Department of Medical Genetics, Maternal and Child Health Hospital of Hunan Province, Changsha, China.
National Health Commission Key Laboratory of Birth Defects Research, Prevention and Treatment, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, China.
Am J Med Genet A. 2021 Jul;185(7):2119-2125. doi: 10.1002/ajmg.a.62174. Epub 2021 Apr 14.
Neurodevelopmental diseases are increasingly recognized to be caused by "de novo" variants with the expanding use of next-generation sequencing. The apparent de novo variants may actually be low-level hereditary parental mosaic variants, which could increase the recurrence risk of disease by >50% and is thought to be an underappreciated cause of neurodevelopmental diseases. Our study aimed to investigate the frequency of parental mosaicism in "de novo" neurodevelopmental diseases. A total of 237 patients (and parents) with neurodevelopmental diseases carrying apparent de novo pathogenic or likely pathogenic variants were recruited consecutively. Deep next-generation sequencing was performed on parental samples to identify parental mosaicism. Fourteen parental disease-causing mosaicism variants (3.0%) in 11 genes were detected with alternate allele frequency (AAF) 0.22%-34%. Three parents showed milder clinical phenotypes than their offspring with relatively high AAF (23.33%, 25%, 34% separately). One recurrent variant was identified prenatally. A review of cohort study on parental mosaicism in neurodevelopmental diseases was performed. Our study highlights that identifying the parental mosaic disease-causing variants especially the low-level mosaicism will contribute to improving the accuracy of genetic counseling and prenatal diagnosis for reproductive risks.
神经发育疾病越来越被认为是由“新生”变异引起的，随着下一代测序技术的广泛应用。明显的新生变异实际上可能是低水平的遗传性父母镶嵌变异，这可能会使疾病的复发风险增加>50%，并被认为是神经发育疾病被低估的一个原因。我们的研究旨在调查“新生”神经发育疾病中父母镶嵌体的频率。连续招募了 237 名携带明显新生致病性或可能致病性变异的神经发育疾病患者（及其父母）。对父母样本进行深度下一代测序，以鉴定父母镶嵌体。在 11 个基因中检测到 14 个父母致病性镶嵌变异（3.0%），等位基因频率（AAF）为 0.22%-34%。有 3 位父母的临床表现比他们的后代轻，且 AAF 相对较高（分别为 23.33%、25%、34%）。一个反复出现的变异是在产前检测到的。对神经发育疾病中父母镶嵌体的队列研究进行了综述。我们的研究强调，识别父母致病的镶嵌变体，特别是低水平的镶嵌体，将有助于提高遗传咨询和产前诊断的准确性，以降低生殖风险。
