Congenital Sucrase-isomaltase Deficiency: A Novel Compound Heterozygous Mutation Causing Aberrant Protein Localization

J Pediatr Gastroenterol Nutr 2017 May;64(5):770-776. doi: 10.1097/MPG.0000000000001424.

PMID: 27749612

Yael Haberman, Ayelet Di Segni, Nurit Loberman-Nachum

Highlights: The novel compound heterozygote V577G/C1531W SI mutations lead to lack of SI expression in the duodenal brush border, confirming the diagnosis of CSID.

Abstract:

Objectives: Congenital diarrheal diseases are a set of hereditary enteropathies that manifest in infancy and necessitate parenteral nutrition. Genetics may be the key to a precise diagnosis in the majority of cases. We present an infant girl who had persistent congenital diarrhea that went away once she was given fructose-based formula, although no mutations in the SLC5A1 gene were found. Other mutations that better indicated dietary modifications were discovered using whole exome sequencing (WES).

Methods: A WES was performed on the patient and her parents. The study concentrated on the recessive model, which included compound heterozygous mutations. The patient's newborn sister and grandparents were screened using Sanger sequencing to confirm the mutations found. Immunohistochemistry was used to examine expression and localization in the patient's duodenal samples.

Results: We discovered a new compound heterozygote mutation in the sucrase-isomaltase (SI) gene, as well as a known maternally inherited V577G mutation and a novel paternally inherited C1531W mutation, using WES. Importantly, the compound heterozygous mutations in the newborn progeny were comparable. According to computational predictions, both mutations severely destabilize the protein. SI expression and localization investigations revealed that in the patient's duodenal biopsies, the mutated SI protein was not expressed on the brush border membrane, confirming the diagnosis of congenital sucrase-isomaltase deficiency (CSID).

Conclusions: The novel compound heterozygote V577G/C1531W SI mutations lead to lack of SI expression in the duodenal brush border, confirming the diagnosis of CSID. These CSID cases broaden the disease's molecular scope, allowing for a more targeted dietary prescription for the patient and her newborn sibling.

Keywords: congenital sucrase-isomaltase deficiency, CSID, whole exome sequencing, novel mutation