Genetic variants in DGAT1 cause diverse clinical presentations of malnutrition through a specific molecular mechanism. Eur J Med Genet 2020 Apr;63(4):103817
Date
11/30/2019Pubmed ID
31778854DOI
10.1016/j.ejmg.2019.103817Scopus ID
2-s2.0-85076241133 (requires institutional sign-in at Scopus site) 8 CitationsAbstract
BACKGROUND: DGAT1, a gene encoding a protein involved in lipid metabolism, has been recently implicated in causing a rare nutritional and digestive disease presenting as Congenital Diarrheal Disorder (CDD). Genetic causes of malnutrition can be classified as metabolic disorders, caused by loss of a specific enzyme's function. However, disease driven by genetic variants in lipid metabolism genes is not well understood, and additional information is needed to better understand these effects.
METHODS: We gathered a multi-institutional cohort of undiagnosed patients with a constellation of phenotypes presenting as malnutrition and metal ion dysregulation. Clinical Whole Exome Sequencing (WES) was performed on four patients and their unaffected parents. We prioritized genetic variants based on multiple criteria including population allele frequency and presumed inheritance pattern, and identified a candidate gene. Computational modeling was used to investigate if the altered amino acids are likely to result in a dysfunctional enzyme.
RESULTS: We identified a multi-institutional cohort of patients presenting with malnutrition-like symptoms and likely pathogenic genomic variants within DGAT1. Multiple approaches were used to profile the effect these variants have on protein structure and function. Laboratory and nutritional intervention studies showed rapid and robust patient responses.
CONCLUSIONS: This report adds on to the database for existing mutations known within DGAT1, a gene recently implicated with CDD, and also expands its clinical spectrum. Identification of these DGAT1 mutations by WES has allowed for changes in the patients' nutritional rehabilitation, reversed growth failure and enabled them to be weaned off of total parenteral nutrition (TPN).
Author List
Gupta A, Dsouza NR, Zarate YA, Lombardo R, Hopkin R, Linehan AR, Simpson J, McCarrier J, Agre KE, Gavrilova RH, Stephens MC, Grothe RM, Monaghan KG, Xie Y, Basel D, Urrutia RA, Cole CR, Klee EW, Zimmermann MTAuthors
Donald Basel MD Chief, Professor in the Pediatrics department at Medical College of WisconsinRaul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin
Michael T. Zimmermann PhD Director, Assistant Professor in the Clinical and Translational Science Institute department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Diacylglycerol O-AcyltransferaseDiarrhea
Female
Humans
Infant
Infant, Newborn
Male
Malnutrition
Mutation
