Heterozygous Deletion ofFOXA2Segregates with Disease in a Family with Heterotaxy, Panhypopituitarism, and Biliary Atresia

Abstract

Biliary atresia (BA) is a pediatric cholangiopathy with unknown etiology occurring in isolated and syndromic forms. Laterality defects affecting the cardiovascular and gastrointestinal systems are the most common features present in syndromic BA. Most cases are sporadic, although reports of familial cases have led to the hypothesis of genetic susceptibility in some patients. We identified a child with BA, malrotation, and interrupted inferior vena cava whose father presented with situs inversus, polysplenia, panhypopituitarism, and mildly dysmorphic facial features. Chromosomal microarray analysis demonstrated a 277kb heterozygous deletion on chromosome 20 which included a single gene, FOXA2, in the proband and her father. This deletion was confirmed to be de novo in the father. The proband and her father share a common diagnosis of heterotaxy, but they also each presented with a variety of other issues. Further genetic screening revealed that the proband carried an additional protein-altering polymorphism (rs1904589; p.His165Arg) in the NODAL gene that is not present in the father, and this variant has been shown to decrease expression of the gene. As FOXA2 can be a regulator of NODAL expression, we propose that haploinsufficiency for FOXA2 combined with a decreased expression of NODAL is the likely cause for syndromic BA in this proband.

Identification of Polycystic Kidney Disease 1 Like 1 Gene Variants in Children With Biliary Atresia Splenic Malformation Syndrome

“…and Table ; Supporting Table ). Pathogenic variants in several previously proposed BASM candidate genes (i.e., CFC1 , FOXA2 , INVS , NODAL , and ZIC3 ) were not observed (Supporting Table ) . In primary cilia, PKD1L1 heterodimerizes with PKD2L1 to form a transmembrane ciliary calcium channel that ultimately influences downstream Hedgehog signaling .…”

“…In addition to PKD1L1 gene variants as a potential contributor to the BASM syndrome, it is possible that reduced or temporally modified PKD1L1 RNA expression could play a role. Tsai et al reported a heterozygous deletion of FOXA2 in a child with BA, intestinal malrotation, and an interrupted inferior vena cava whose father had situs inversus and polysplenia but not BA . The potential link between FOXA2 and PKD1L1 gene expression stems from activation of Pkd1l1 transcription by Foxa2 in mice .…”

Biliary Atresia: Clinical and Research Challenges for the Twenty‐First Century

“…Genetic approaches to understanding BA have included candidate gene analyses, copy number variation (CNV) association studies, genome‐wide association studies (GWAS), and exome sequencing. Some of the genes, such as forkhead box A2 ( FOXA2 ), have been linked to BA only in members of a single family . ADD3 was found in some single‐nucleotide polymorphism GWAS, and GPC1 was identified through CNV studies; disruption of either of these genes in zebrafish results in biliary defects .…”

“…Some of the genes, such as forkhead box A2 (FOXA2), have been linked to BA only in members of a single family. (22) ADD3 was found in some single-nucleotide polymorphism GWAS, and GPC1 was identified through CNV studies; disruption of either of these genes in zebrafish results in biliary defects. (23,24) Preliminary data presented at the symposium on ongoing genetic studies using whole-exome sequencing of BASM trios identified PKD1L1 variants, raising the potential that abnormal ciliary function contributes to disease susceptibility.…”

Update on investigations pertaining to the pathogenesis of biliary atresia

“…The FOXA2 deletion is believed to have contributed to the patient’s interrupted inferior vena cava and abdominal heterotaxy, while the NODAL polymorphism was theorized to contribute to the development of BA. On further evaluation of other patients with Syndromic BA, seven additional cases of FOXA2 sequence changes with a polymorphic NODAL gene were identified [23]. These studies suggest that in the rare cases of syndromic BA or BA with other anomalies, a genetic mutation may contribute to defects in bile duct development.…”