Skip to main content
Premium Trial:

Request an Annual Quote

Exome Sequencing Prompts Treatment Changes for Neurometabolic Disorders in 44 Percent of Cases

NEW YORK (GenomeWeb) – A University of British Columbia-led team has found that exome sequencing resulted in treatment changes for 44 percent of patients with rare metabolism-related intellectual disability disorders and had a high diagnostic rate of almost 70 percent.

As they reported yesterday in the New England Journal of Medicine, the researchers did extensive phenotyping and exome sequencing on 41 individuals with intellectual delay and unusual metabolic features. In the process, they were able to diagnose 68 percent of the cases, uncovering 11 genes not linked to such conditions in the past and expanding the phenotypes attributed to mutations in another 22 genes.

"However, the most important outcome of our genomics study was the effect of diagnosis by means of whole-exome sequencing on the clinical treatment of 44 percent of the probands who were analyzed," the authors wrote.

"Our findings open the door to life-changing treatments for a small yet meaningful percentage of patients," senior author Clara van Karnebeek, a pediatrician and biochemical diseases researcher at BC Children's Hospital and the University of British Columbia' Centre for Molecular Medicine and Therapeutics, said in a statement.

Dozens of inborn errors of metabolism have already been implicated in intellectual developmental disorders, the team noted, suggesting still more treatable metabolic maladies might turn up by testing individuals with undiagnosed conditions characterized by both developmental and metabolic symptoms.

The researchers used the Agilent SureSelect capture kit or the Ion AmpliSeq exome kit to nab protein-coding sequences in the genome from 47 individuals with intellectual developmental delay who were suspected of having inborn errors of metabolism, and from their parents and siblings when possible. They then sequenced these exomes with either the Illumina HiSeq 2000 or the Thermo Fisher Scientific Ion Proton platform.

Five of the children were subsequently excluded from the study based on other diagnoses, and one withdrew. When the team analyzed detailed phenotyping information, metabolic profiles, and exome sequencing data from the remaining 41 affected individuals and their families, it uncovered suspicious genetic changes in 37 of the cases.

The alterations affected nine genes already implicated in similar neurodevelopmental symptoms. But the researchers also saw apparent phenotype expansions for 22 genes linked to other single gene conditions and identified 11 new candidate genes, including two with conclusive ties to disease: CA5A and NANS.

In five of the families, the team determined that the complicated symptoms present in affected individuals stemmed from a combination of two co-existing monogenic conditions. In one case, it uncovered clinically relevant incidental findings involving the cystic fibrosis gene CFTR.

All told, the exome sequences led to molecular diagnoses for 28 of the children, or 68 percent of cases considered, and prompted treatment changes for 44 percent of the affected individuals. In a patient with a newly described condition called carbonic anhydrase VA deficiency, for example, the researchers found that treatment with carglumic acid could combat a dangerous sleep-inducing metabolite imbalance caused by mutations affecting both copies of the mitochondrial carbonic anhydrase VA gene CA5A.

In a six-year-old boy with microcephaly, sleep problems, and seizures caused by compound heterozygous mutations affecting the mitochondrial glutamate oxaloacetate transaminase-coding gene GOT2, meanwhile, the team reportedly saw a decline in seizures and other symptoms and improved head growth after treatment with oral serine and pyridoxine vitamin B6 supplements. 

The study's authors noted that the "relatively high diagnostic yield that we report here may stem from the inclusion criterion of a metabolic abnormality, the prevalence of recessive conditions in metabolic disorders, or the close consultation with clinical specialists in our bioinformatics pipeline."