FOXP1 Haploinsufficiency Contributes to the Development of Congenital Diaphragmatic Hernia

Authors

Katherine E Pendleton
Andres Hernandez-Garcia
Jennifer M Lyu
Ian M Campbell
Chad A Shaw
Julie Vogt
Frances A High
Patricia K Donahoe
Wendy K Chung
Daryl A Scott

Publication Date

3-1-2024

Journal

Journal of Pediatric Genetics

DOI

10.1055/s-0043-1767731

PMID

38567173

PMCID

PMC10984716

PubMedCentral® Posted Date

3-28-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

CDH, FOXP1, FOXP2, FOXP3, FOXP4

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 In this report, we present a previously unpublished case of an individual with congenital diaphragmatic hernia (CDH) who carries an approximately 3.8 Mb deletion.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