Analysis of MYCN, CHD7, EFTUD2, FOXF1, MID1, RFX6, SOX2, TTC7A, CCDC11 (CFAP53), FANCB and FANCC genes

Gastro-intestinal atresia is a malformation of the gastro-intestinal tract in which the bowel is effectively ‘blocked’ from birth, meaning that food cannot pass through the digestive tract.  Syndromic disorders of which gastro-intestinal atresias are a feature are described briefly below:

Feingold syndrome: Dominantly inherited multiple malformation syndrome caused by disease-causing variants in the MYCN gene and is characterised by oesophageal atresia, duodenal atresia, jejunal atresia or anal atresia, congenital heart defects (most commonly patent ductus arteriosus, PDA) and renal anomalies (small kidneys, cystic dysplastic kidneys). Microcephaly with mild learning difficulties is commonly observed. Dysmorphic features and minor digital malformations are also associated. 

CHARGE syndrome: CHARGE (Coloboma of the iris, Heart defect, choanal Atresia, Retarded growth, Genital hypoplasia and Ear anomalies).  Oesophageal atresia occurs in 10-20% of affected individuals. Heterozygous variants in the CHD7 gene cause CHARGE syndrome.

Mandibulofacial dysostosis with microcephaly (MFDM): One of the group of mandibulofacial dysostoses, of which MFDM is characterised by extreme microcephaly, with head circumference typically 3.5 to 5 standard deviations below the mean. Other features include malar and mandibular hypoplasia, and dysplastic ears with microtia. Cleft palate may be present. Oesophageal atresia is a frequent clinical feature of this condition. Disease-causing variants in the EFTUD2 gene cause MFDM.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV): Multiple malformation syndrome of which intestinal manifestations may include both malrotation and atresia.  Patients also have a defect in alveolar capillarization which is incompatible with life.  Approximately 80% of patients with this condition have associated malformations, involving organs of gastrointestinal, cardiovascular, and genitourinary systems.  Intestinal malrotation is the most frequently observed gastro-intestinal malformation; atresias of the oesophagus, small bowel and anus also occur. ACD/MPV is caused by disease-causing variants in the FOXF1 gene.

Opitz G/BBB (oculo-genital-laryngeal) syndrome: X-linked recessive congenital midline malformation syndrome characterized by hypertelorism, hypospadias, cleft lip/palate, laryngotracheoesophageal abnormalities, imperforate anus, developmental delay, and cardiac defects. Tracheo-esophageal fistula has also been reported. Disease-causing variants in the MID1 gene cause Opitz G/BBB.

Mitchell-Riley syndrome: Well-characterized syndrome of small intestinal atresias with neonatal diabetes and other malformations.  It is autosomal recessive and caused by biallelic variants in the RFX6 gene.  Multiple organs within the gastro-intestinal tract are affected, including the small intestine (intestinal malrotation, duodenal atresia, jejunal atresia), pancreas (annular pancreas, hypoplastic pancreas), and hepatobiliary system (gall bladder agenesis, extra- and intra-hepatic biliary atresia).

Anophthalmia-esophageal-genital (AEG) syndrome (Microphthalmia Syndromic 3): The association of oesophageal atresia with anophthalmia and genital abnormalities is rare though well-documented in the genetics literature, with fewer than 20 cases reported. AEG syndrome is caused by disease-causing variants in the SOX2 gene.

Multiple gastro-intestinal atresias: Multiple gastro-intestinal atresias (MGIA) is an autosomal recessive disorder resulting in small bowel atresias, distinct from Mitchell-Riley syndrome.  It has been reported in multiple pedigrees of French-Canadian ethnicity.  The intestinal atresias may be associated with cystic dilation and calcification of the gut.  It may be associated with severe combined immunodeficiency.   MGIA is caused by disease-causing variants in the TTC7A gene.   

Visceral Heterotaxy type 6: Heterotaxy (situs ambiguous), is a developmental condition characterized by randomization of the placement of visceral organs, including the heart, lungs, liver, spleen, and stomach. The organs are oriented randomly with respect to the left-right axis and with respect to one another. Disease-causing variants in the CCDC11 gene cause Visceral Heterotaxy type 6.

Fanconi anaemia:  Fanconi syndrome is an autosomal recessive disorder with high genetic heterogeneity. To date, 15 genes have been associated with the syndrome.  Principally it is associated with defective hemopoiesis and an increased susceptibility to acute myeloid leukaemia and solid tumours. However, there is also a striking incidence of congenital malformations including skeletal (radial ray aplasia typically), and, in the gastrointestinal tract, oesophageal, duodenal, and anal atresia. Many other malformations occur. Short stature, growth restriction, and café-au-lait patches are frequently present.  Variants in FANCB and FANCC have been associated with malformations in the VACTERL spectrum.