Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5.
McMillin MJ., Beck AE., Chong JX., Shively KM., Buckingham KJ., Gildersleeve HIS., Aracena MI., Aylsworth AS., Bitoun P., Carey JC., Clericuzio CL., Crow YJ., Curry CJ., Devriendt K., Everman DB., Fryer A., Gibson K., Giovannucci Uzielli ML., Graham JM., Hall JG., Hecht JT., Heidenreich RA., Hurst JA., Irani S., Krapels IPC., Leroy JG., Mowat D., Plant GT., Robertson SP., Schorry EK., Scott RH., Seaver LH., Sherr E., Splitt M., Stewart H., Stumpel C., Temel SG., Weaver DD., Whiteford M., Williams MS., Tabor HK., Smith JD., Shendure J., Nickerson DA., University of Washington Center for Mendelian Genomics None., Bamshad MJ.
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.