Di Pede Alessandra, Magliozzi Monia, Valfré Laura, Dentici Maria Lisa, Pugnaloni Flaminia, Alesi Viola, Conforti Andrea, Capolupo Irma, Braguglia Annabella, Dotta Andrea, Bagolan Pietro, Novelli Antonio, Digilio Maria Cristina
Medical and Neonatal Sub-Intensive Unit, Bambino Gesù Children's Hospital IRCCS, 00165 Rome, Italy.
Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital IRCCS, 00165 Rome, Italy.
Genes (Basel). 2025 Sep 10;16(9):1066. doi: 10.3390/genes16091066.
The etiology of congenital diaphragmatic hernia (CDH) remains unknown in over 50% of cases, although multiple heterogeneous causative defects have been identified. Emerging evidence suggests that specific genes and molecular pathways involved in connective tissue biology may contribute to CDH development. Associations between CDH and connective tissue disorders have been reported, including cases in Marfan syndrome and a prevalence of CDH in 34% of patients with arterial tortuosity syndrome. Noticing joint laxity in several CDH patients, we aimed to investigate the presence of genetic variants linked to connective tissue disorders in this subgroup, focusing on patients enrolled in the follow-up program at Bambino Gesù Children's Hospital. : We selected patients diagnosed with CDH who also exhibited joint laxity based on a positive Beighton scale. These individuals underwent molecular analysis targeting genes known to be associated with heritable connective tissue disorders. Genetic testing revealed variants in several genes across our patient series. These included mutations in , , , , , , , and . In some cases, the variants were inherited paternally, while others appeared de novo. Most of these variants were classified as of unknown significance according to ACMG guidelines. (1) Several "variants of unknown significance" in different genes causative for connective tissue disorders have been detected in half of the present series of patients with CDH and joint laxity; (2) although the majority of the variants are classified accordingly to the ACMG as "variants of unknown significance", a role of predisposition or susceptibility to CDH cannot be excluded; (3) a precise clinical evaluation for features of connective disorders should be recommended in the diagnostic workflow of patients with CDH.
超过50%的先天性膈疝（CDH）病例病因仍不明，尽管已确定多种异质性致病缺陷。新出现的证据表明，参与结缔组织生物学的特定基因和分子途径可能导致CDH的发生。已有报道称CDH与结缔组织疾病之间存在关联，包括马凡综合征病例以及动脉迂曲综合征患者中34%患有CDH。注意到一些CDH患者存在关节松弛，我们旨在调查该亚组中与结缔组织疾病相关的基因变异情况，重点关注在 Bambino Gesù儿童医院参加随访项目的患者。我们选择了根据Beighton量表呈阳性诊断为CDH且伴有关节松弛的患者。这些个体接受了针对已知与遗传性结缔组织疾病相关基因的分子分析。基因检测在我们的患者系列中发现了多个基因的变异。这些变异包括 、 、 、 、 、 、 和 中的突变。在某些情况下，变异是父系遗传的，而其他变异则是新发的。根据美国医学遗传学与基因组学学会（ACMG）指南，这些变异大多被分类为意义不明。（1）在本系列半数患有CDH和关节松弛的患者中检测到不同基因中几个“意义不明的变异”；（2）尽管大多数变异根据ACMG被分类为“意义不明的变异”，但不能排除其对CDH的易感性或易患性作用；（3）在CDH患者的诊断流程中，应建议对结缔组织疾病特征进行精确的临床评估。
