case_images: PMC4875968_01
case_images: A timeline indicating the 8-year diagnostic odyssey for patients C1 and C2.
case_images: BMRI2016-6421039.001.jpg
case_images: PMC4875968_01_BMRI2016-6421039.001.jpg
case_images: fig1
case_images: The length of the diagnostic odyssey in the older brother spanned eight years (Figure 1, Table 3).
case_images: PMC4875968_02
case_images: KARS has two isoforms, one retained in the cytoplasm and one transported to the mitochondria. A mitochondrial targeting sequence spans exons 2 and 3; the cytoplasmic isoform skips exon 2 and is not transported. Case 3 has two inherited mutations that disrupt the gene. An Ala29Pro missense mutation alters the end of the mitochondrial targeting sequence; we predict that it is not transported, but the cytoplasmic isoform is still functional. The other allele has an approximately 8 kb deletion spanning exons 2-4, resulting in a frameshift and early termination.
case_images: BMRI2016-6421039.002.jpg
case_images: PMC4875968_02_BMRI2016-6421039.002.jpg
case_images: fig2
case_images: Two variants, a paternally inherited NM_005548:c.85G>C, p.Ala29Pro variant, and a maternally inherited 7601-base pair deletion at chr16:75672800-75680400 on 16q23.1, in the Lysyl-tRNA Synthetase (KARS) gene were identified, consistent with autosomal recessive inheritance of KARS-mediated disease (Figure 2).
case_images: PMC4875968_03