Abstract：
Syndromic intellectual disability (ID) with accompanying primary microcephaly is a group of rare neurodevelopmental disorders exhibiting extreme genetic and clinical heterogeneity. This layered heterogeneity can partially be resolved by unbiased genetic approaches targeting the genome with next generation sequencing (NGS) technologies, including exome sequencing (ES).
This study was performed to dissect the clinical and genetic features in five distinct IDM cases.
Singleton or trio ES approach followed by in-depth variant analysis using alternative inheritance models was performed.
We have identified biallelic loss of function variants in genes WDR62 and AP4M1 in three families, together with de novo missense variants in genes SOX11 and TRIO in two families. ES based haplotype analysis in two cases upon identification of an identical WDR62 variant in the homozygous state in two cases was suggestive of a small shared haplotype of 0.1 Mb. Additionally, we have shown a paternal origin for the de novo variant in TRIO via a polymorphic tag SNP, which enlightens the mutational mechanism for this variant.
In populations with high parental consanguinity, an autosomal recessive inheritance pattern for data analysis is usually the most obvious choice. Therefore, heterozygous variants may be overlooked in standard NGS analyses in consanguineous families. Our findings underlie the importance of using multiple inheritance models in NGS data analysis.
This study was performed to dissect the clinical and genetic features in five distinct IDM cases.
Singleton or trio ES approach followed by in-depth variant analysis using alternative inheritance models was performed.
We have identified biallelic loss of function variants in genes WDR62 and AP4M1 in three families, together with de novo missense variants in genes SOX11 and TRIO in two families. ES based haplotype analysis in two cases upon identification of an identical WDR62 variant in the homozygous state in two cases was suggestive of a small shared haplotype of 0.1 Mb. Additionally, we have shown a paternal origin for the de novo variant in TRIO via a polymorphic tag SNP, which enlightens the mutational mechanism for this variant.
In populations with high parental consanguinity, an autosomal recessive inheritance pattern for data analysis is usually the most obvious choice. Therefore, heterozygous variants may be overlooked in standard NGS analyses in consanguineous families. Our findings underlie the importance of using multiple inheritance models in NGS data analysis.
摘要：
背景：伴有原发性小头畸形的综合征性智力障碍（ID）是一组罕见的神经发育障碍，表现出极端的遗传和临床异质性。这种分层的异质性可以通过使用下一代测序（NGS）技术靶向基因组的无偏遗传方法来部分解决。包括外显子组测序(ES)。
目的：本研究旨在剖析5例不同IDM病例的临床和遗传特征。
方法：进行单例或三重奏ES方法，然后使用替代继承模型进行深入的变异分析。
结果：我们已经在三个家族中确定了WDR62和AP4M1基因的双等位基因功能缺失变体，以及两个家族中SOX11和TRIO基因中的从头错义变体。在两种情况下基于ES的单倍型分析中,在两种情况下在纯合状态下鉴定相同的WDR62变体后,暗示0.1Mb的小的共享单倍型。此外,我们已经通过多态标签SNP显示了TRIO中从头变体的父系起源，这启发了这种变体的突变机制。
结论：在父母血缘关系较高的人群中，用于数据分析的常染色体隐性遗传模式通常是最明显的选择。因此,在近亲家族的标准NGS分析中可能忽略了杂合变体。我们的发现强调了在NGS数据分析中使用多个继承模型的重要性。
目的：本研究旨在剖析5例不同IDM病例的临床和遗传特征。
方法：进行单例或三重奏ES方法，然后使用替代继承模型进行深入的变异分析。
结果：我们已经在三个家族中确定了WDR62和AP4M1基因的双等位基因功能缺失变体，以及两个家族中SOX11和TRIO基因中的从头错义变体。在两种情况下基于ES的单倍型分析中,在两种情况下在纯合状态下鉴定相同的WDR62变体后,暗示0.1Mb的小的共享单倍型。此外,我们已经通过多态标签SNP显示了TRIO中从头变体的父系起源，这启发了这种变体的突变机制。
结论：在父母血缘关系较高的人群中，用于数据分析的常染色体隐性遗传模式通常是最明显的选择。因此,在近亲家族的标准NGS分析中可能忽略了杂合变体。我们的发现强调了在NGS数据分析中使用多个继承模型的重要性。
