PMC8155743_01
A) MRI brain, 9 days of life: small dysgenic cerebral cortex with relative sparing of
deep gray nuclei and thalami, T2 hyperintensity in the optic radiations. B) MRI brain, 9
years 8 months: profound white matter loss with resultant ventriculomegaly, T2
hyperintenisities in the posterior limb of the internal capsule and frontal white
matter.
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Representative MRI images at age 9 days (Figure 1A) and 9 years (Figure 1B) are included.
A) Structural model of DARS2 homodimer, with one monomer in gray and the other shown as
a surface plot in cyan. Amino acids in red are known pathogenic variants and the patient
variant in magenta. B) Zoom in view of A262 (magenta) and R263 at the dimer interface.
C) Deep evolutionary analysis of DARS2 in 259 species on a 21-codon window. D)
Conservation scores of amino acids around site 262. E) Alignment data for position 262.
F) Impact scores based on PolyPhen2, Provean, SIFT, Align-GVGD, conservation score, and
21 codon linear motif scores for ClinVar Pathogenic/likely pathogenic (red), patient
(magenta), and uncertain significance (VUS, black). G) Impact score of A262V (magenta)
relative to ClinVar Pathogenic/likely pathogenic (red), and VUS (black).
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DARS2 protein is a homodimer and the Ala262 amino acid is located at the protein dimer interface (magenta, Figure 2A-B). The Ala262 falls within a critical stretch of amino acids that are evolutionarily conserved (Figure 2C-E). DARS2 shows a high variant impact score (combination of conservation, PolyPhen2, Provean, SIFT, and Align-GVGD scores) comparable to other pathogenic variants (Figure 2F-G), including the pathogenic R263Q seen in a patient with LBSL (red, Figure 2A-E). Details of the bioinformatics methods have been previously published.