Deletion Testing of the Gene Should Be Part of the Diagnostic Pipeline for Hypomyelinating Leukodystrophy (HLD18).

Hypomyelinating leukodystrophies are a heterogeneous group of disorders characterized by abnormal myelin formation in the central nervous system. Thanks to the increased use of NGS, a growing number of pathogenic single nucleotide variants in have recently been reported to be responsible for hypomyelinating leukodystrophy 18 (HLD18), a rare and severe autosomal recessive form. is a small gene (4 exons and 17 kb) encoding 4-dihydroceramide desaturase, which catalyzes the final step in ceramide biosynthesis. Here, we present two patients from unrelated families affected by severe and progressive white matter disease with developmental delay with or without regression and severe intellectual disability. Trio exome sequencing (ES) revealed in both probands two homozygous missense variants in the gene, p.Asp16His and p.Asn255Ser, both inherited from their heterozygous healthy mothers and with a noncarrier father. This curious finding of inconsistent segregation data raises the need for further testing. There is no MLPA test available for this gene, as no deletions have been reported. However, we tried a customized high-resolution 1 M CGH array, which was surprisingly positive in both cases: a 63-kb heterozygous deletion encompassing the entire gene in one proband and a 7-kb heterozygous deletion of Exons 2-3 in the second case. Previously reported cases of HLD18 have all been found to carry single nucleotide pathogenic variants in , and the two patients described here are the first to carry whole or partial microdeletions involving that unmask pathogenic missense variants on the other allele. These two cases report the first examples of microdeletions of that unmask recessive allele pathogenic variants, underscoring the importance of considering whole or partial gene deletions in the diagnostic pipeline.