Clinical OMICS

MAY-JUN 2019

Healthcare magazine for research scientists, labs, pathologists, hospitals, cancer centers, physicians and biopharma companies providing news articles, expert interviews and videos about molecular diagnostics in precision medicine

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24 Clinical OMICs May/June 2019 www.clinicalomics.com D iagnosing diseases of inborn errors of metabolism (IEM) has come a long way from the days of Sir Archibald Garrod who, in the late 1800s, relied on the darkening in the color of a person's urine to diagnose the genetic IEM dis- ease alkaptonuria. Today, researchers are combining genom- ics and metabolomics to identify genes that, when mutated, give rise to metabolic diseases in children. By integrating whole exome sequencing (WES) with broad analysis of the chemical makeup of the blood, a team from the University of Texas Southwestern Medical Center was able to home in on the genetic changes that caused the previously undiagnosed disease of an 8-year-old patient who presented with developmental delay, seizures, and lactic acidemia. Led by Ralph DeBerardinis, M.D., Ph.D., chief of the divi- sion of pediatric genetics and metabolism at the Children's Medical Center Research Institute (CRI) at UT Southwest- ern Medical Center, the team found that the disease was caused by a genetic mutation in LIPT1, the lipoyltransferase required for 2-ketoacid dehydrogenase (2KDH) function. The study that describes a new approach to understand the causes of rare genetic diseases is published in Cell Reports in a paper entitled "Functional Assessment of Lipoyltransferase-1 Deficiency in Cells, Mice, and Humans." "It's a needle in a haystack problem" DeBerardinis told Clinical OMICs. The levels of some metabolites in patients' blood are measured routinely. "The problem is that we only measure a few dozen of those compounds in the hospital. But, the chemical makeup of the blood is incredibly complex with thousands of metabolites. If you only test a subset, it's easy to miss what you may need to find. So, we want to build a broader test. To do this, we combined the genetic and chemical information." The group's ability to test the significance of the mutations in a wet lab is what makes their results so meaningful. DeBe- rardinis notes that sequencing routinely identifies genetic vari- ants. But, the critical component of this study is their ability to determine whether those variants cause the phenotype. To do this, the team first identified metabolic abnormalities. After searching for sequence differences in the pathways that made sense with the metabolomics, they created the mutation in patient-derived fibroblasts and mice to analyze the resulting metabolic abnormalities. Although the mice died mid-gesta- tion, the embryonic tissue could be used for metabolomic anal- Omics-based Method Identifies Causes of Rare Metabolic Diseases in Children By Julianna LeMieux, Ph.D. Finding the Needle in a Metabolic Haystack DISORDER INCIDENCE MANIFESTATION Phenylketonuria 1 in 15,000 Mental retardation, acquired microcephaly Galactosemia 1 in 40,000 Hepatocellular dysfunction, cataracts Gaucher's disease 1 in 60,000 1 in 900 in Askenazi Jews Coarse facial features, hepatosplenomegaly Fabry's disease 1 in 80,000 Acroparesthesias, angiokeratomas hypohidrosis, corneal opacities, renal insufficiency Zellweger syndrome 1 in 50,000 Hypotonia, seizures, liver dysfunction Examples of Inborn Errors of Metabolism

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