Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5.
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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.Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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keywords
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Abnormalities, Multiple
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Arachnodactyly
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Arthrogryposis
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Blepharophimosis
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Child
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Child, Preschool
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Cleft Palate
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Clubfoot
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Connective Tissue Diseases
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Contracture
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Exome
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Female
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Hand Deformities, Congenital
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Humans
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Ion Channels
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Male
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Mutation
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Ophthalmoplegia
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Pedigree
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Retinal Diseases
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