Bellardita Michela, Romano Ferruccio, Menta Ludovica, Da Silva Joana Soraia Martinheira, Ognibene Marzia, Baldassari Simona, Di Duca Marco, Panicucci Chiara, Baratto Serena, Brolatti Noemi, Pedemonte Marina, Fiorillo Chiara, Bruno Claudio, Scala Marcello, Zara Federico, Faravelli Francesca, Madia Francesca, Cappato Serena, Bocciardi Renata, Capra Valeria
DINOGMI-Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.
Genomics and Clinical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Mol Genet Genomic Med. 2025 Aug;13(8):e70126. doi: 10.1002/mgg3.70126.
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.
伴有本体感觉和触觉受损的远端关节挛缩症（DAIPT）是一种罕见的常染色体隐性神经疾病，其特征为机械感觉的进行性改变。DAIPT 由 PIEZO2 基因的功能丧失变异引起，该基因编码一种参与机械转导信号传导的离子通道。我们的研究始于一名 11 岁男孩的病例，其骨骼和神经肌肉特征提示为 DAIPT。
对三联体进行外显子组测序。通过 Sanger 测序验证 PIEZO2 中鉴定出的变异。使用 NMD 抑制剂，通过在 HEK-293 细胞中的小基因检测以及对患者来源细胞进行功能检测，对变异进行功能分析。
三联体外显子组测序揭示了 PIEZO2 基因中存在两个新变异：一个无义变异（c.1924G>T；p.Glu642*）和一个意义不确定的内含子变异（c.2170-15A>G）。功能分析表明，内含子变异破坏剪接，导致过早的终止密码子形成，并可能使 mRNA 靶向无义介导的 mRNA 降解（NMD）。使用特异性 NMD 抑制剂对患者来源的成纤维细胞进行分子研究表明，来自两个等位基因的转录本均被 NMD 降解，从而证实了无义变异的作用，并使意义不确定的变异得以重新分类。
我们展示了一名具有 DAIPT 特征的患者的表型和基因描述，该患者携带 PIEZO2 中的新型双等位基因变异，其中一个变异在功能检测后可重新分类为致病性变异。本研究还对所有已发表的 DAIPT 患者进行了详细综述，并扩展了对 DAIPT 的表型和基因理解，有助于诊断、遗传咨询和临床管理。
