Aditi Gupta1, Nikita R Dsouza2, Yuri A Zarate3, Rachel Lombardo4, Robert Hopkin4, Allison R Linehan2, Jamela Simpson2, Julie McCarrier5, Katherine E Agre6, Ralitza H Gavrilova7, Michael C Stephens8, Rayna M Grothe8, Kristin G Monaghan9, Yili Xie9, Donald Basel5, Raul A Urrutia10, Conrad R Cole11, Eric W Klee12, Michael T Zimmermann13. 1. Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA; Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA. 2. Bioinformatics Research and Development Laboratory, Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA. 3. Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Arkansas Children's Hospital, Little Rock, AR, 72202, USA. 4. Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA. 5. Division of Genetics, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, 53226, USA. 6. Clinical Genomics, Mayo Clinic, Rochester, MN, 55905, USA. 7. Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA; Clinical Genomics, Mayo Clinic, Rochester, MN, 55905, USA. 8. Pediatric Gastroenterology, Mayo Clinic, Rochester, MN, 55905, USA. 9. GeneDx, Gaithersburg, MD, 20877, USA. 10. Bioinformatics Research and Development Laboratory, Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA; Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, 53226, USA. 11. Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA. 12. Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA; Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA; Clinical Genomics, Mayo Clinic, Rochester, MN, 55905, USA; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA. Electronic address: klee.eric@mayo.edu. 13. Bioinformatics Research and Development Laboratory, Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA; Clinical and Translational Sciences Institute, Medical College of Wisconsin, Milwaukee, WI, 53226, USA. Electronic address: mtzimmermann@mcw.edu.
Abstract
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).
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).
Authors: Ellen Deolet; Bert Callewaert; Jeroen Geldof; Stephanie Van Biervliet; Saskia Vande Velde; Jo Van Dorpe; Myriam Van Winckel; Anne Hoorens Journal: Virchows Arch Date: 2022-06-28 Impact factor: 4.064
Authors: Young-In Chi; Timothy J Stodola; Thiago M De Assuncao; Elise N Leverence; Swarnendu Tripathi; Nikita R Dsouza; Angela J Mathison; Donald G Basel; Brian F Volkman; Brian C Smith; Gwen Lomberk; Michael T Zimmermann; Raul Urrutia Journal: Orphanet J Rare Dis Date: 2021-02-05 Impact factor: 4.123
Authors: Margot A Cousin; Filippo Pinto E Vairo; Joel A Morales-Rosado; Erica L Macke; Eric W Klee; W Garrett Jenkinson; Alejandro Ferrer; Laura E Schultz-Rogers; Rory J Olson; Gavin R Oliver; Ashley N Sigafoos; Tanya L Schwab; Michael T Zimmermann; Raul A Urrutia; Charu Kaiwar; Aditi Gupta; Patrick R Blackburn; Nicole J Boczek; Carri A Prochnow; Rebecca J Lowy; Lindsay A Mulvihill; Tammy M McAllister; Stacy L Aoudia; Teresa M Kruisselbrink; Lauren B Gunderson; Jennifer L Kemppainen; Laura J Fisher; Jessica M Tarnowski; Megan M Hager; Sarah A Kroc; Nicole L Bertsch; Katherine E Agre; Jessica L Jackson; Sarah K Macklin-Mantia; Marine I Murphree; Laura M Rust; Jolene M Summer Bolster; Scott A Beck; Paldeep S Atwal; Marissa S Ellingson; Sarah S Barnett; Kristen J Rasmussen; Carrie A Lahner; Zhiyv Niu; Linda Hasadsri; Matthew J Ferber; Cherisse A Marcou; Karl J Clark; Pavel N Pichurin; David R Deyle; Eva Morava-Kozicz; Ralitza H Gavrilova; Radhika Dhamija; Klaas J Wierenga; Brendan C Lanpher; Dusica Babovic-Vuksanovic; Gianrico Farrugia; Lisa A Schimmenti; A Keith Stewart; Konstantinos N Lazaridis Journal: Genet Med Date: 2020-11-04 Impact factor: 8.822