ClinVar

In affected individuals from 9 families with distal arthrogryposis type 3 (DA3; 114300), including the family originally reported by Becker and Splitt (2001), McMillin et al. (2014) identified heterozygosity for a c.8057G-A transition in exon 52 of the PIEZO2 gene, resulting in an arg2686-to-his (R2686H) substitution. The mutation, which segregated with disease in each family, was not present in the ESP6500 or 1000 Genomes Project databases, or in more than 1,400 chromosomes from internal databases. In addition, 2 probands who had been diagnosed with distal arthrogryposis type 5 (DA5; 108145), 1 of whom was the Dutch patient described by Schrander-Stumpel et al. (1993), were found to be heterozygous for R2686H. Neither proband exhibited the characteristic DA3 feature of cleft palate; however, given the reduced penetrance of cleft palate in DA3, McMillin et al. (2014) suggested that the correct diagnosis in the 2 cases was DA3 rather than DA5. The authors also noted that the presence of cleft palate was significantly associated with R2686H (p less than 0.0001).

In a father and 2 sons with DA3, who also exhibited mild intellectual disability and psychomotor delay, Alisch et al. (2017) identified heterozygosity for the recurrent R2686H mutation.