The phenotypic spectrum of germline YARS2 variants: from isolated sideroblastic anemia to mitochondrial myopathy, lactic acidosis and sideroblastic anemia 2

Haematologica
Lisa G RileyMark D Fleming

Abstract

YARS2 variants have previously been described in patients with myopathy, lactic acidosis and sideroblastic anemia 2 (MLASA2). YARS2 encodes the mitochondrial tyrosyl-tRNA synthetase, which is responsible for conjugating tyrosine to its cognate mt-tRNA for mitochondrial protein synthesis. Here we describe 14 individuals from 11 families presenting with sideroblastic anemia and YARS2 variants that we identified using a sideroblastic anemia gene panel or exome sequencing. The phenotype of these patients ranged from MLASA to isolated congenital sideroblastic anemia. As in previous cases, inter- and intra-familial phenotypic variability was observed, however, this report includes the first cases with isolated sideroblastic anemia and patients with biallelic YARS2 variants that have no clinically ascertainable phenotype. We identified ten novel YARS2 variants and three previously reported variants. In vitro amino-acylation assays of five novel missense variants showed that three had less effect on the catalytic activity of YARS2 than the most commonly reported variant, p.(Phe52Leu), associated with MLASA2, which may explain the milder phenotypes in patients with these variants. However, the other two missense variants had a more seve...Continue Reading

Citations

Nov 8, 2018·Blood·Sarah Ducamp, Mark D Fleming
Jun 12, 2019·IUBMB Life·Catherine Florentz, Richard Giegé
Mar 19, 2021·Genetic Testing and Molecular Biomarkers·Mehwish ZehraviTehseen Fatima
May 1, 2021·International Journal of Molecular Sciences·Sonia FigucciaPaola Goffrini
Aug 28, 2021·Journal of Clinical Medicine·Lidia Carreño-GagoElena Garcia-Arumí
Jan 6, 2022·Muscle & Nerve·Grayson BeecherTeerin Liewluck

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Methods Mentioned

BETA
exome sequencing
bone marrow aspiration
biopsy
transmission electron microscopy

Software Mentioned

Alamut Visual
SureCall
Sequencher
PolyPhen2
SIFT

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