Submission Details

Autosomal recessive

07/28/2020

The PIEZO2 gene is located on chromosome 18 at p11.22-p11.21 and encodes the piezo type mechanosensitive ion channel component 2 protein, a rapidly adapting mechanically-activated cation channel that is required for touch sensation and proprioception (25471886: Ranade et al. 2014; 26551544: Woo et al. 2014). PIEZO2 was first reported in association with autosomal recessive distal arthrogryposis with impaired proprioception and touch in 2016 (27653382: Chesler et al. 2016). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included eight unique variants reported in seven cases from four publications (27653382: Chesler et al. 2016; 27843126: Delle Vedove et al. 2016; 27607563: Mahmud et al. 2017; 30941898: Yamaguchi et al. 2019). One variant was a missense with experimental evidence of a loss-of-function effect; the remainder were predicted null variants. No segregation evidence was scored, but variants in this gene co-segregated with disease in additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. Biallelic loss of function is implicated as the mechanism of disease. This gene-disease relationship is supported by tissue-specific expression in mechanoreceptors that sense mechanical stimuli relevant to touch sensation and in all types of proprioceptive peripheral endings (20813920: Coste et al. 2010; 25471886: Ranade et al. 2014; 26551544: Woo et al. 2014). Conditional knockout of PIEZO2 in sensory neurons and epidermal Merkel cells causes impaired touch sensation, and conditional knockout in proprioceptors resulted in impaired proprioception and difficulty walking (25471886: Ranade et al. 2014; 26551544: Woo et al. 2014). In summary, PIEZO2 is definitively associated with autosomal recessive distal arthrogryposis with impaired proprioception and touch. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

27653382 27843126 27607563 30941898 25471886 26551544