Genetic and clinical spectrum of PIEZO2-related disorders: insights from a multicenter study of 26 patients

PIEZO2 is a mechanosensitive ion channel essential for somatosensation, including proprioception, touch and interoception, enabling the detection of external and internal mechanical stimuli. Pathogenic variants in PIEZO2 cause mechanosensitivity disorders, predominantly affecting musculoskeletal system. This multicenter study reports on 26 patients (14 females and 12 males; ages 1–51 years) from 23 independent families; 21 with biallelic and 5 with heterozygous variants. We identified 20 unique PIEZO2 variants, including 14 novel variants. Patients with biallelic PIEZO2 variants presented with hypotonia, joint contractures, feeding and respiratory difficulties, followed by delayed motor milestones and progressive scoliosis. Findings of disrupted proprioception along with areflexia were key neurological findings, and electrophysiologic studies showed sensory neuropathy. Clinical characteristics were distinct; however, there were considerable variations in disease severity. Heterozygous variants (de novo variants in three cases) exhibiting clinical features associated with PIEZO2-related disorders led to a heterogeneous disease spectrum, including distal arthrogryposis, restricted eye movements, ptosis, short stature, scoliosis, cleft palate, metacarpal/metatarsal synostosis, glaucoma, keratoconus, and restrictive pulmonary function. This is the largest cohort of patients with biallelic PIEZO2 variants across ages. Our findings highlight the role of impaired proprioception in biallelic PIEZO2-related disease and channelopathy in heterozygous PIEZO2-related disorders, shaping diverse clinical presentations and expanding understanding of PIEZO2-related disorders.