Genetic sequencing of children with malrotation and midgut volvulus: A cross-sectional study.

OBJECTIVES

Intestinal malrotation with midgut volvulus can cause a particularly severe form of pediatric intestinal failure and is often a cause of ultra-short bowel syndrome (SBS), with longer dependence on parenteral nutrition. While malrotation can be found in several genetic syndromes, most occurrences of this condition are not associated with any identifiable genetic conditions or syndromes. This study aimed at identifying specific genes associated with this phenotype in humans.

METHODS

Children with a history of SBS due to malrotation with midgut volvulus were identified. Children with SBS due to multiple diagnoses, with non-midgut volvulus, or with an identified genetic syndrome were excluded. Whole-genome sequencing (WGS) was performed on the proband and their biological parents.

RESULTS

Twenty-three families provided consent to be enrolled in the study, and WGS was obtained from 21 complete families (proband and two parents). Two patients had variants in the glutathione S-transferase theta 4 gene (GSTT4). Two patients had variants in the coiled-coil domain-containing 175 gene (CCDC175). Two patients had a de novo heterozygous variant in the WW domain-containing binding protein 4 gene (WBP4). Three patients had de novo heterozygous likely pathogenic variants in TFRC, which encodes the transferrin receptor.

CONCLUSIONS

We identified four genes of potential interest in the etiology of malrotation and midgut volvulus, suggesting that the condition may be genetically heterogeneous. While the genes of interest identified have not yet been shown to be involved in the pathophysiology of this condition, they provide important areas for further investigation.