Chelleri Cristina, Scala Marcello, De Marco Patrizia, Guerriero Vittorio, Ognibene Marzia, Madia Francesca, Guerrisi Sara, Di Duca Marco, Torre Michele, Tamburro Serena, Scudieri Paolo, Piccolo Gianluca, Mattioli Girolamo, Buffelli Francesca, Uva Paolo, Vozzi Diego, Fulcheri Ezio, Striano Pasquale, Diana Maria Cristina, Zara Federico
Pediatric Neurology and Neuromuscular Disorders Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy.
Hum Mutat. 2023 Apr 28;2023:3160653. doi: 10.1155/2023/3160653. eCollection 2023.
Neurofibromatosis type 1 (NF1) is a neurocutaneous genetic disorder with a broad spectrum of associated signs and symptoms, including skeletal anomalies. The association of NF1 with anterior chest wall deformities has been recently reported, especially the pectus excavatum (PE). Over the years, several authors have suggested loss of heterozygosity (LOH) as the possible pathogenic mechanism underlying the development of the typical NF1 skeletal features. Here, we report a NF1 patient with severe chest deformity and harboring the germline heterozygous pathogenic variant NM_001042492.3: c.4271delC p.(Ala1424Glufs4). Through next-generation sequencing (NGS), we investigated the affected cartilage from the PE deformity and identified the additional frameshift variant NM_001042492.3: c.2953delC p.(Gln985Lysfs7), occurring as a somatic NF1 second hit mutation. Exome sequencing confirmed the absence of additional variants of potential pathogenic relevance. Western blot analysis showed the absence of wild-type NF1 protein in the cartilage of the patient, consistent with a somatic double inactivation (SDI) of . Taken together, our findings support the role of SDI in NF1-related PE, widening the spectrum of the pathophysiological mechanisms involved in NF1-related skeletal features.
1型神经纤维瘤病（NF1）是一种神经皮肤遗传性疾病，伴有广泛的相关体征和症状，包括骨骼异常。最近有报道称NF1与前胸壁畸形有关，尤其是漏斗胸（PE）。多年来，几位作者提出杂合性缺失（LOH）是典型NF1骨骼特征发展的潜在致病机制。在此，我们报告一名患有严重胸部畸形且携带种系杂合性致病变体NM_001042492.3:c.4271delC p.(Ala1424Glufs4)的NF1患者。通过下一代测序（NGS），我们研究了PE畸形中受影响的软骨，并鉴定出额外的移码变体NM_001042492.3:c.2953delC p.(Gln985Lysfs7)，它作为体细胞NF1第二次打击突变出现。外显子测序证实不存在其他具有潜在致病相关性的变体。蛋白质印迹分析显示患者软骨中不存在野生型NF1蛋白，这与体细胞双失活（SDI）一致。综上所述，我们的研究结果支持SDI在NF1相关PE中的作用，拓宽了NF1相关骨骼特征所涉及的病理生理机制范围。
