Establish the positive diagnostic rate (PDR) of genetic testing for patient with leukodystrophies and provide evidence that concurrent testing of parents (Trio) combined with a comprehensive gene list is an effective method.

Leukodystrophies are a clinically and genetically heterogeneous group of myelin disorders caused by abnormal development or destruction of the white matter in CNS.

A retrospective review of genetic testing of a large number of genes for patient with leukodystorphy. Outcomes of ES (~20,000 genes, n= 541 patients) and a panel (~300 genes, n=108 patients) are presented. A positive result was defined as the identification of one or two clinically relevant pathogenic or likely pathogenic variants (PV) in a single gene, depending on the mode of inheritance.

Similar results were observed between ES and a 300-gene panel. A PDR of 32.5% was observed using ES while the panel yielded a PDR of 32.4%. ES-Trio testing yielded a PDR of 34.1% which was significantly higher than proband-only testing (22.6%, p < 0.05). 51% of positive findings were in genes associated with autosomal recessive disorders. 41% of positive findings were in genes associated with autosomal dominant disorder, of which 81% were found to be de novo. Younger patients (<3 years old at testing) had a significantly higher PDR than adults (>17 years old at testing); 41.0% vs. 21.5% respectively (p<0.01). PVs were reported in 133 different genes by ES highlighting the vast genetic heterogeneity of leukodystrophies. Over 8% of these positive genes have only recently been described in association with disease. Additionally, 3.4% (6/176, average age 7.7 years) of positive findings were found in genes associated with disorders with an available treatment option. 

Genetic testing for patients with leukodystrophgy revealed a genetic etiology in one-third of patient when utilizing a trio-based, large gene panel or ES.