Mutations in PIEZO2 Cause Gordon Syndrome, Marden-Walker Syndrome, and Distal Arthrogryposis Type 5


McMillin M. J. , Beck A. E. , Chong J. X. , Shively K. M. , Buckingham K. J. , Gildersleeve H. I. S. , ...More

AMERICAN JOURNAL OF HUMAN GENETICS, vol.94, no.5, pp.734-744, 2014 (Peer-Reviewed Journal) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 94 Issue: 5
  • Publication Date: 2014
  • Doi Number: 10.1016/j.ajhg.2014.03.015
  • Journal Name: AMERICAN JOURNAL OF HUMAN GENETICS
  • Journal Indexes: Science Citation Index Expanded, Scopus
  • Page Numbers: pp.734-744

Abstract

Gordon syndrome (GS), or distal arthrogyposis 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 mechano-sensitive 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.