Massive parallel sequencing of 70 genes in a girl with a suspicion of chromatinopathy detected the (NM_015443.4:)c.985_986delTT variant in exon 2 of KANSL1, which led to a diagnostic consideration of Koolen De Vries syndrome. The same variant was present in the healthy mother, consistent with either incomplete penetrance or variant mismapping. A network of second opinion was implemented among clinical geneticists first, and a diagnosis of Koolen De Vries syndrome was considered unlikely. By MLPA, a duplication spanning exons 1-3 of KANSL1 was detected in both the mother and the daughter. On cDNA sequencing, biallelic wild type mRNA was observed. We concluded that the variant affects the noncoding duplicated gene region in our family, and we finally classified it as benign. Parallel wide genomic sequencing is increasingly the first genetic investigation in individuals with intellectual disability. The c.985_986delTT variant in KANSL1 was described both in individuals with typical KdVS and in a limited number of healthy subjects. This report highlights the role of clinical genetics to correctly classify variants and to define proper clinical and diagnostic correlations.

中文翻译：

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临床遗传学可以解决全基因组研究的陷阱：从错误映射 KANSL1 中功能丧失变体的经验教训

对一名疑似染色质病的女孩的 70 个基因进行大规模平行测序，在 KANSL1 的外显子 2 中检测到 (NM_015443.4:)c.985_986delTT 变异，这导致了对 Koolen De Vries 综合征的诊断考虑。相同的变异存在于健康的母亲中，与不完全外显率或变异错误映射一致。首先在临床遗传学家中实施了第二意见网络，并认为不太可能诊断为 Koolen De Vries 综合征。通过 MLPA，在母亲和女儿身上都检测到了跨越 KANSL1 外显子 1-3 的重复。在 cDNA 测序中，观察到双等位基因野生型 mRNA。我们得出结论，该变异影响我们家族中的非编码重复基因区域，我们最终将其归类为良性。平行宽基因组测序越来越多地成为智障个体的首个基因调查。KANSL1 中的 c.985_986delTT 变异在具有典型 KdVS 的个体和数量有限的健康受试者中均有描述。该报告强调了临床遗传学在正确分类变异和定义适当的临床和诊断相关性方面的作用。