TY - JOUR
T1 - Genetic variants in DGAT1 cause diverse clinical presentations of malnutrition through a specific molecular mechanism
AU - Gupta, Aditi
AU - Dsouza, Nikita R.
AU - Zarate, Yuri A.
AU - Lombardo, Rachel
AU - Hopkin, Robert
AU - Linehan, Allison R.
AU - Simpson, Jamela
AU - McCarrier, Julie
AU - Agre, Katherine E.
AU - Gavrilova, Ralitza H.
AU - Stephens, Michael C.
AU - Grothe, Rayna M.
AU - Monaghan, Kristin G.
AU - Xie, Yili
AU - Basel, Donald
AU - Urrutia, Raul A.
AU - Cole, Conrad R.
AU - Klee, Eric W.
AU - Zimmermann, Michael T.
N1 - Publisher Copyright:
© 2019 Elsevier Masson SAS
PY - 2020/4
Y1 - 2020/4
N2 - 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).
AB - 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).
KW - Congenital diarrheal disorder
KW - DGAT1
KW - Malnutrition
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U2 - 10.1016/j.ejmg.2019.103817
DO - 10.1016/j.ejmg.2019.103817
M3 - Article
C2 - 31778854
AN - SCOPUS:85076241133
SN - 1769-7212
VL - 63
JO - European Journal of Medical Genetics
JF - European Journal of Medical Genetics
IS - 4
M1 - 103817
ER -