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 In this report, we present a previously unpublished case of an individual with congenital diaphragmatic hernia (CDH) who carries an approximately 3.8 Mb deletion.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

Fig. 1

Photographs of Subject 2 at 2.5 years of age. Subject 2 has macrocephaly, a tall forehead with frontal bossing, a pointed chin, and low-set ears.

Fig. 2

FOXP1 is located in a CDH critical region on chromosome 3p13. The maximum region of overlap between the deletion identified in DECIPHER Patient 306207 and the deletion identified in Subject 1 (orange bars) defines a CDH critical region on chromosome 3p13 (chr3:70,664,791–72,700,418; hg19) (green bar). This region contains five protein protein-coding genes ( red and blue bars ). Of these genes, only FOXP1 is expressed in the developing diaphragm, exhibits high loss-of-function intolerance in gnomAD (pLI = 1; e/o ratio = 0.07), and has a high level of similarity to known CDH genes ( Table 1 ).