Exploring the genetic basis of Leukodystrophies through an in-house targeted panel approach in resource-poor settings

Introduction: Leukodystrophies are a group of genetically determined neurodegenerative disorders that affect predominantly white matter. We aimed to study the clinical, radiologic and genetic features of childhood-onset Leukodystrophies by in-house genetic testing using a targeted genetic panel. Methods: All children with clinico-radiological suspicion of leukodystrophy were evaluated by an in-house Ion Torrent next-generation sequencing technology. A custom gene panel was designed based on clinical experience with the most common causes of leukodystrophy in the given setting. Genes included in the panel were GFAP, ASPA, EIF2B1-B5, GALC, L2HGDH, DARS2, EARS2, MLC1, HEPACAM , ARSA, PSAP, SUMF1, PLP1, GJC2, RNASET2, ALDH3A2, POLR3A, POLR3B and ABCD1. Results: N=28 children with suspected leukodystrophy have been tested on our in-house panel. Of these, 18 patients (64.28%) were genetically confirmed. The most common diagnoses were: Vanishing-white-matter disease-22.22% (n=4), POL-III related leukodystrophy-22.22% (n=4), Metachromatic leukodystrophy-16.66% (n=3), L-2-hydroxyglutaric aciduria-11.11% (n=2), XL-ALD-11.11% (n=2), Alexander disease-11.11% (n=2), Multiple sulfatase deficiency-11.11% (n=2), Krabbe disease-5.55% (n=1) and Pelizaeus-Merzbacher-like disease1-5.55% (n=1). Pathogenic variations were detected in ABCD1, EIF2B5, EIF2B3, EIF2B1, GFAP, L2HGDH, ARSA, GJC2, SUMF1, GALC, POLR3B and POLR3A genes respectively. The majority of the children were male 72.22% (n=13). The most common clinical features were seizures, abnormal body movement, lethargy, and developmental delay. MRI showed characteristic bilateral symmetrical white matter involvement in all children.

Conclusion: The advent of next-generation sequencing has helped in the early genetic confirmation and prenatal counseling for these disorders. The use of in-house targeted genetic panels helps in significant cost reduction and feasibility for patients in resource-poor settings.