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.

Figure 1

Phenotypic Characteristics of Each GS Individual Used for Exome Sequencing and the MWS Individual with a Mutation in PIEZO2 (A–F) Faces of individuals affected by GS. All individuals shown had PIEZO2 mutations. Note the deep-set eyes and micrognathia. Each individual had either cleft palate or a bifid uvula. (H and I) The hands (H) and feet (I) of an individual with GS demonstrate curved fingers with straight thumbs and clubfeet, respectively. (G) The face of an individual with MWS and a mutation in PIEZO2. Case identifiers for the individuals shown in this figure are A:I-2 (A), A:II-1 (B), B:II-1 (C), C:II-1 (D, H, and I), D:II-1 (E), E:II-1 (F), and II:II-1 (G) and correspond to those in Table 1, which includes a detailed description of the phenotype of each affected individual. Figure S1 provides a pedigree of each GS-affected family, and Figure S3 provides a pedigree of the MWS-affected family (II).

Figure 2

Genomic Structure and Spectrum of PIEZO2 Mutations that Cause GS, DA5, or MWS PIEZO2 is composed of 52 exons that encode protein-coding sequence (blue). Arrows indicate the locations of 13 different mutations found in 35 families affected by GS, DA5 or MWS. The ¥ symbol indicates mutations that were inherited in families with an autosomal-dominant pattern of inheritance, and the † symbol indicates mutations that were confirmed to be de novo in simplex cases. PIEZO2 mutations identified in GS, DA5, and MWS individuals are indicated by red, yellow, and green circles, respectively.

Figure 3

Phenotype Overlap among Families Affected by PIEZO2 Mutations and GS, DA5, or MWS Individuals with GS, DA5, or MWS share common clinical findings, including short stature, curved fingers with straight thumbs, and foot contractures and/or an increased space between the first and second toes (the so-called “sandal gap”). Specific additional clinical features (e.g., cleft palate in GS, ophthalmoplegia in DA5, and cerebellar malformations in MWS) are typically used for distinguishing these conditions from one another. Representative facial photos of individuals with GS (C:II-1), DA5 (Y:II-1), and MWS (II:II-1) are shown. In families affected by PIEZO2 mutations, some individuals had “intermediate phenotypes,” that is, they shared so-called “distinguishing features” among GS, DA5, and MWS. Individual E:II-1 had both cleft palate and ophthalmoplegia, individual I:II-1 had both cleft palate and a cerebellar malformation, and individual J:I-2 had cleft palate, ophthalmoplegia, and a cerebellar malformation.