A novel multisystem disease associated with recessive mutations in the tyrosyl‐tRNA synthetase (YARS) gene

Abstract

Aminoacyl-tRNA synthetases (ARSs) are a group of ubiquitously expressed enzymes that are best known for their function in the first step of protein translation but have been increasingly associated with secondary functions including transcription and translation control and extracellular signaling. Mutations in numerous ARSs have been linked to a growing number of both autosomal dominant and autosomal recessive human diseases. The tyrosyl-tRNA synthetase (YARS) links the amino acid tyrosine to its cognate tRNA. We report two siblings who presented with failure to thrive (FTT), hypertriglyceridemia, developmental delay, liver dysfunction, lung cysts, and abnormal subcortical white matter. Using exome sequencing the siblings were found to harbor bi-allelic pathogenic-appearing variants within the YARS gene (NM_003680.3):c.638C>T p.(Pro213Leu) and c.1573G>A p.(Gly525Arg). These YARS variants occur in the catalytic domain and the C-terminal domain, respectively. Mutations in YARS have been previously associated with an autosomal dominant form of Charcot-Marie-Tooth (CMT); our findings suggest the disease spectrum associated with YARS dysregulation is broader than peripheral neuropathy. © 2016 Wiley Periodicals, Inc.

Compound heterozygosity for loss-of-function FARSB variants in a patient with classic features of recessive aminoacyl-tRNA synthetase-related disease

“…In addition to the overlap with individual features of other ARS‐related recessive syndromes, the phenotype of our patient displayed remarkable overlap with features previously associated with homozygosity or compound heterozygosity for loss‐of‐function methionyl‐tRNA synthetase ( MARS ) variants including: intrauterine growth restriction; failure to thrive; developmental delay; inguinal hernia; hypotonia; recurrent infections; interstitial lung disease; and liver dysfunction (van Meel et al., ; Hadchouel et al., ; Sun et al., ). Similarly, our patient shared many clinical features previously associated with homozygosity or compound heterozygosity for loss‐of‐function tyrosyl‐tRNA synthetase ( YARS ) variants including: intrauterine growth restriction; failure to thrive; developmental delay; emesis; deep‐set eyes; prominent cheeks; high palate; joint hypermobility; hypotonia; abnormal white matter; and liver dysfunction (Nowaczyk et al., ; Tracewska‐Siemiątkowska et al., ). Importantly, the phenotypic overlap between our patient and other patients with recessive ARS‐related diseases strongly supports the pathogenicity of the FARSB variants reported here.…”

FARSA mutations mimic phenylalanyl‐tRNA synthetase deficiency caused by FARSB defects

“…Furthermore, heterogeneous enhancement of the MR signal and calcifications in the caudate nuclei suggested the presence of degenerative lesions. Periventricular cysts were not associated with the FARSB defects but were found in the YARS deficiency . However, the cysts in our patient could be CMV related …”

“…The phenotype of aaRS disorders is variable but often includes intrauterine growth retardation and postnatal growth restriction. Notably, MARS , YARS and FARSB biallelic pathogenic variants have been consistently associated with interstitial lung disease (ILD) …”

The role of tRNA synthetases in neurological and neuromuscular disorders

“…Solid line indicates dominant mode of inheritance, dashed line indicates recessive mode of inheritance. References: AARS , DARS , HARS , IARS MARS , RARS , S ARS , W ARS , ARS , QARS , GARS , KARS , AARS 2 , CARS 2 , DARS 2 , EARS 2 , FARS 2 , HARS 2 , IARS 2 , LARS 2 , MARS 2 , NARS 2 , PARS 2 , RARS 2 , S ARS 2 , TARS 2 , VARS 2 , WARS 2 , YARS 2 .…”