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

Overview

Journal BMC Med Genomics

Publisher Biomed Central

Specialty Genetics

Date 2020 Mar 8

PMID 32143628

Citations 11

Authors

Justyna A Karolak

Tomasz Gambin

Engela M Honey

Tomas Slavik

Edwina Popek

Pawel Stankiewicz

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Pulmonary Hypertension: Molecular Mechanisms and Clinical Studies.

Adu-Amankwaah J, You Q, Liu X, Jiang J, Yang D, Liu K MedComm (2020). 2025; 6(3):e70134.

PMID: 40066229 PMC: 11892029. DOI: 10.1002/mco2.70134.

The Glu86 Residue in TBX4 Proves Critical for Human Lung Development.

Szafranski P, Gambin T, Deutsch G, Nassef S, Bailey M, Kearney D Am J Med Genet A. 2024; 197(3):e63936.

PMID: 39552269 PMC: 11821427. DOI: 10.1002/ajmg.a.63936.

A novel frameshift TBX4 variant in a family with ischio-coxo-podo-patellar syndrome and variable severity.

Moresco G, Rondinone O, Mauri A, Gorgoglione R, Graziani D, Dziuback M Genes Genomics. 2024; 47(3):341-349.

PMID: 39467966 PMC: 11906559. DOI: 10.1007/s13258-024-01589-5.

Neonatal persistent pulmonary hypertension related to a novel TBX4 mutation: case report and review of the literature.

Maddaloni C, Ronci S, De Rose D, Bersani I, Campi F, Di Nardo M Ital J Pediatr. 2024; 50(1):41.

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Diminished 100 Expression in a Newborn With Acinar Dysplasia and a Novel Variant: A Case Report.

Szafranski P, Patrizi S, Gambin T, Afzal B, Schlotterbeck E, Karolak J Pediatr Dev Pathol. 2023; 27(3):255-259.

PMID: 38044468 PMC: 11087193. DOI: 10.1177/10935266231213464.

References

McDonald-McGinn D, Sullivan K, Marino B, Philip N, Swillen A, Vorstman J . 22q11.2 deletion syndrome. Nat Rev Dis Primers. 2016; 1:15071. PMC: 4900471. DOI: 10.1038/nrdp.2015.71. View

Li Q, Newbury-Ecob R, Terrett J, Wilson D, Curtis A, Yi C . Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Nat Genet. 1997; 15(1):21-9. DOI: 10.1038/ng0197-21. View

Ben-Shachar S, Ou Z, Shaw C, Belmont J, Patel M, Hummel M . 22q11.2 distal deletion: a recurrent genomic disorder distinct from DiGeorge syndrome and velocardiofacial syndrome. Am J Hum Genet. 2008; 82(1):214-21. PMC: 2253964. DOI: 10.1016/j.ajhg.2007.09.014. View

Maurac A, Lardenois E, Eyries M, Ghigna M, Petit I, Montani D . mutation causing pulmonary arterial hypertension and lung disease. Eur Respir J. 2019; 54(2). DOI: 10.1183/13993003.00388-2019. View

Posey J, Harel T, Liu P, Rosenfeld J, James R, Coban Akdemir Z . Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation. N Engl J Med. 2016; 376(1):21-31. PMC: 5335876. DOI: 10.1056/NEJMoa1516767. View

Parmeggiani G, Bigoni S, Buldrini B, Garani G, Clauser L, Galie M . Double Interstitial Deletion of the Long Arm of Chromosome 6 in a Patient with Pierre Robin Sequence, Dysmorphisms, and Severe Developmental Delay. Mol Syndromol. 2018; 9(1):30-37. PMC: 5803729. DOI: 10.1159/000480159. View

Swischuk L, Richardson C, Nichols M, Ingman M . Primary pulmonary hypoplasia in the neonate. J Pediatr. 1979; 95(4):573-7. DOI: 10.1016/s0022-3476(79)80773-8. View

Kurotaki N, Stankiewicz P, Wakui K, Niikawa N, Lupski J . Sotos syndrome common deletion is mediated by directly oriented subunits within inverted Sos-REP low-copy repeats. Hum Mol Genet. 2005; 14(4):535-42. DOI: 10.1093/hmg/ddi050. View

Vincent M, Karolak J, Deutsch G, Gambin T, Popek E, Isidor B . Clinical, Histopathological, and Molecular Diagnostics in Lethal Lung Developmental Disorders. Am J Respir Crit Care Med. 2019; 200(9):1093-1101. PMC: 6888654. DOI: 10.1164/rccm.201903-0495TR. View

10.

