Non-Penetrance for Ocular Phenotype in Two Individuals Carrying Heterozygous Loss-of-Function ZEB1 Alleles.
Non-Penetrance for Ocular Phenotype in Two Individuals Carrying Heterozygous Loss-of-Function ZEB1 Alleles.
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DOI：
10.3390/genes12050677
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发表时间：
2021-04-30
期刊：
影响因子：
3.5
通讯作者：
Liskova P
中科院分区：
文献类型：
--
作者：
Dudakova L;Stranecky V;Piherova L;Palecek T;Pontikos N;Kmoch S;Skalicka P;Vaneckova M;Davidson AE;Liskova P
ZEB1 功能丧失 (LoF) 等位基因已知会导致一种罕见的常染色体显性遗传疾病——后部多形性角膜营养不良 3 型 (PPCD3)。迄今为止，50 种致病性 LoF 变异已被确定为致病基因，家族研究表明 PPCD3 表型在大约 95% 的携带者中存在。在这项研究中，我们询问了内部外显子组 (n = 3616) 和基因组 (n = 88)，以了解 ZEB1 中是否存在假定的杂合 LoF 变异。接下来，我们对携带新型 LoF c.1279C>T 的父亲和他的儿子进行了详细的表型分析； p.(Glu427*) ZEB1 (NM_030751.6) 中的变体在 gnomAD v.2.1.1 数据集中不存在。两名受试者的眼部检查未显示 PPCD3 的任何异常特征。 GnomAD（n = 141,456 名受试者）也接受了 LoF ZEB1 变异的询问，特别是已确定了 8 个不同的杂合性变化，这些变化被认为会导致 ZEB1 单倍体不足，但未报告与 PPCD3 相关。 NM_030751.6 转录本的 pLI 分数 ≥ 0.99，表明对单倍体不足的极度不耐受。总之，ZEB1 LoF 变异在一般人群中的出现频率极低。由于 PPCD3 可能无症状，ZEB1 LoF 变体的真实外显率目前仍未知，但可能低于迄今为止采用的家族主导方法估计的值。
ZEB1 loss-of-function (LoF) alleles are known to cause a rare autosomal dominant disorder—posterior polymorphous corneal dystrophy type 3 (PPCD3). To date, 50 pathogenic LoF variants have been identified as disease-causing and familial studies have indicated that the PPCD3 phenotype is penetrant in approximately 95% of carriers. In this study, we interrogated in-house exomes (n = 3616) and genomes (n = 88) for the presence of putative heterozygous LoF variants in ZEB1. Next, we performed detailed phenotyping in a father and his son who carried a novel LoF c.1279C>T; p.(Glu427*) variant in ZEB1 (NM_030751.6) absent from the gnomAD v.2.1.1 dataset. Ocular examination of the two subjects did not show any abnormalities characteristic of PPCD3. GnomAD (n = 141,456 subjects) was also interrogated for LoF ZEB1 variants, notably 8 distinct heterozygous changes presumed to lead to ZEB1 haploinsufficiency, not reported to be associated with PPCD3, have been identified. The NM_030751.6 transcript has a pLI score ≥ 0.99, indicating extreme intolerance to haploinsufficiency. In conclusion, ZEB1 LoF variants are present in a general population at an extremely low frequency. As PPCD3 can be asymptomatic, the true penetrance of ZEB1 LoF variants remains currently unknown but is likely to be lower than estimated by the familial led approaches adopted to date.
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