Clinical, radiological, and genomic characteristics of inherited white matter disorders in Iran: A registry-based cohort study

Background: This study reports a registry-database of inherited white matter disorders (IWMDs) for an inbreed population. Methods: Relevant data of patients with supposedly IWMDs were recorded on the Iranian Leukodystrophy Registry (ILR) from 2016 to 2019. Targeted metabolic, imaging, and genome-wide studies (GWS) were utilized to establish a diagnosis. Diagnosed patients were further categorized into two groups: cohort A, hypomyelination pattern, and cohort B, other patterns, based on their initial brain magnetic resonance imaging. Results: From 680 patients in ILR, 342 individuals consented to participate for further investigation. Of these 342, genotype-phenotype correlations were established in 228 patients and 17 patients were diagnosed merely based on targeted metabolic tests which resulted in a diagnostic rate of 71.6% (245/342). These 245 confirmed cases were further classified into cohorts’ A (24.5%) and B (75.5%). Among 228 patients with molecular diagnosis, 206 sequence variants in 108 genes were identified, out of which 78 were novel. Variants in ARSA, HEXA, ASPA, MLC1, GALC, GJC2, ABCD1, L2HGDH, and GCDH were responsible for 39% of IWMDs cases. In our GWS with 247 exome sequencing on probands, the diagnostic yield was 60.7%, but in 97 patients it was unyielding. Mitochondrial leukodystrophies, GM2-Gangliosidosis, Canavan disease, metachromatic leukodystrophy, and megalencephalic leukoencephalopathy with subcortical cyst were the five most common confirmed diagnoses. Conclusion: Our genetic study of IWMD patients corroborates extensive genetic heterogeneity in an inbreed population and necessitate utility of WES as a vital diagnostic tool for management of these patients in a clinical setting.
Keywords: Leukodystrophies; Magnetic resonance imaging; Whole-exome Sequencing