Table 1.

Molecular Genetic Testing Used in Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation

Gene 1MethodProportion of Pathogenic Variants 2 Detectable by This Method
DARS2 Sequence analysis 3~90% 4, 5
Gene-targeted deletion/duplication analysis 6Rare 7
UnknownNASee footnote 8.
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Affected individuals are almost invariably compound heterozygous for two pathogenic variants in DARS2. A few individuals with homozygous pathogenic variants have been identified.

5.

In a few individuals it has not been possible to determine both pathogenic variants: in four of 43 families the second pathogenic variant could not be found in gDNA; in two of three the second pathogenic variant was detected using cDNA; cells of the fourth individual were not available for isolation of mRNA for cDNA synthesis.

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

7.

Intragenic deletion of exon 12 has been reported [Lan et al 2017].

8.

In one person fulfilling the MRI criteria for LBSL, no pathogenic variants in DARS2 were detected in either gDNA or cDNA [Scheper et al 2007; Scheper & van der Knaap, personal communication].

From: Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation

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