BACKGROUND Application of whole genome sequencing (WGS) enables identification of non-coding variants that play a phenotype-modifying role and are undetectable by exome sequencing. Recently, non-coding regulatory single nucleotide variants (SNVs) have been reported in patients with lethal lung developmental disorders (LLDDs) or congenital scoliosis with recurrent copy-number variant (CNV) deletions at 17q23.1q23.2 or 16p11.2, respectively. CASE PRESENTATION Here, we report a deceased newborn with pulmonary hypertension and pulmonary interstitial emphysema with features suggestive of pulmonary hypoplasia, resulting in respiratory failure and neonatal death soon after birth. Using the array comparative genomic hybridization and WGS, two heterozygous recurrent CNV deletions: ~ 2.2 Mb on 17q23.1q23.2, involving TBX4, and ~ 600 kb on 16p11.2, involving TBX6, that both arose de novo on maternal chromosomes were identified. In the predicted lung-specific enhancer upstream to TBX4, we have detected seven novel putative regulatory non-coding SNVs that were absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. CONCLUSIONS Our findings further support a recently reported model of complex compound inheritance of LLDD in which both non-coding and coding heterozygous TBX4 variants contribute to the lung phenotype. In addition, this is the first report of a patient with combined de novo heterozygous recurrent 17q23.1q23.2 and 16p11.2 CNV deletions.

中文翻译：

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从头开始的2.2 Mb复发17q23.1q23.2缺失揭示了与致死性肺发育不全和肺动脉高压相关的新型推定调节性非编码SNV：一个病例报告。

背景技术全基因组测序（WGS）的应用使得能够鉴定发挥表型修饰作用并且不能通过外显子组测序检测的非编码变体。最近，有致死性肺发育障碍（LLDDs）或先天性脊柱侧凸的患者分别报告了17q23.1q23.2或16p11.2的反复拷贝数变异（CNV）缺失的非编码调节性单核苷酸变异（SNV）。 。病例介绍在这里，我们报道了一位已死亡的新生儿，患有肺动脉高压和肺间质性肺气肿，其特征是提示肺发育不全，导致出生后不久呼吸衰竭和新生儿死亡。使用阵列比较基因组杂交和WGS，两个杂合的递归CNV缺失：在17q23.1q23.2上约为2.2 Mb，涉及TBX4，在16p11.2上约为600 kb，涉及TBX6，鉴定出两者均在母亲染色体上重新出现。在预测的TBX4上游的肺特异性增强子中，我们检测到7个新颖的假定非编码SNV，这些SNV在13个具有重叠缺失但没有任何结构性肺异常的对照个体中不存在。结论我们的发现进一步支持了最近报道的LLDD复杂化合物遗传的模型，其中非编码和编码杂合TBX4变体都参与了肺表型。此外，这是首次合并杂合性复发17q23.1q23.2和16p11.2 CNV缺失的患者的首次报道。我们已经检测到13个对照个体中缺失的7种新型推定性非编码SNV，这些个体具有重叠的缺失，但没有任何结构性肺部异常。结论我们的发现进一步支持了最近报道的LLDD复杂化合物遗传的模型，其中非编码和编码杂合TBX4变体都参与了肺表型。此外，这是首次合并杂合性复发17q23.1q23.2和16p11.2 CNV缺失的患者的首次报道。我们已经检测到13个对照个体中缺失的7种新型推定性非编码SNV，这些个体具有重叠的缺失，但没有任何结构性肺部异常。结论我们的发现进一步支持了最近报道的LLDD复杂化合物遗传的模型，其中非编码和编码杂合TBX4变体都参与了肺表型。此外，这是首次合并杂合性复发17q23.1q23.2和16p11.2 CNV缺失的患者的首次报道。