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Abstract：
Au-Kline syndrome is a severe multisystemic syndrome characterized by several congenital defects, including intellectual disability. Loss-of-function and missense variants in the HNRNPK gene are associated with a range of dysmorphic features. This report describes an eleven-year-old Chinese boy with intellectual disability and developmental delays. Family-based whole-exome and Sanger sequencing identified a de novo missense variant in HNRNPK (NM_002140.3: c.143T > A, p. Leu48Val). In silico analysis predicted that this variant would be damaged in a highly conserved residue in the K homology 1 (KH1) domain. Bioinformatic analysis showed that the affinity change (ΔΔG) caused by this variant was -0.033 kcal/mol, indicating that it would have reduced affinity for RNA binding. Transcript analysis of the peripheral blood from this case found 42 aberrantly expressed and 86 aberrantly spliced genes (p-value <0.01). Functional enrichment analysis confirmed that the biological functions of these genes, including protein binding and transcriptional regulation, are associated with HNRNPK. In summary, this study identifies the first Chinese patient with a novel de novo heterozygous HNRNPK gene variant that contributes to Au-Kline syndrome and expands current knowledge of the clinical spectrum of HNRNPK variants.
摘要：
Au-Kline综合征是一种严重的多系统综合征，以多种先天性缺陷为特征，包括智力残疾。HNRNPK基因中的功能缺失和错义变体与一系列异形特征相关。这份报告描述了一名11岁的中国男孩，患有智力障碍和发育迟缓。基于家族的全外显子组和Sanger测序确定了HNRNPK中的从头错义变体（NM_002140.3：c.143T>A，p.Leu48Val）。计算机模拟分析预测，该变体将在K同源性1（KH1）域中的高度保守残基中受损。生物信息学分析表明，该变体引起的亲和力变化（ΔΔG）为-0.033kcal/mol，表明它对RNA结合的亲和力降低。对该病例外周血的转录本分析发现42个异常表达和86个异常剪接的基因（p值<0.01）。功能富集分析证实了这些基因的生物学功能,包括蛋白质结合和转录调控，与HNRNPK有关。总之,这项研究确定了首例中国患者，该患者具有新的从头杂合HNRNPK基因变异，该变异可导致Au-Kline综合征，并扩展了HNRNPK变异临床谱的最新知识。
