Nantes Université, CHU Nantes, Service de Génétique Médicale, 44000, Nantes, France.
Nantes Université, CHU Nantes, Service de Génétique Médicale, 44000, Nantes, France; Nantes Université, CHU Nantes, CNRS, INSERM, L'institut Du Thorax, 44000 Nantes, France.
Eur J Med Genet. 2024 Jun;69:104932. doi: 10.1016/j.ejmg.2024.104932. Epub 2024 Mar 5.
Incomplete penetrance is observed for most monogenic diseases. However, for neurodevelopmental disorders, the interpretation of single and multi-nucleotide variants (SNV/MNVs) is usually based on the paradigm of complete penetrance.
From 2020 to 2022, we proposed a collaboration study with the French molecular diagnosis for intellectual disability network. The aim was to recruit families for whom the index case, diagnosed with a neurodevelopmental disorder, was carrying a pathogenic or likely pathogenic variant for an OMIM morbid gene and inherited from an asymptomatic parent. Grandparents were analyzed when available for segregation study.
We identified 12 patients affected by a monogenic neurodevelopmental disorder caused by likely pathogenic or pathogenic variant (SNV/MNV) inherited from an asymptomatic parent. These genes were usually associated with de novo variants. The patients carried different variants (1 splice-site variant, 4 nonsense and 7 frameshift) in 11 genes: CAMTA1, MBD5, KMT2C, KMT2E, ZMIZ1, MN1, NDUFB11, CUL3, MED13, ARID2 and RERE. Grandparents have been tested in 6 families, and each time the variant was confirmed de novo in the healthy carrier parent.
Incomplete penetrance for SNV and MNV in neurodevelopmental disorders might be more frequent than previously thought. This point is crucial to consider for interpretation of variants, family investigation, genetic counseling, and prenatal diagnosis. Molecular mechanisms underlying this incomplete penetrance still need to be identified.
大多数单基因疾病存在不完全外显率。然而，对于神经发育障碍，单核苷酸变异（SNV/MNV）的解释通常基于完全外显率的范式。
在 2020 年至 2022 年期间，我们提出了与法国智力障碍分子诊断网络合作研究的建议。目的是招募携带神经发育障碍的索引病例的家庭，这些病例携带致病性或可能致病性的 OMIM 疾病基因变体，并从无症状的父母那里遗传。如果可用于分离研究，将对祖父母进行分析。
我们确定了 12 名患有单基因神经发育障碍的患者，这些患者携带来自无症状父母遗传的可能致病性或致病性变体（SNV/MNV）。这些基因通常与新生变异有关。这些患者携带了 11 个基因中的不同变体（1 个剪接位点变体、4 个无义突变和 7 个移码突变）：CAMTA1、MBD5、KMT2C、KMT2E、ZMIZ1、MN1、NDUFB11、CUL3、MED13、ARID2 和 RERE。在 6 个家庭中对祖父母进行了测试，每次在健康携带者父母中都确认了变体是新生的。
神经发育障碍中的 SNV 和 MNV 不完全外显率可能比之前认为的更为常见。这一点对于变体的解释、家族研究、遗传咨询和产前诊断至关重要。这种不完全外显率的潜在分子机制仍有待确定。
