Evidence map›Paper›PMID 42063190›Full record

ArticleHuman genomics2026

Inherited TBX4 frameshifting variants predicted to escape nonsense mediated decay in two families with variable phenotypes, including lethal lung developmental disorders.

Shruti A Pande, Hiuling Chan Joiner, Przemyslaw Szafranski, Tomasz Gambin, Michelle Wright, Qian Wang, Maiah Walters, Jan M Friedman, Jessica Saunders, Nicholas Avdimiretz and 4 more

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Article in Human genomics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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1 · What the graph read from it

What it found

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2 · The registry

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3 · Its place in the literature

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4 · The record

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5 · Who and what money

Authors and funding

14 authors.

Shruti A Pande *Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.
Hiuling Chan Joiner *Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.
Przemyslaw SzafranskiDepartment of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.
Tomasz GambinInstitute of Computer Science, Warsaw University of Technology, Warsaw, Poland.
Michelle WrightDepartment of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
Qian WangDepartment of Pathology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
Maiah WaltersMedical Genetics Graduate Program, University of British Columbia, Vancouver, BC, Canada.
Jan M FriedmanDepartment of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
Jessica SaundersDepartment of Pathology and Laboratory Medicine, British Columbia Children's Hospital and Women's Health Center, Vancouver, BC, Canada.
Nicholas AvdimiretzDivision of Pediatric Respiratory Medicine, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada.
Cornelius F BoerkoelDepartment of Medical Genetics and Provincial Medical Genetics Program, University of British Columbia and Women's Hospital of British Columbia, Vancouver, BC, Canada.
Nahir Cortes-SantiagoDepartment of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA.
Gail DeutschDepartment of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, USA.
Pawel StankiewiczDepartment of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA. pawels@bcm.edu.

Funding

NIH HHS 1R01HL165301- 01A1
6 · The paper itself

Abstract

backgroundPathogenic variants involving the transcription factor TBX4 gene have been associated with various skeletal and pulmonary abnormalities, including lethal lung developmental disorders (LLDD).

methodsWhole-genome sequencing (WGS) with AI-powered platform for variant detection and interpretation followed by Sanger sequencing targeted variant segregation analysis were used. Reverse transcription quantitative PCR (RT-qPCR) and immunohistochemistry (IHC) studies were performed to assess gene and protein expression levels, respectively.

resultsWe describe two unrelated families with intrafamilial variability in the TBX4 phenotypic expressivity, including LLDDs. WGS analyses revealed two frameshift variants, c.1019del; p.(Arg340GlnfsTer40) in the penultimate exon and c.1167dup; p.(Arg390GlnfsTer30) in the last exon of TBX4, both predicted to escape nonsense mediated mRNA decay (NMD) and associated with highly variable phenotypes. RT-qPCR and IHC studies implied incomplete NMD in one family.

conclusionsOur data expand the phenotypic and genotypic landscape of TBX4-associated pulmonary disease to include asthma. We propose incompleteness and variability of NMD escape contributing to the observed wide phenotypic spectrum and increased risk of LLDDs.

Indexed as

Frameshift MutationLung DiseasesNonsense Mediated mRNA DecayT-Box Domain ProteinsFemaleHumansMalePedigreePhenotypeWhole Genome SequencingT-Box Domain ProteinsTBX4 protein, humanCongenital alveolar dysplasiaGain-of-functionLoss-of-functionPremature stop codon-mediated decaySmall patella syndromeVariable expressivity

Identifiers

PMID42063190
PMCPMC13281638

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