Biallelic <scp><i>FGF4</i></scp> Variants Linked to Thoracic Dystrophy and Respiratory Insufficiency
The thoracic dystrophies are inherited skeletal conditions where abnormal embryonic development of the thoracic skeleton results in a narrow chest, pulmonary hypoplasia, and respiratory insufficiency, which can be severe or lethal. The majority of thoracic dystrophies are due to biallelic alterations in genes needed for normal ciliary function. However, despite the identification of over 20 genes as causal for the thoracic dystrophy phenotype, around 20% of patients remain without a molecular diagnosis. We present two unrelated families with a clinical diagnosis of thoracic dystrophy with associated respiratory insufficiency without a molecular diagnosis on previous genetic testing. Both harbor rare biallelic and predicted deleterious missense substitutions in FGF4, a gene known to be essential for formation of the thoracic skeleton in mice. We demonstrate that the phenotype is restricted to short ribs, abnormally narrow chest, and respiratory insufficiency, without other diagnostic clinical or radiological signs. We suggest that biallelic alterations in FGF4 are a newly identified disease association of thoracic dystrophy.
Authors
- Jenny C. Taylor (ORCID: https://orcid.org/0000-0003-3602-5704)
- Donald R. Latner (ORCID: https://orcid.org/0009-0005-0324-6916)
- Gregory M. Cooper (ORCID: https://orcid.org/0000-0001-5509-9923)
- Laura Watts (ORCID: https://orcid.org/0000-0003-3391-4389)
- Stephen R.F. Twigg (ORCID: https://orcid.org/0000-0001-5024-049X)
- Alistair T. Pagnamenta (ORCID: https://orcid.org/0000-0001-7334-0602)
- Jessica Patrick‐Esteve (ORCID: https://orcid.org/0000-0003-2471-2945)
- Esther Kinning (ORCID: https://orcid.org/0009-0002-9505-5954)
- Marla Johnston
Institutions
- Nuffield Orthopaedic Centre (GB)
- University of Oxford (GB)
- Birmingham Women's Hospital (GB)
- MRC Weatherall Institute of Molecular Medicine (GB)
- Children's Hospital of New Orleans (US)
- HudsonAlpha Institute for Biotechnology (US)
- Oxford BioMedica (United Kingdom) (GB)
- Louisiana State University Health Sciences Center New Orleans (US)
Publication Details
- Journal
- Clinical Genetics
- Published
- 2025-04-22
- DOI
- https://doi.org/10.1111/cge.14758
- Primary Topic
- Congenital Diaphragmatic Hernia Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Wellcome Trust
- National Institute for Health and Care Research
- Medical Research Council
- NIHR Oxford Biomedical Research Centre
- National Human Genome Research Institute
- National Cancer Institute
- National Institute on Minority Health and Health Disparities