We report ten individuals of four independent consanguineous families from 
Turkey, India, Libya, and Pakistan with a variable clinical phenotype that 
comprises arthrogryposis, spontaneously resolving respiratory insufficiency at 
birth, muscular atrophy predominantly of the distal lower limbs, scoliosis, and 
mild distal sensory involvement. Using whole-exome sequencing, SNPchip-based 
linkage analysis, DNA microarray, and Sanger sequencing, we identified three 
independent homozygous frameshift mutations and a homozygous deletion of two 
exons in PIEZO2 that segregated in all affected individuals of the respective 
family. The mutations are localized in the N-terminal and central region of the 
gene, leading to nonsense-mediated transcript decay and consequently to lack of 
PIEZO2 protein. In contrast, heterozygous gain-of-function missense mutations, 
mainly localized at the C terminus, cause dominant distal arthrogryposis 3 
(DA3), distal arthrogryposis 5 (DA5), or Marden-Walker syndrome (MWKS), which 
encompass contractures of hands and feet, scoliosis, ophthalmoplegia, and 
ptosis. PIEZO2 encodes a mechanosensitive ion channel that plays a major role in 
light-touch mechanosensation and has recently been identified as the principal 
mechanotransduction channel for proprioception. Mice ubiquitously depleted of 
PIEZO2 are postnatally lethal. However, individuals lacking PIEZO2 develop a not 
life-threatening, slowly progressive disorder, which is likely due to loss of 
PIEZO2 protein in afferent neurons leading to disturbed proprioception causing 
aberrant muscle development and function. Here we report a recessively inherited 
PIEZO2-related disease and demonstrate that depending on the type of mutation 
and the mode of inheritance, PIEZO2 causes clinically distinguishable 
phenotypes.