The recurrent missense mutation p.(Arg367Trp) in YARS1 causes a distinct neurodevelopmental phenotype

Abstract

Pathogenic variants in aminoacyl-tRNA synthetases (ARS1) cause a diverse spectrum of autosomal recessive disorders. Tyrosyl tRNA synthetase (TyrRS) is encoded by YARS1 (cytosolic, OMIM*603,623) and is responsible of coupling tyrosine to its specific tRNA. Next to the enzymatic domain, TyrRS has two additional functional domains (N-Terminal TyrRSMini and C-terminal EMAP-II-like domain) which confer cytokine-like functions. Mutations in YARS1 have been associated with autosomal-dominant Charcot-Marie-Tooth (CMT) neuropathy type C and a heterogenous group of autosomal recessive, multisystem diseases. We identified 12 individuals from 6 families with the recurrent homozygous missense variant c.1099C > T;p.(Arg367Trp) (NM_003680.3) in YARS1. This variant causes a multisystem disorder with developmental delay, microcephaly, failure to thrive, short stature, muscular hypotonia, ataxia, brain anomalies, microcytic anemia, hepatomegaly, and hypothyroidism. In silico analyses show that the p.(Arg367Trp) does not affect the catalytic domain responsible of enzymatic coupling, but destabilizes the cytokine-like C-terminal domain. The phenotype associated with p.(Arg367Trp) is distinct from the other biallelic pathogenic variants that reside in different functional domains of TyrRS which all show some common, but also divergent clinical signs [(e.g., p.(Phe269Ser)—retinal anomalies, p.(Pro213Leu)/p.(Gly525Arg)—mild ID, p.(Pro167Thr)—high fatality)]. The diverse clinical spectrum of ARS1-associated disorders is related to mutations affecting the various non-canonical domains of ARS1, and impaired protein translation is likely not the exclusive disease-causing mechanism of YARS1- and ARS1-associated neurodevelopmental disorders. Key messages The missense variant p.(Arg367Trp) in YARS1 causes a distinct multisystem disorder. p.(Arg367Trp) affects a non-canonical domain with cytokine-like functions. Phenotypic heterogeneity associates with the different affected YARS1 domains. Impaired protein translation is likely not the exclusive mechanism of ARS1-associated disorders.

Case Report: A new case of YARS1-associated autosomal recessive disorder with compound heterozygous and concurrent 47, XXY

“…Our case stands out due to the identification of the YARS1 p.Arg367Trp variant in the patient's father. This particular variant has been previously documented by Averdunk et al ( 9 ) as recurrently homozygous in their study of 12 cases, with 8% (1/12) exhibiting mild hearing impairment ( 9 ) Interestingly, our patient failed both the initial and subsequent newborn hearing screens in the left ear. Meanwhile, the patient's father, now 48 years old, encountered adult-onset hearing loss, necessitating the use of hearing aids.…”

“…These children presented with a broader spectrum of symptoms, including brain dysmyelination, nystagmus, exocrine pancreatic insufficiency, renal dysfunction, hypoglycemia, anemia, intermittent proteinuria, and recurrent bloodstream infections ( 16 ). Averdunk et al ( 9 ) identified 12 individuals from six families with a recurrent homozygous missense variant c.1099C > T, p.(Arg367Trp) in YARS1, who also exhibited microcephaly, short stature, ataxia, microcytic anemia, and hypothyroidism. A subset of individuals additionally suffered from hearing impairment, gastroesophageal reflux, vomiting, and pulmonary disease ( 9 ).…”

“…Averdunk et al ( 9 ) identified 12 individuals from six families with a recurrent homozygous missense variant c.1099C > T, p.(Arg367Trp) in YARS1, who also exhibited microcephaly, short stature, ataxia, microcytic anemia, and hypothyroidism. A subset of individuals additionally suffered from hearing impairment, gastroesophageal reflux, vomiting, and pulmonary disease ( 9 ). In 2021, Zeiad et al described an infant with a novel homozygous variant of uncertain significance, c.611A > C, p.(Tyr204Cys) in YARS1, who additionally presented with hyperinsulinemic hypoglycemia, exocrine pancreatic insufficiency, primary hypothyroidism, recurrent infections, anemia, and coagulopathy ( 17 ).…”

“…The results unveiled a likely pathogenic variant (c.1099C > T, p.Arg367Trp, paternally inherited) and a variant of uncertain significance (c.782T > G, Leu.L261Arg, maternally inherited) in the YARS1 gene (NM_003680.3) (See Figure 3 ). The YARS1 p.Arg367Trp variant has been described in ClinVar (ID:567612) which was first reported by Adverdunk ( 9 ) as homozygous variant. It is exceedingly rare in the healthy population (<0.001% in gnomAD).…”

A missense, loss-of-functionYARS1variant in a patient with proximal-predominant motor neuropathy

“…Importantly, two YARS1 subunits must form an asymmetric homodimeric complex with two tyrosyl tRNAs for the aminoacylation reaction to occur (J Ward and Fersht, 1988). Previously, homozygosity or compound heterozygosity for loss-of-function YARS1 variants have been associated with severe, early-onset, multisystem disease, with phenotypes including liver dysfunction, developmental delay, brain anomalies, and sensorineural hearing loss (Averdunk et al, 2021;Estève et al, 2021;Nowaczyk et al, 2017;Williams et al, 2019). Furthermore, heterozygosity for missense variants or a small, in-frame deletion in YARS1 have been associated with dominant intermediate Charcot-Marie-Tooth neuropathy, type C (DI-CMTC; MIM #608323), which is characterized by progressive weakness and sensory loss in the distal upper and lower extremities, with intermediate motor nerve conduction velocities between 25 and 45 m/s (Hyun et al, 2013;Jordanova et al, 2003Jordanova et al, , 2006.…”