Non-syndromic familial congenital anorectal malformations

Gene: FOXF1

Genomics England clinical team suggest inclusion of this gene as an infant might be investigated for anorectal malformation before recognising the cause of the respiratory problems.

Created: 9 Oct 2018, 10:03 a.m.

Comment on list classification: Rating as green. 3 cases/families with point mutations in FOXF1 in individuals showing a anorectal malformation phenotype in patients with Alveolar capillary dysplasia with misalignment of pulmonary veins (PMID: 23505205) and a further case described in PMID: 26294094 from a patient with VATER/VACTERL or VATER/VACTERL-like phenotype.

Created: 9 Oct 2018, 9:59 a.m.

FOXF1 is associated with Alveolar capillary dysplasia with misalignment of pulmonary veins in OMIM and Gene2Phenotype (confirmed). Although the main features of this disorder are pulmonary related, gastrointestinal phenotypes may also be seen.

Stankiewicz et al. (2009)(PMID: 19500772) identified four different heterozygous mutations (frameshift, nonsense, and no-stop) in the candidate FOXF1 gene in unrelated patients with sporadic Alveolar capillary dysplasia with misalignment of pulmonary veins and multiple congenital anomalies. They also identified microdeletions encompassing the FOX transcription factor gene cluster in chromosome 16q24.1q24.2 in some patients. They note an association of point mutations in FOXF1 with bowel malrotation, and that microdeletions of FOXF1 were associated with hypoplastic left heart syndrome and gastrointestinal atresias, probably due to haploinsufficiency for the neighboring FOXC2 and FOXL1 genes.

Sen et al. (2013)(PMID: 23505205) report a further set of 34 novel de novo and four familial mutations of which three are maternally inherited, in unrelated patients with ACD/MPV that imply a role for FOXF1 DNA-binding domain. Three maternally inherited cases are consistent with the finding that FOXF1 is paternally imprinted. Out of 42 patients with point mutations they report imperforate anus or anal atresia in 3 patients (7%), and other intestinal problems such as duedenal atresia, and intestinal malrotation in several more.

Slot et al (2018)(PMID: 30058937) provide a more recent review of the now over 200 reported cases. They state that mutations located in the FOXF1 transcription region are found on both paternal and maternal alleles, and that more studies are needed before imprinting can be confirmed.

Created: 8 Oct 2018, 2:41 p.m.

Comment on list classification: Rating Amber as is on expert list.

Created: 19 Sep 2018, 4:14 p.m.

Gene added from expert list from Dr Charles Shaw-Smith (Royal Devon and Exeter NHS Foundation Trust)

Created: 19 Sep 2018, 4:14 p.m.

Comment on phenotypes: Added phenotypes from publication PMID:26294094

Created: 14 Aug 2018, 3:44 p.m.

Gene added to panel as found to be candidate gene by Hilger et al 2015 (PMID: 26294094) who performed targeted sequencing of 123 patients with VATER/VACTERL or VATER/VACTERL-like phenotype. All patients had anorectal malformations. They found de novo mutation (p.Gly220Cys) in FOXF1 in one patient.

Created: 4 Aug 2018, 10:09 p.m.