and perhaps represent variable expressivity of the same condition.

SUBMITTER: McMillin MJ

PROVIDER: S-EPMC4067551 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5.

McMillin Margaret J MJ Beck Anita E AE Chong Jessica X JX Shively Kathryn M KM Buckingham Kati J KJ Gildersleeve Heidi I S HI Aracena Mariana I MI Aylsworth Arthur S AS Bitoun Pierre P Carey John C JC Clericuzio Carol L CL Crow Yanick J YJ Curry Cynthia J CJ Devriendt Koenraad K Everman David B DB Fryer Alan A Gibson Kate K Giovannucci Uzielli Maria Luisa ML Graham John M JM Hall Judith G JG Hecht Jacqueline T JT Heidenreich Randall A RA Hurst Jane A JA Irani Sarosh S Krapels Ingrid P C IP Leroy Jules G JG Mowat David D Plant Gordon T GT Robertson Stephen P SP Schorry Elizabeth K EK Scott Richard H RH Seaver Laurie H LH Sherr Elliott E Splitt Miranda M Stewart Helen H Stumpel Constance C Temel Sehime G SG Weaver David D DD Whiteford Margo M Williams Marc S MS Tabor Holly K HK Smith Joshua D JD Shendure Jay J Nickerson Deborah A DA Bamshad Michael J MJ

American journal of human genetics 20140410 5

Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83%] individuals), and nine families had an identical c.8057G>A (p ...[more]

PMID: 24726473

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Project description:BackgroundArthrogryposis multiplex congenita (AMC) is a group of clinically and etiologically heterogeneous conditions, characterized by prenatal onset contractures affecting two or more joints. Its incidence is about 1 in 3000 live births. AMC may be distinguished into amyoplasia, distal and syndromic arthrogryposis. Distal arthrogryposis (DA) predominantly affects hands and feet. It is currently divided into more than ten subtypes (DA1, DA2A/B, DA3-10), based on clinical manifestations, gene mutations and inheritance pattern. Among them, only a few patients with DA5 have been reported. It is associated to a gain-of-function pathogenic variant of the PIEZO2 gene, encoding for an ion-channel necessary to convert mechanical stimulus to biological signals and crucial for the development of joints, neuromuscular and respiratory systems. Main clinical features include multiple distal contractures, short stature, ptosis, ophthalmoplegia and, in some cases, restrictive lung disease.Case presentationHereby, we report on a four-generation Italian family with DA5. Our first proband was a newborn with prenatal suspicion of AMC. At birth, clinical findings were compatible with a DA diagnosis. Family history was positive for the mother with short stature, ophthalmoplegia, short neck, and contractures of the joints of distal extremities, and for three other relatives on the maternal side, including grandfather and great-grandmother, who all shared similar findings. Thus, we performed a next generation sequencing analysis (NGS) of the genes associated to AMC and of those involved in DA. The gain-of-function heterozygous mutation c.8181_8183delAGA (p.Glu2727del) of PIEZO2 was identified in the proband, and the same mutation was also found in the mother, confirming the autosomal dominant inheritance of the condition.ConclusionsOur patients contribute to the current DA5 genomic database, and to a better characterization of the disease. Clinicians may have suspicion of a DA diagnosis based on suggestive (also prenatal) clinical findings, which must be then confirmed by NGS analysis. Since natural history varies widely among different DA disorders, detection of the underlying causal variant is essential for the identification of the exact subtype, and to its adequate management, which must rely on a multidisciplinary and individualized approach.

Dataset Information

Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5.

Publications

Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5.

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