Abstract：
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
目的：在大多数单基因疾病中观察到不完全的外显率。然而,神经发育障碍，单核苷酸和多核苷酸变体（SNV/MNV）的解释通常基于完全外显率的范式。
方法：从2020年到2022年，我们提出了与法国分子诊断进行智力障碍网络的合作研究。目的是招募索引案例的家庭，被诊断患有神经发育障碍,携带OMIM病态基因的致病性或可能的致病性变异体，并遗传自无症状的父母。在可用于隔离研究时，对祖父母进行了分析。
结果：我们确定了12例受单基因神经发育障碍影响的患者，该疾病是由无症状父母遗传的可能的致病性或致病性变异（SNV/MNV）引起的。这些基因通常与从头变体相关。患者携带不同的变体（1个剪接位点变体，11个基因中的4个无义和7个移码）：CAMTA1，MBD5，KMT2C，KMT2E,ZMIZ1、MN1、NDUFB11、CUL3、MED13、ARID2和RERE。祖父母已经在6个家庭接受了测试，并且每次在健康携带者亲本中从头确认变体。
结论：神经发育障碍中SNV和MNV的不完全外显率可能比以前认为的更常见。这一点对于解释变体至关重要，家庭调查,遗传咨询,和产前诊断。这种不完全外显率的分子机制仍需鉴定。
方法：从2020年到2022年，我们提出了与法国分子诊断进行智力障碍网络的合作研究。目的是招募索引案例的家庭，被诊断患有神经发育障碍,携带OMIM病态基因的致病性或可能的致病性变异体，并遗传自无症状的父母。在可用于隔离研究时，对祖父母进行了分析。
结果：我们确定了12例受单基因神经发育障碍影响的患者，该疾病是由无症状父母遗传的可能的致病性或致病性变异（SNV/MNV）引起的。这些基因通常与从头变体相关。患者携带不同的变体（1个剪接位点变体，11个基因中的4个无义和7个移码）：CAMTA1，MBD5，KMT2C，KMT2E,ZMIZ1、MN1、NDUFB11、CUL3、MED13、ARID2和RERE。祖父母已经在6个家庭接受了测试，并且每次在健康携带者亲本中从头确认变体。
结论：神经发育障碍中SNV和MNV的不完全外显率可能比以前认为的更常见。这一点对于解释变体至关重要，家庭调查,遗传咨询,和产前诊断。这种不完全外显率的分子机制仍需鉴定。
