J Pediatr Genet 2024; 13(01): 029-034
DOI: 10.1055/s-0043-1767731
Original Article

FOXP1 Haploinsufficiency Contributes to the Development of Congenital Diaphragmatic Hernia

1   Genetics and Genomics Program, Baylor College of Medicine, Houston, Texas, United States
2   Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
,
2   Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
,
Jennifer M. Lyu
3   Department of Surgery, Boston Children's Hospital, Boston, Massachusetts, United States
4   Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, Massachusetts, United States
,
5   Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
,
Chad A. Shaw
2   Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
,
Julie Vogt
6   West Midlands Regional Genetics Service, Birmingham Women's and Children's Hospital, Birmingham, United Kingdom
,
Frances A. High
3   Department of Surgery, Boston Children's Hospital, Boston, Massachusetts, United States
4   Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, Massachusetts, United States
7   Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, United States
,
4   Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, Massachusetts, United States
8   Department of Surgery, Harvard Medical School, Boston, Massachusetts, United States
,
Wendy K. Chung
9   Departments of Pediatrics, Columbia University, New York, New York, United States
10   Department of Medicine, Columbia University, New York, New York, United States
,
2   Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
11   Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, United States
› Institutsangaben

Funding This work was supported by the National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development grants R01 HD098458 to D.A.S and P01 HD068250 to F.H, P.K.D, and W.K.C. The work of K.E.P. was funded by the National Institutes of Health Ruth L. Kirschstein National Research Service Award (NRSA) Predoctoral Institutional Research grant T32 GM139534. K.E.P received funding from The Cullen Foundation.
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Abstract

FOXP1 encodes a transcription factor involved in tissue regulation and cell-type-specific functions. Haploinsufficiency of FOXP1 is associated with a neurodevelopmental disorder: autosomal dominant mental retardation with language impairment with or without autistic features. More recently, heterozygous FOXP1 variants have also been shown to cause a variety of structural birth defects including central nervous system (CNS) anomalies, congenital heart defects, congenital anomalies of the kidney and urinary tract, cryptorchidism, and hypospadias. In this report, we present a previously unpublished case of an individual with congenital diaphragmatic hernia (CDH) who carries an approximately 3.8 Mb deletion. Based on this deletion, and deletions previously reported in two other individuals with CDH, we define a CDH critical region on chromosome 3p13 that includes FOXP1 and four other protein-coding genes. We also provide detailed clinical descriptions of two previously reported individuals with CDH who carry de novo, pathogenic variants in FOXP1 that are predicted to trigger nonsense-mediated mRNA decay. A subset of individuals with putatively deleterious FOXP4 variants has also been shown to develop CDH. Since FOXP proteins function as homo- or heterodimers and the homologs of FOXP1 and FOXP4 are expressed at the same time points in the embryonic mouse diaphragm, they may function together as a dimer, or in parallel as homodimers, to regulate gene expression during diaphragm development. Not all individuals with heterozygous, loss-of-function changes in FOXP1 develop CDH. Hence, we conclude that FOXP1 acts as a susceptibility factor that contributes to the development of CDH in conjunction with other genetic, epigenetic, environmental, and/or stochastic factors.

Note

This study uses the data generated by the DECIPHER community. A full list of centers that contributed to the generation of the data is available at https://deciphergenomics.org/about/stats and via email from contact@deciphergenomics.org. We note that those who performed the original analysis and collection of the DECIPHER data bear no responsibility for the further analysis or interpretation of the data.


Data Availability

The deletion seen in Subject 1 has been submitted to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/).




Publikationsverlauf

Eingereicht: 28. Oktober 2021

Angenommen: 11. April 2022

Artikel online veröffentlicht:
28. März 2023

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