Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Language and Genetics, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands; International Max Planck Research School for Language Sciences, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.
Genet Med. 2022 Jun;24(6):1283-1296. doi: 10.1016/j.gim.2022.02.014. Epub 2022 Mar 26.
Common diagnostic next-generation sequencing strategies are not optimized to identify inherited variants in genes associated with dominant neurodevelopmental disorders as causal when the transmitting parent is clinically unaffected, leaving a significant number of cases with neurodevelopmental disorders undiagnosed.
We characterized 21 families with inherited heterozygous missense or protein-truncating variants in CHD3, a gene in which de novo variants cause Snijders Blok-Campeau syndrome.
Computational facial and Human Phenotype Ontology-based comparisons showed that the phenotype of probands with inherited CHD3 variants overlaps with the phenotype previously associated with de novo CHD3 variants, whereas heterozygote parents are mildly or not affected, suggesting variable expressivity. In addition, similarly reduced expression levels of CHD3 protein in cells of an affected proband and of healthy family members with a CHD3 protein-truncating variant suggested that compensation of expression from the wild-type allele is unlikely to be an underlying mechanism. Notably, most inherited CHD3 variants were maternally transmitted.
Our results point to a significant role of inherited variation in Snijders Blok-Campeau syndrome, a finding that is critical for correct variant interpretation and genetic counseling and warrants further investigation toward understanding the broader contributions of such variation to the landscape of human disease.
常见的诊断下一代测序策略并未针对在传递亲本临床无影响的情况下，鉴定与显性神经发育障碍相关的基因中的遗传变异作为因果关系进行优化，导致大量神经发育障碍病例未得到诊断。
我们对 21 个家族进行了研究，这些家族的先证者携带有 CHD3 基因的杂合错义或蛋白截断变异，该基因中的新生变异会导致 Snijders Blok-Campeau 综合征。
基于计算的面部和人类表型本体的比较表明，携带 CHD3 遗传变异的先证者的表型与先前与新生 CHD3 变异相关的表型重叠，而杂合子父母则受到轻度或未受影响，表明存在可变外显率。此外，受影响的先证者和携带 CHD3 蛋白截断变异的健康家族成员的 CHD3 蛋白表达水平相似降低，表明野生型等位基因的表达补偿不太可能是潜在的机制。值得注意的是，大多数遗传 CHD3 变异是母系遗传的。
我们的结果表明，遗传变异在 Snijders Blok-Campeau 综合征中具有重要作用，这一发现对于正确的变异解释和遗传咨询至关重要，并需要进一步研究，以了解这种变异对人类疾病谱的更广泛贡献。
