Biallelic variants in ZNF526 cause a severe neurodevelopmental disorder with microcephaly, bilateral cataract, epilepsy and simplified gyration
Biallelic variants in ZNF526 cause a severe neurodevelopmental disorder with microcephaly, bilateral cataract, epilepsy and simplified gyration
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DOI：
10.1136/jmedgenet-2020-107430
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发表时间：
2021-01-04
影响因子：
4
通讯作者：
Novelli, Antonio
中科院分区：
文献类型：
--
作者：
Dentici, Maria Lisa;Alesi, Viola;Novelli, Antonio
背景下一代测序与国际病例汇总相结合，令人印象深刻地促进了孟德尔神经发育障碍基因的发现，特别是在受临床未诊断疾病影响的个体中。迄今为止，编码 Kruppel 型锌指蛋白的 ZNF526 基因中的双等位基因错义变异已在三个非综合征性智力障碍家族中报道。方法在这里，我们描述了来自四个不相关家庭的五名患有未确诊神经发育障碍的个体，我们对基于三人组（4 名受试者）或单一先证者（1 名受试者）的组合进行了外显子组测序。结果我们通过全外显子组测序鉴定出来自四个不相关家庭的五名患者具有纯合 ZNF526 变异。其中四个具有导致 ZNF526 截断的变异；他们患有严重的产前和产后小头畸形（范围从 -4 SD 到 -8 SD）、严重的精神运动迟缓、高渗性肌张力障碍运动、癫痫和 MRI 上的简化回旋模式。他们都患有双侧进行性白内障。第五名患者患有纯合错义变异和稍微不太严重的疾病，患有出生后小头畸形（-2 SD）、进行性双侧白内障、严重智力障碍和不明显的脑部 MRI。突变的 znf526 斑马鱼幼虫的眼睛和中枢神经系统有明显的畸形，类似于人类前脑无裂畸形谱中的发现。结论 我们的研究结果支持 ZNF526 双等位基因变异在复杂的神经发育障碍中的作用，主要影响大脑和眼睛，导致严重的小头畸形、简化脑旋模式、癫痫性脑病和双侧白内障。
Background Next-generation sequencing, combined with international pooling of cases, has impressively enhanced the discovery of genes responsible for Mendelian neurodevelopmental disorders, particularly in individuals affected by clinically undiagnosed diseases. To date, biallelic missense variants in ZNF526 gene, encoding a Kruppel-type zinc-finger protein, have been reported in three families with non-syndromic intellectual disability. Methods Here, we describe five individuals from four unrelated families with an undiagnosed neurodevelopmental disorder in which we performed exome sequencing, on a combination of trio-based (4 subjects) or single probands (1 subject). Results We identified five patients from four unrelated families with homozygous ZNF526 variants by whole exome sequencing. Four had variants resulting in truncation of ZNF526; they were affected by severe prenatal and postnatal microcephaly (ranging from -4 SD to -8 SD), profound psychomotor delay, hypertonic-dystonic movements, epilepsy and simplified gyral pattern on MRI. All of them also displayed bilateral progressive cataracts. A fifth patient had a homozygous missense variant and a slightly less severe disorder, with postnatal microcephaly (-2 SD), progressive bilateral cataracts, severe intellectual disability and unremarkable brain MRI. Mutant znf526 zebrafish larvae had notable malformations of the eye and central nervous system, resembling findings seen in the human holoprosencephaly spectrum. Conclusion Our findings support the role of ZNF526 biallelic variants in a complex neurodevelopmental disorder, primarily affecting brain and eyes, resulting in severe microcephaly, simplified gyral pattern, epileptic encephalopathy and bilateral cataracts.