Highly Variable Expressivity of a CNV Deletion Involving TBX4 in Three Deceased Siblings With Lung Developmental Disorder and Their Mildly Affected Mother and Grandfather.

IF 2.3 3区 医学 Q2 GENETICS & HEREDITY
Przemyslaw Szafranski, Tomasz Gambin, Michal Kadlof, Michał Denkiewicz, Dariusz Plewczynski, Hyun Jeong Kim, Gail Deutsch, Nahir Cortes-Santiago, Salmo Raskin, Paweł Stankiewicz
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引用次数: 0

Abstract

Single nucleotide variants (SNVs) and copy-number variant (CNV) deletions involving TBX4 have been associated with pulmonary arterial hypertension, ischiocoxopodopatellar syndrome, and lethal lung developmental disorders (LLDDs). Thus far, all large CNV deletions encompassing entire TBX4 have been found to have arisen de novo. Here, we present a three-generation family with three neonate siblings who died within 35-66 days due to histopathologically diagnosed LLDD. Whole-genome sequencing identified an ~108-kb CNV deletion encompassing TBX4 in all three infants. The deletion was also found in their mother with a history of pneumonia and persistent thick upper airway secretions and in the maternal grandfather who had surgically corrected genu valgum. RT-qPCR from the proband's lung biopsy showed a decrease of TBX4 transcript level greater than 50%, suggesting additional deregulation of TBX4 expression. Computational analyses of the TBX4 super-enhancer identified 15 candidate noncoding hypomorphic SNVs transmitted to the children exclusively from their father and absent in their mother and maternal grandfather. We show that SNV rs35827636T > C, previously proposed as potentially hypomorphic in an unrelated AcDys patient, reduced transcriptional activity of the TBX4 promoter in an episomal reporter assay. Moreover, Hi-C analysis predicted inter-TAD interaction between the TBX4 super-enhancer and its promoter-proximal region. Our data further demonstrate complex compound inheritance of LLDDs and resulting challenges for genetic counseling.

涉及TBX4的CNV缺失在三个患有肺发育障碍的已故兄弟姐妹及其轻度影响的母亲和祖父中的高度可变表达性
涉及TBX4的单核苷酸变异(SNVs)和拷贝数变异(CNV)缺失与肺动脉高压、胫韧带综合征和致死性肺发育障碍(lldd)有关。到目前为止,所有包含整个TBX4的大CNV缺失都是从头开始的。在这里,我们报告了一个三代家庭,有三个新生儿兄弟姐妹在35-66天内因组织病理学诊断为LLDD而死亡。全基因组测序在这三个婴儿中发现了包含TBX4的约108 kb CNV缺失。在有肺炎病史和持续上呼吸道厚分泌物的母亲和手术矫正膝外翻的外祖父中也发现了这种缺失。先证者肺活检的RT-qPCR显示TBX4转录物水平下降超过50%,提示TBX4表达进一步失调。TBX4超级增强子的计算分析鉴定出15个候选的非编码半胚性snv,这些snv只遗传给他们的父亲,而不存在于他们的母亲和外祖父。我们发现,SNV rs35827636t> C,之前被认为在一个不相关的AcDys患者中具有潜在的半胚性,在一个单独的报告基因试验中降低了TBX4启动子的转录活性。此外,Hi-C分析预测了TBX4超增强子与其启动子-近端区域之间的tad相互作用。我们的数据进一步证明了lldd复杂的复合遗传和由此带来的遗传咨询挑战。
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来源期刊
Clinical Genetics
Clinical Genetics 医学-遗传学
CiteScore
6.50
自引率
0.00%
发文量
175
审稿时长
3-8 weeks
期刊介绍: Clinical Genetics links research to the clinic, translating advances in our understanding of the molecular basis of genetic disease for the practising clinical geneticist. The journal publishes high quality research papers, short reports, reviews and mini-reviews that connect medical genetics research with clinical practice. Topics of particular interest are: • Linking genetic variations to disease • Genome rearrangements and disease • Epigenetics and disease • The translation of genotype to phenotype • Genetics of complex disease • Management/intervention of genetic diseases • Novel therapies for genetic diseases • Developmental biology, as it relates to clinical genetics • Social science research on the psychological and behavioural aspects of living with or being at risk of genetic disease
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