Combination of exome sequencing and immune testing confirms Aicardi-Goutières syndrome type 5 in a challenging pediatric neurology case.
Combination of exome sequencing and immune testing confirms Aicardi-Goutières syndrome type 5 in a challenging pediatric neurology case.
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外显子组测序和免疫检测相结合，在一个具有挑战性的儿科神经病学病例中证实了 5 型 Aicardi-Goutières 综合征。
DOI：
10.1101/mcs.a002758
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发表时间：
2018
影响因子：
1.8
通讯作者：
Kishnani,Priya
中科院分区：
文献类型：
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作者：
Haskell,GloriaT;Mori,Mari;Powell,Cynthia;Amrhein,TimothyJ;Rice,GillianI;Bailey,Lauren;Strande,Natasha;Weck,KarenE;Evans,JamesP;Berg,JonathanS;Kishnani,Priya
外显子组测序越来越多地用于帮助诊断儿科神经病学病例时，临床表现是不具体的。然而，解释模棱两可的结果，包括变异的不确定意义仍然是一个挑战。在这些情况下，后续测试和临床相关性可以帮助澄清分子结果的临床相关性。在这份报告中，我们描述了一个4岁的女孩谁提出了全球发展迟缓和癫痫发作，与脑白质营养不良的MRI诊断奥德赛。进行临床评价、MRI和综合代谢检测，然后进行全外显子组测序（WES）、亲本检测、随访检测和回顾性详细临床评价。WES在SAMHD 1中鉴定出两种候选致病性变异体，SAMHD 1是一种与5型Aicardi-Goutières综合征（AGS）（OMIM 612952）隐性疾病相关的基因：一种先前报道的致病性变异体NM_015474 c.602T>A（p.I201N），母系遗传，以及一种意义不确定的罕见错义变异体c.1293A>T（p.L431F）。I型干扰素相关生物标志物的分析表明，患者具有AGS的干扰素特征。回顾性详细的临床评估显示，该女孩的表型与AGS 5一致，AGS 5是一种罕见的神经系统疾病。这些结果进一步确定了与特异性SAMHD 1变异体相关的表型谱，包括AGS携带者中的杂合变异体，并支持了自身炎症失调是疾病病理生理学的一部分的观点。更广泛地说，这项工作突出了问题和方法，涉及归因于临床相关性的解释变异检测WES。
Exome sequencing is increasingly being used to help diagnose pediatric neurology cases when clinical presentations are not specific. However, interpretation of equivocal results that include variants of uncertain significance remains a challenge. In those cases, follow-up testing and clinical correlation can help clarify the clinical relevance of the molecular findings. In this report, we describe the diagnostic odyssey of a 4-year-old girl who presented with global developmental delay and seizures, with leukodystrophy seen on MRI. Clinical evaluation, MRI, and comprehensive metabolic testing were performed, followed by whole-exome sequencing (WES), parental testing, follow-up testing, and retrospective detailed clinical evaluation. WES identified two candidate causative pathogenic variants inSAMHD1, a gene associated with the recessive condition Aicardi–Goutières syndrome (AGS) type 5 (OMIM 612952): a previously reported pathogenic variant NM_015474 c.602T>A (p.I201N), maternally inherited, and a rare missense variant of uncertain significance, c.1293A>T(p.L431F). Analysis of type I interferon-related biomarkers demonstrated that the patient has an interferon signature characteristic of AGS. Retrospective detailed clinical evaluation showed that the girl has a phenotype consistent with AGS5, a rare neurological condition. These results further define the phenotypic spectrum associated with specificSAMHD1variants, including heterozygous variants in AGS carriers, and support the idea that autoinflammatory dysregulation is part of the disease pathophysiology. More broadly, this work highlights the issues and methodology involved in ascribing clinical relevance to interpretation of variants detected by WES.