NODAL variants are associated with a continuum of laterality defects from simple D-transposition of the great arteries to heterotaxy

IF 10.4 1区 生物学 Q1 GENETICS & HEREDITY
Zain Dardas, Jawid M. Fatih, Angad Jolly, Moez Dawood, Haowei Du, Christopher M. Grochowski, Edward G. Jones, Shalini N. Jhangiani, Xander H. T. Wehrens, Pengfei Liu, Weimin Bi, Eric Boerwinkle, Jennifer E. Posey, Donna M. Muzny, Richard A. Gibbs, James R. Lupski, Zeynep Coban-Akdemir, Shaine A. Morris
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引用次数: 0

Abstract

NODAL signaling plays a critical role in embryonic patterning and heart development in vertebrates. Genetic variants resulting in perturbations of the TGF-β/NODAL signaling pathway have reproducibly been shown to cause laterality defects in humans. To further explore this association and improve genetic diagnosis, the study aims to identify and characterize a broader range of NODAL variants in a large number of individuals with laterality defects. We re-analyzed a cohort of 321 proband-only exomes of individuals with clinically diagnosed laterality congenital heart disease (CHD) using family-based, rare variant genomic analyses. To this cohort we added 12 affected subjects with known NODAL variants and CHD from institutional research and clinical cohorts to investigate an allelic series. For those with candidate contributory variants, variant allele confirmation and segregation analysis were studied by Sanger sequencing in available family members. Array comparative genomic hybridization and droplet digital PCR were utilized for copy number variants (CNV) validation and characterization. We performed Human Phenotype Ontology (HPO)-based quantitative phenotypic analyses to dissect allele-specific phenotypic differences. Missense, nonsense, splice site, indels, and/or structural variants of NODAL were identified as potential causes of heterotaxy and other laterality defects in 33 CHD cases. We describe a recurrent complex indel variant for which the nucleic acid secondary structure predictions implicate secondary structure mutagenesis as a possible mechanism for formation. We identified two CNV deletion alleles spanning NODAL in two unrelated CHD cases. Furthermore, 17 CHD individuals were found (16/17 with known Hispanic ancestry) to have the c.778G > A:p.G260R NODAL missense variant which we propose reclassification from variant of uncertain significance (VUS) to likely pathogenic. Quantitative HPO-based analyses of the observed clinical phenotype for all cases with p.G260R variation, including heterozygous, homozygous, and compound heterozygous cases, reveal clustering of individuals with biallelic variation. This finding provides evidence for a genotypic-phenotypic correlation and an allele-specific gene dosage model. Our data further support a role for rare deleterious variants in NODAL as a cause for sporadic human laterality defects, expand the repertoire of observed anatomical complexity of potential cardiovascular anomalies, and implicate an allele specific gene dosage model.
NODAL 变体与侧位缺陷的连续性有关,从单纯的大动脉 D 型横位到异侧位
NODAL 信号在脊椎动物的胚胎形态和心脏发育中起着至关重要的作用。导致TGF-β/NODAL信号通路紊乱的基因变异已被证实可导致人类侧位缺陷。为了进一步探究这种关联并改进基因诊断,本研究旨在从大量侧位缺陷患者中鉴定更广泛的 NODAL 变异并确定其特征。我们利用基于家族的罕见变异基因组分析,重新分析了临床诊断为侧位先天性心脏病(CHD)患者的 321 个仅有概率的外显子组。在这一队列中,我们添加了12名来自机构研究和临床队列的已知NODAL变体和CHD的受影响受试者,以研究等位基因系列。对于具有候选致病变体的受试者,我们通过对现有家庭成员进行桑格测序来研究变体等位基因的确认和分离分析。阵列比较基因组杂交和液滴数字 PCR 被用于拷贝数变异(CNV)的验证和特征描述。我们进行了基于人类表型本体论(HPO)的定量表型分析,以剖析等位基因特异性表型差异。在33例CHD病例中,NODAL的错义、无义、剪接位点、嵌合和/或结构变异被鉴定为导致异位和其他侧位缺陷的潜在原因。我们描述了一种反复出现的复杂吲哚变异,其核酸二级结构预测表明二级结构突变是可能的形成机制。我们在两个不相关的 CHD 病例中发现了两个横跨 NODAL 的 CNV 缺失等位基因。此外,我们还发现 17 例 CHD 患者(其中 16/17 有已知的西班牙裔血统)具有 c.778G > A:p.G260R NODAL 错义变异,我们建议将该变异从意义不确定变异(VUS)重新归类为可能致病变异。对所有 p.G260R 变异病例(包括杂合、同源和复合杂合病例)的临床表型进行基于 HPO 的定量分析后发现,具有双倍拷贝变异的个体聚集在一起。这一发现为基因型-表型相关性和等位基因特异性基因剂量模型提供了证据。我们的数据进一步证明,NODAL 中的罕见致畸变异是导致人类散发性侧位缺陷的原因之一,扩大了所观察到的潜在心血管异常解剖学复杂性的范围,并暗示了等位基因特异性基因剂量模型。
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来源期刊
Genome Medicine
Genome Medicine GENETICS & HEREDITY-
CiteScore
20.80
自引率
0.80%
发文量
128
审稿时长
6-12 weeks
期刊介绍: Genome Medicine is an open access journal that publishes outstanding research applying genetics, genomics, and multi-omics to understand, diagnose, and treat disease. Bridging basic science and clinical research, it covers areas such as cancer genomics, immuno-oncology, immunogenomics, infectious disease, microbiome, neurogenomics, systems medicine, clinical genomics, gene therapies, precision medicine, and clinical trials. The journal publishes original research, methods, software, and reviews to serve authors and promote broad interest and importance in the field.
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