Short-read whole genome sequencing identifies causative variants in most individuals with previously unexplained aniridia.
Short-read whole genome sequencing identifies causative variants in most individuals with previously unexplained aniridia.
复制标题
短读长全基因组测序可识别大多数患有先前无法解释的无虹膜的个体的致病变异。
DOI：
10.1136/jmg-2023-109181
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发表时间：
2023
影响因子：
4
通讯作者：
Hall HN
中科院分区：
文献类型：
--
作者：
Hall HN
背景经典型无虹膜症是一种高度显性遗传的常染色体显性遗传疾病，其特征为先天性虹膜缺失、中心凹发育不全、视盘异常和进行性角膜混浊。>90%的经典无虹膜病例是由杂合的、功能丧失的变异体影响thePAX 6 locus.MethodsShort-read全基因组测序对来自37个不同家族的51个（39个受影响的）个体进行了筛选，这些个体在thePAX 6编码区的突变为阴性。在22个家系中，有19个家系的致病基因组变化对PAX 6位点有可解释的有害影响。在这19个家族中，1个家族具有在先前筛选中遗漏的新的异源PAX 6移码变体，4个家族具有影响PAX 65 ′非编码外显子的必需剪接位点的单核苷酸变体（SNV）（1个新的），2个家族具有导致供体剪接位点获得的深内含子SNV（1个新的）。在19个中的12个中，致病变异是大规模的结构变异; 5个具有PAX 6的部分或整个基因缺失，3个具有包含关键PAX 6顺式调控元件的缺失，2个具有平衡倒位，在PAX 6基因座内具有破坏性断点，2个具有破坏PAX 6的复杂重排。22个家族中剩下的3个家族有FOXC 1（一种已知的非典型无虹膜的原因）的缺失。其中7个致病性变异发生于新生儿，1个与家族性无虹膜共分离。我们无法确定其余先证者的遗传状态。在PAX 6顺式调节elements.ConclusionWhole genome sequencing被证明是一种有效的诊断测试，在大多数人与以前无法解释的无虹膜。
BackgroundClassic aniridia is a highly penetrant autosomal dominant disorder characterised by congenital absence of the iris, foveal hypoplasia, optic disc anomalies and progressive opacification of the cornea. >90% of cases of classic aniridia are caused by heterozygous, loss-of-function variants affecting thePAX6locus.MethodsShort-read whole genome sequencing was performed on 51 (39 affected) individuals from 37 different families who had screened negative for mutations in thePAX6coding region.ResultsLikely causative mutations were identified in 22 out of 37 (59%) families. In 19 out of 22 families, the causative genomic changes have an interpretable deleterious impact on thePAX6locus. Of these 19 families, 1 has a novel heterozygousPAX6frameshift variant missed on previous screens, 4 have single nucleotide variants (SNVs) (one novel) affecting essential splice sites ofPAX65′ non-coding exons and 2 have deep intronic SNV (one novel) resulting in gain of a donor splice site. In 12 out of 19, the causative variants are large-scale structural variants; 5 have partial or whole gene deletions ofPAX6, 3 have deletions encompassing criticalPAX6 cis-regulatory elements, 2 have balanced inversions with disruptive breakpoints within thePAX6locus and 2 have complex rearrangements disruptingPAX6. The remaining 3 of 22 families have deletions encompassingFOXC1(a known cause of atypical aniridia). Seven of the causative variants occurredde novoand one cosegregated with familial aniridia. We were unable to establish inheritance status in the remaining probands. No plausibly causative SNVs were identified inPAX6 cis-regulatory elements.ConclusionWhole genome sequencing proves to be an effective diagnostic test in most individuals with previously unexplained aniridia.