Functional Characterization of a Novel Intronic Variant in PIEZO2 in a Recessive Form of Distal Arthrogryposis With...

Distal arthrogryposis with impaired proprioception and touch (DAIPT) is a rare autosomal recessive neurological disease characterized by progressive alteration of mechanosensation. DAIPT is caused by loss of function variants in the PIEZO2 gene that encodes an ionic channel involved in mechanotransduction signaling. Our study started from the case of an 11-year-old boy with skeletal and neuromuscular features suggestive of DAIPT.

Exome sequencing was performed on the trio. The identified variants in PIEZO2 were validated by Sanger sequencing. Functional assays of the variants were performed by minigene assay in HEK-293 cells and on patient-derived cells using NMD inhibitors.

Trio exome sequencing revealed the presence of two novel variants in the PIEZO2 gene: a nonsense variant (c.1924G>T; p.Glu642*) and an intronic variant of uncertain significance (c.2170-15A>G). Functional analysis demonstrated that the intronic variant disrupts splicing, leading to premature stop codon formation and possible mRNA targeting to nonsense-mediated mRNA decay (NMD). Molecular study in patient-derived fibroblasts with specific NMD inhibitors shows that transcripts derived from both alleles are degraded by NMD, thus confirming the effect of the nonsense variant and enabling reclassification of the VUS.

We present the phenotypic and genetic description of a patient with features suggestive of DAIPT carrying novel biallelic variants in PIEZO2, one of which could be reclassified as pathogenic after functional assays. This study also provides a detailed review of all the published patients with DAIPT and expands the phenotypic and genetic understanding of DAIPT, aiding in diagnosis, genetic counseling, and clinical management.