A massively parallel sequencing solution for clinical diagnosis of genetically diverse metabolic disorders

see Clinical application of massively parallel sequencing in the molecular diagnosis of glycogen storage diseases of genetically heterogeneous origin

For metabolic disorders with similar symptoms and multiple potential genetic origins, definitive diagnosis has relied on sequencing individual candidate genes. Whole-exome sequencing pre­sents an attractive alternative, as demonstrated in a proof-of-concept report by a collaborative group at Baylor College of Medicine and National Taiwan University Hospital. The panel test included 16 genes known to cause either liver or muscle forms of glycogen storage disease (GSD). Obtaining definitive results for 17 patients with clinical, histochemical, and/or enzymatic evidence of a GSD but negative or inconclusive molecular findings, took about eight weeks, including confirmatory Sanger sequencing. The test correctly identified all types of genetic alterations, from single-nucleotide substitutions to large deletions involving more than one exon. By contrast, the current conventional approach is more expensive and much more time-consuming, leaving families in limbo and delaying potentially lifesaving treatment. The authors point out that the technique is well suited for clinical diagnostics and can be scaled up and automated with robotic liquid handling. The technique is likely to be employed in situations such as this example, in which genetically heterogeneous biochemical disorders can be sorted out, but its use in many other clinical contexts will certainly grow. —Karyn Hede, News Editor

Gaucher disease patients and GBA mutation carriers face little overall increased risk of Parkinson disease

see Age-specific Parkinson disease risk in GBA mutation carriers: information for genetic counseling

As the use of comprehensive genomic sequencing accelerates, it becomes imperative to clarify disease risk, particularly for carriers of common mutations with uncertain health consequences. An example is mutations in the β-glucocerebrosidase (GBA) gene, which cause Gaucher disease (GD), the most common inherited lysosomal storage disease. Carrier status is relatively common, ranging from about 1 in 100 among the general population to more than 8% among Ashkenazi Jews. Several studies have suggested that carrier status is associated with a greater risk of developing Parkinson disease (PD). However, Rana et al., in a survey of GD patients and their families attending a clinic at Mount Sinai Medical Center, New York City, found a very modest risk of PD. Among nearly 600 patients and families with GD, 11 parents, 5 siblings, and no children had been diagnosed with PD. The researchers estimated the overall PD risk of carriers of GBA mutations to be 2.2% by age 65, a figure similar to the risk in the general population, and 10.9% by age 85. This information may reassure individuals who learn that they are carriers, because it suggests that their risk of developing PD is not much higher than that in noncarriers. The study should be of immediate benefit to genetic counselors returning findings to families of Ashkenazi Jewish descent, who are more likely to be screened for GBA-mutation carrier status. —Karyn Hede, News Editor