A de novo 2.2 Mb recurrent 17q23.1q23.2 deletion unmasks novel putative regulatory non-coding SNVs associated with lethal lung hypoplasia and pulmonary hypertension: A case report

Justyna A. Karolak , Tomasz Gambin , Engela M. Honey , Tomas Slavik , Edwina Popek , P. Stankiewicz


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.

Author Justyna A. Karolak - [Baylor College of Medicine]
Justyna A. Karolak,,
, Tomasz Gambin (FEIT / IN)
Tomasz Gambin,,
- The Institute of Computer Science
, Engela M. Honey - [Universiteit van Pretoria]
Engela M. Honey,,
, Tomas Slavik - [Universiteit van Pretoria]
Tomas Slavik,,
, Edwina Popek - [Baylor College of Medicine]
Edwina Popek,,
, P. Stankiewicz - [Baylor College of Medicine]
P. Stankiewicz,,
Journal seriesBMC Medical Genomics, ISSN 1755-8794
Issue year2020
ASJC Classification2716 Genetics(clinical); 1311 Genetics
Languageen angielski
Score (nominal)100
Score sourcejournalList
ScoreMinisterial score = 100.0, 25-05-2020, ArticleFromJournal
Publication indicators Scopus Citations = 0; WoS Citations = 0; Scopus SNIP (Source Normalised Impact per Paper): 2018 = 0.922; WoS Impact Factor: 2018 = 2.568 (2) - 2018=3.062 (5)
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