title: Heterozygous deletion of FOXA2 segregates 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 277 kb 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.
authors.affiliation: Genomics and Computational Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Ellen A
authors.initials: EA
authors.lastname: Tsai
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Grochowski
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Falsey
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Ramakrishnan
authors.initials: R
authors.lastname: Rajagopalan
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Danielle
authors.initials: D
authors.lastname: Wendel
authors.affiliation: Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.|Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.|Department of Molecular Medicine, University La Sapienza, Rome, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Devoto
authors.affiliation: Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Krantz
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Loomes
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.|Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Nancy B
authors.initials: NB
authors.lastname: Spinner
mesh_terms: D000328:Adult; D000483:Alleles; D001656:Biliary Atresia / Q000175:diagnosis / Q000235:genetics*; D056915:DNA Copy Number Variations; D019066:Facies; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics*; D059446:Heterotaxy Syndrome / Q000175:diagnosis / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007018:Hypopituitarism / Q000175:diagnosis / Q000235:genetics*; D007223:Infant; D008297:Male; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion
chemical_list: C496502:FOXA2 protein, human; D051542:Hepatocyte Nuclear Factor 3-beta
keywords: 20p11; copy number variation; liver disease; variable expressivity