DEGS1-Related Hypomyelinating Leukodystrophy

Objectives: DEGS1-related leukodystrophy has been described in 33 individuals to date with varying degrees of neurologic symptoms and atrophy/hypomyelination on MRI brain. We describe a family of 4 individuals with DEGS1-related leukodystrophy with phenotypic heterogeneity both within the family and in previously reported individuals. Methods: Four related individuals were followed by the neurology, genetics, and neurometabolic teams with clinical examinations, MRI brain, and genetic/metabolic investigations. Trio exome sequencing (ES) was completed after initial investigations returned normal. Results: ES revealed homozygous pathogenic variants in DEGS1, c.110T>C (p.Met37Thr), for the proband with subsequent confirmatory testing of remaining affected family members. While the affected individuals share many similarities, there is notable variability in severity between them as well as with other 33 previously reported individuals, including 2 with the same pathogenic variant. This variability is highlighted in the presence of seizures, nystagmus, failure to thrive, microcephaly, MRI brain findings, and age at disease onset. Discussion: This report expands on the documented knowledge of DEGS1-related leukodystrophy and adds to the current understanding of the phenotypic range of affected individuals. Consideration of variability in the condition's natural history and outcome is key to appropriately counsel patients and families.