Expanding the genetic heterogeneity of intellectual disability
Expanding the genetic heterogeneity of intellectual disability
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DOI：
10.1007/s00439-017-1843-2
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发表时间：
2017-11-01
期刊：
影响因子：
5.3
通讯作者：
Alkuraya, Fowzan S.
中科院分区：
文献类型：
--
作者：
Anazi, Shams;Maddirevula, Sateesh;Alkuraya, Fowzan S.
智力障碍（ID）是一种常见的疾病，其病因多种多样。近年来，由于基因组测序技术的实施，ID 的单基因形式的列表迅速增加。在这项研究中，我们描述了 68 个家族（105 名患者）的表型和遗传发现，所有这些家族都具有新的 ID 相关变异。除了已确定的 ID 基因（包括我们描述的不寻常突变机制的基因）外，其中一些变异代表了继先前报告（TRAK1、GTF3C3、SPTBN4 和 NKX6-2）之后首次确认的疾病基因联系，其中一些是基于单个家族。此外，我们描述了 14 个基因中的新变异，我们建议将其作为新候选基因（ANKHD1、ASTN2、ATP13A1、FMO4、MADD、MFSD11、NCKAP1、NFASC、PCDHGA10、PPP1R21、SLC12A2、SLK、STK32C 和 ZFAT）。我们强调 MADD 和 PCDHGA10 作为特别引人注目的候选者，我们在两个独立的 ID 家族中分别鉴定了双等位基因可能有害的变异。我们还强调 NCKAP1 作为常染色体显性轻度智力障碍大家族中另一个引人注目的候选者，该家族与杂合截短变体完全分离。 NCKAP1 的生物学功能以及我们在人脑中相关表达的演示进一步支持了 NCKAP1 的候选资格。我们的研究扩展了 ID 的基因座和等位基因异质性，并证明了位置作图揭示不寻常突变机制的能力。
Intellectual disability (ID) is a common morbid condition with a wide range of etiologies. The list of monogenic forms of ID has increased rapidly in recent years thanks to the implementation of genomic sequencing techniques. In this study, we describe the phenotypic and genetic findings of 68 families (105 patients) all with novel IDrelated variants. In addition to established ID genes, including ones for which we describe unusual mutational mechanism, some of these variants represent the first confirmatory disease-gene links following previous reports (TRAK1, GTF3C3, SPTBN4 and NKX6-2), some of which were based on single families. Furthermore, we describe novel variants in 14 genes that we propose as novel candidates (ANKHD1, ASTN2, ATP13A1, FMO4, MADD, MFSD11, NCKAP1, NFASC, PCDHGA10, PPP1R21, SLC12A2, SLK, STK32C and ZFAT). We highlight MADD and PCDHGA10 as particularly compelling candidates in which we identified biallelic likely deleterious variants in two independent ID families each. We also highlight NCKAP1 as another compelling candidate in a large family with autosomal dominant mild intellectual disability that fully segregates with a heterozygous truncating variant. The candidacy of NCKAP1 is further supported by its biological function, and our demonstration of relevant expression in human brain. Our study expands the locus and allelic heterogeneity of ID and demonstrates the power of positional mapping to reveal unusual mutational mechanisms.