Exome Sequencing Provides New Approach to Diagnosis of Rare Genetic Disorders

A genetic testing approach called exome sequencing—which provides a clinically practical alternative to whole-genome sequencing—led to correct diagnosis and life-saving treatment in a child with a previously unknown genetic disease, reports an upcoming paper in Genetics in Medicine, the official peer-reviewed journal of The American College of Medical Genetics (ACMG). The journal is published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health.

"We are now entering an era in which comprehensive genomic analysis at the nucleotide level, such as whole-exome sequencing, has been added to the clinician's armamentarium," write Howard J. Jacob, Ph.D., and colleagues of the Medical College of Wisconsin, Milwaukee, in a commentary accompanying the new clinical report. "Our view from the bedside was that exome sequencing enabled us to offer a treatment based on a diagnosis rooted in natural disease history and laboratory science." Dr. Jacob is Director of the Human and Molecular Genetics Center at MCW.

Exome Sequencing Allows Diagnosis of Mysterious Genetic Disorder

Elizabeth A. Worthey, Ph.D., and Alan D. Mayer, Ph.D., led an interdisciplinary team investigating a serious and mysterious illness in a young boy. Beginning at age 15 months, the child developed an "unusually aggressive" form of inflammatory bowel disease that did not respond to the usual treatments.

Testing showed numerous abnormalities of the child's immune system, but none that pointed to any specific diagnosis. "Over a 3-year period, there were more than 100 surgical procedures, clinical consultations with physicians from around the world, innumerable informal discussions, weekly clinical care meetings, and informal e-mail consultations with world-leading experts," the authors write. "Despite these measures, we enjoyed little strategic success."

Finally, they tried a new approach: whole-exome sequencing. As an alternative to sequencing of all of an individual's genes (genome), exome sequencing focuses on the protein-coding region (exome). This limited range of target genes provides a feasible approach to identifying the gene responsible for an unknown disease.

Of more than 16,000 gene variants identified by exome sequencing, about 1,500 were previously unknown. Through a process of elimination, medical geneticists identified the most likely culprit: a mutation of the gene XIAP, which plays a critical role in the inflammatory process and programmed cell death (apoptosis).

Other XIAP mutations have been linked to a rare but potentially fatal blood disease called hemophagocytic lymphohistiocytosis (HLH)—which can be successfully treated by bone marrow transplantation. Because the doctors considered their patient to be at high risk of developing HLH, they performed a hematopoietic progenitor cell transplant using unrelated donor cord blood as the blood stem cell source. Within a few weeks, the donor cells engrafted, providing the patient with normally functioning XIAP genes.