Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Department of Pediatric Cardiology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Am J Med Genet A. 2020 Apr;182(4):689-696. doi: 10.1002/ajmg.a.61511. Epub 2020 Feb 6.
Trio exome sequencing is a powerful tool in the molecular investigation of monogenic disorders and provides an incremental diagnostic yield over proband-only sequencing, mainly due to the rapid identification of de novo disease-causing variants. However, heterozygous variants inherited from unaffected parents may be inadvertently dismissed, although multiple explanations are available for such scenarios including mosaicism in the parent, incomplete penetrance, imprinting, or skewed X-inactivation. We report three probands, in which a pathogenic or likely pathogenic variant was identified upon exome sequencing, yet was inherited from an unaffected parent. Segregation of the variants (in NOTCH1, PHF6, and SOX10) in the grandparent generation revealed that the variant was de novo in each case. Additionally, one proband had skewed X-inactivation. We discuss the possible genetic mechanism in each case, and urge caution in data interpretation of exome sequencing data. We illustrate the utility of expanding segregation studies to the grandparent generation and demonstrate the impact on exome interpretation strategies, by showing that objective genotype data can overcome subjective parental report of lack of symptoms.
三重外显子组测序是一种强大的工具，可用于单基因疾病的分子研究，与仅对先证者进行测序相比，它提供了增量诊断收益，主要是因为可以快速识别新生致病变异。然而，来自未受影响父母的杂合变异可能会被无意中忽略，尽管对于这种情况有多种解释，包括父母的嵌合体、不完全外显率、印迹或偏性 X 失活。我们报告了三个先证者，在外显子组测序中发现了致病性或可能致病性的变异，但该变异是从未受影响的父母那里遗传的。在祖孙一代中变异（在 NOTCH1、PHF6 和 SOX10 中）的分离表明，在每种情况下变异都是新生的。此外，一个先证者存在偏性 X 失活。我们讨论了每种情况下可能的遗传机制，并敦促谨慎解释外显子组测序数据。我们通过展示客观的基因型数据可以克服父母报告的缺乏症状的主观性，说明了将分离研究扩展到祖孙一代的实用性，并展示了它对外显子解释策略的影响。