Nimmakayalu M, Major H, Sheffield V, Solomon D, Smith R, Patil S . Microdeletion of 17q22q23.2 encompassing TBX2 and TBX4 in a patient with congenital microcephaly, thyroid duct cyst, sensorineural hearing loss, and pulmonary hypertension. Am J Med Genet A. 2011; 155A(2):418-23. DOI: 10.1002/ajmg.a.33827. View

11.

Kariminejad A, Szenker-Ravi E, Lekszas C, Tajsharghi H, Moslemi A, Naert T . Homozygous Null TBX4 Mutations Lead to Posterior Amelia with Pelvic and Pulmonary Hypoplasia. Am J Hum Genet. 2019; 105(6):1294-1301. PMC: 6904794. DOI: 10.1016/j.ajhg.2019.10.013. View

12.

Egolf L, Vaksman Z, Lopez G, Rokita J, Modi A, Basta P . Germline 16p11.2 Microdeletion Predisposes to Neuroblastoma. Am J Hum Genet. 2019; 105(3):658-668. PMC: 6731370. DOI: 10.1016/j.ajhg.2019.07.020. View

13.

Hernando C, Plaja A, Rigola M, Perez M, Vendrell T, Egocue J . Comparative genomic hybridisation shows a partial de novo deletion 16p11.2 in a neonate with multiple congenital malformations. J Med Genet. 2002; 39(5):E24. PMC: 1735111. DOI: 10.1136/jmg.39.5.e24. View

14.

Potocki L, Shaw C, Stankiewicz P, Lupski J . Variability in clinical phenotype despite common chromosomal deletion in Smith-Magenis syndrome [del(17)(p11.2p11.2)]. Genet Med. 2003; 5(6):430-4. DOI: 10.1097/01.gim.0000095625.14160.ab. View

15.

Al-Kateb H, Khanna G, Filges I, Hauser N, Grange D, Shen J . Scoliosis and vertebral anomalies: additional abnormal phenotypes associated with chromosome 16p11.2 rearrangement. Am J Med Genet A. 2014; 164A(5):1118-26. DOI: 10.1002/ajmg.a.36401. View

16.

Willatt L, Cox J, Barber J, Dachs Cabanas E, Collins A, Donnai D . 3q29 microdeletion syndrome: clinical and molecular characterization of a new syndrome. Am J Hum Genet. 2005; 77(1):154-60. PMC: 1226188. DOI: 10.1086/431653. View

17.

Ranganath P, Perala S, Nair L, Pamu P, Shankar A, Murugan S . A newly recognized multiple malformation syndrome with caudal regression associated with a biallelic c.402G>A variant in TBX4. Eur J Hum Genet. 2020; 28(5):669-673. PMC: 7170885. DOI: 10.1038/s41431-020-0572-5. View

18.

Rosenfeld J, Coppinger J, Bejjani B, Girirajan S, Eichler E, Shaffer L . Speech delays and behavioral problems are the predominant features in individuals with developmental delays and 16p11.2 microdeletions and microduplications. J Neurodev Disord. 2011; 2(1):26-38. PMC: 3125720. DOI: 10.1007/s11689-009-9037-4. View

19.

Vlaskamp D, Callenbach P, Rump P, Giannini L, Brilstra E, Dijkhuizen T . PRRT2-related phenotypes in patients with a 16p11.2 deletion. Eur J Med Genet. 2018; 62(4):265-269. DOI: 10.1016/j.ejmg.2018.08.002. View

20.

Liu N, Schoch K, Luo X, Pena L, Bhavana V, Kukolich M . Functional variants in TBX2 are associated with a syndromic cardiovascular and skeletal developmental disorder. Hum Mol Genet. 2018; 27(14):2454-2465. PMC: 6030957. DOI: 10.1093/hmg/ddy146. View