FOXP1 Haploinsufficiency Contributes to the Development of Congenital Diaphragmatic Hernia

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 In this report, we present a previously unpublished case of an individual with congenital diaphragmatic hernia (CDH) who carries an approximately 3.8 Mb deletion.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.

Keywords

CDH - FOXP1 - FOXP2 - FOXP3 - FOXP4

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 [e-mail]. 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/).

Publication History

Received: 28 October 2021

Accepted: 11 April 2022

Article published online:
28 March 2023

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