CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
Role of exome sequencing in managing neurometabolic disorders
The discovery of genes associated with rare mendelian diseases has been revolutionized by next-generation sequencing technologies. An estimated three percent of the population is affected by an unexplained intellectual developmental disorder. It has been suggested that whole-exome sequencing be used to find a causative diagnosis so that appropriate genetic counseling and medical support can be provided. In some cases, especially for the neurometabolic disorders, there may even be disease-modifying treatments. The authors performed whole-exome sequencing on 41 patients who had intellectual developmental disorders and an unexplained phenotype, which was defined as abnormalities in urine, blood, or cerebrospinal fluid metabolites, abnormal biochemistry studies, abnormal histology findings, such as storage vacuoles, or abnormal clinical history, physical exam, or imaging findings. They established a genetic diagnosis in 28 of 41 (68 percent) of the patients. The study also identified 58 diagnostic variants in 42 genes, including the discovery of two novel genes that are newly implicated in human disease and are defined as novel because they had damaging variants in at least two unrelated patients with phenotypic overlap. In addition, nine candidate genes, 22 genes with newly identified phenotypes, and nine genes with expected phenotypes were found. The study further described the two novel genes with illustrative cases. The first case was caused by a homozygous missense variant in CA5A, encoding mitochondrial carbonic anhydrase VI. Deficiency in this enzyme causes neonatal hyperammonemia, hyperlactemia, and hypoglycemia, and can be treated with carglumic acid. The second case was caused by compound heterozygous variants in NANS, encoding N-acetylneuraminic acid phosphate synthase. To confirm the diagnosis, the substrate of the enzyme N-acetylated mannosamine was detected in the patient’s urine, plasma, and cerebrospinal fluid. In addition to the discovery of the two novel genes, new clinical phenotypes were seen in some patients who had variants in genes previously reported to cause other conditions or syndromes. The study also found a few patients that had variants in multiple genes known to cause a few separate syndromes, resulting in an overlapping complex phenotype. Perhaps the most promising finding of the study was that the genetic diagnosis was able to affect clinical treatment of 18 of the 41 (44 percent) patients. The authors concluded that the application of germline whole-exome sequencing to patients with neurometabolic disorders may lead to increased understanding of the biochemical pathogenesis of these disorders and afford clinicians the opportunity to treat with nutritional manipulation or other targeted treatments.
Tarailo-Graovac M, Shyr C, Ross CJ, et al. Exome sequencing and the management of neurometabolic disorders. N Engl J Med. 2016; 374:2246–2255.
Correspondence: Dr. C. D. van Karnebeek at cvankarnebeek@cw.bc.ca