Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome and distal arthrogryposis type 5. M. J. McMillin1, A. E. Beck1,2, J. X. Chong1,2, K. M. Shively1, K. J. Buckingham1, H. I. Gildersleeve1, M. Splitt4, A. S. Aylsworth5, I. P. C. Krapels6, C. J. Curry7, M. I. Aracena8,9, J. T. Hecht10, J. A. Hurst11, R. H. Scott11, K. Devriendt12, J. M. Graham, Jr.13, J. D. Smith3, H. K. Tabor14, J. Shendure3, D. A. Nickerson3, M. J. Bamshad1,2,3, University of Washington Center for Mendelian Genomics 1) Department of Pediatrics, University of Washington, Seattle, WA; 2) Seattle Children's Hospital, Seattle, WA; 3) Department of Genome Sciences, University of Washington, Seattle, WA; 4) Institute of Genetic Medicine, Center for Life, Newcastle upon Tyne Hospitals, Newcastle, UK; 5) Departments of Pediatrics and Genetics, University of North Carolina, Chapel Hill, NC; 6) Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, Netherlands; 7) Genetic Medicine Central California, Fresno/UCSF; 8) Unidad de Genética, Hospital Dr. Luis Calvo Mackenna, Santiago-Chile; 9) División de Pediatría, Facultad de Medicina, Pontificia Universidad Católica de Chile; 10) Department of Pediatrics, University of Texas Medical School, Houston, TX; 11) NE Thames Genetic Service, Great Ormond Street Hospital, London; 12) Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium; 13) Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angles, CA; 14) Treuman Katz Center for Pediatric Bioethics, Seattle Children's Research Institute, Seattle, WA.

   Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal dominant disorder characterized by congenital contractures of the hands and feet, cleft palate, dysmorphic facial features, and short stature. Analysis of exome sequencing data from five families with GS identified mutations in the gene piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Specifically, a novel substitution predicted to result in a missense mutation (p.R2686H) was transmitted from an affected mother to her three affected offspring in one GS family, and was confirmed to be de novo in three sporadic GS cases. A three base pair deletion predicted to result in the deletion of a single amino acid (p.E2727del) was confirmed to be de novo in the fifth GS family. The p.E2727del mutation is one of two mutations in PIEZO2 recently reported to cause distal arthrogryposis type 5 (DA5). DA5 is distinguished from other DAs by the presence of ocular abnormalities, such as ptosis, ophthalmoplegia and keratoconus. However, there is considerable overlap between the phenotypes of GS and DA5. Accordingly, we used molecular inversion probe (MIP) sequencing to screen PIEZO2 in 16 familial and 12 sporadic cases of DA5, three families with GS and seven families with distal arthrogryposis and cleft palate. PIEZO2 mutations were found in 23/28 (82%) DA5 families and in the three additional GS families. In the DA5 cohort, the most common mutations were the p.E2727del mutation (n=10) and p.R2686H (n=4), the same two mutations originally found in the GS cases. Finally, the phenotypes of both GS and DA5 overlap with Marden-Walker syndrome (MWS) and indeed, sequencing of PIEZO2 in a sporadic case of MWS revealed a novel mutation at a recurrent site resulting in a predicted p.R2686C substitution. Collectively, while DA5, GS and MWS have traditionally been considered distinct disorders, our findings indicate they are etiologically related and perhaps represent different manifestations of a single syndrome.

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