Clinical characteristics.

YARS1 deficiency is characterized by developmental delay / intellectual disability, poor prenatal and postnatal growth, gastrointestinal (GI) involvement (feeding difficulties, recurrent vomiting, GI bleeding, chronic diarrhea, pancreatic insufficiency), liver involvement (increased transaminases, cholestasis, steatosis, fibrosis, episodes of hepatic failure), chronic anemia, endocrine involvement (hypothyroidism, hypoglycemia), lung disease (cystic disease, interstitial fibrosis), retinitis pigmentosa, and sensorineural hearing loss. Other less frequent findings include kidney disease and primary amenorrhea. The multisystem clinical manifestations of YARS1 deficiency typically vary from individual to individual.

Diagnosis/testing.

The diagnosis of YARS1 deficiency is established in a proband with suggestive findings and biallelic pathogenic variants in YARS1 identified by molecular genetic testing.

Management.

Treatment of manifestations: Multidisciplinary care by specialists in relevant fields including developmental pediatrics, pediatric neurology, gastroenterology, hepatology, pulmonology, medicine, kidney disease, otolaryngology and audiology, ophthalmology, low vision services, hematology, endocrinology, social work, and clinical genetics. General recommendations for urgent treatment of acute episodic illnesses include: increase protein intake (up to 2-2.5 g/kg/day), avoid prolonged fasting, aggressively treat fever with antipyretics, and provide appropriate steroid coverage for individuals with known adrenal insufficiency.

Surveillance: Routinely scheduled visits with treating specialists.

Agents/circumstances to avoid: Catabolism and insufficient protein intake (i.e., less than 1.5-2 g/kg/day) and prolonged fasting given the increased risk of hypoglycemia.

Genetic counseling.

YARS1 deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a YARS1 pathogenic variant, at conception each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial YARS1 pathogenic variants. Once the YARS1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

YARS1 deficiency should be considered in probands with the following clinical and imaging findings and family history.

Clinical findings [Estève et al 2021]

• Premature birth (typically 27-31 weeks' gestation)
• Growth
  • Intrauterine growth restriction (z score = −2.95 to −1.95)
  • Poor postnatal linear growth and weight gain
• Neurologic
  • Developmental delay or intellectual disability of variable degree
  • Hypotonia with impaired gross motor function
  • Impaired fine motor development
  • Impaired speech development
  • Acquired microcephaly
• Gastrointestinal
  • Feeding difficulties
  • Gastroesophageal reflux disease
  • Recurrent vomiting
  • Exocrine pancreatic insufficiency in severely affected individuals
• Liver disease
  • Hepatomegaly with hyperechogenicity on ultrasound examination
  • Cholestasis, increased liver transaminases
  • Steatosis
  • Fibrosis
  • Episodes of hepatic failure
• Frequent infections
  • Pneumonia
  • Tracheobronchitis
• Hematologic. Microcytic, hypochromic anemia
• Endocrinologic/metabolism
  • Hypoglycemia ranging from transient to recurrent; sometimes associated with liver failure; rarely associated with hyperinsulinism
  • Primary hypothyroidism
• Pulmonary
  • Cystic disease
  • Interstitial fibrosis
• Vison. Retinitis pigmentosa
• Hearing. Sensorineural hearing loss
• Facial features. Although the range of facial features (such as deeply set eyes, full cheeks, large ears, narrow forehead, low hanging columella) tend to be nonspecific (see Figure 2 in Averdunk et al [2021] and Figure 1 in Kuan et al [2023]), these features can sometimes be helpful when considering the diagnosis [L Averdunk, personal observation].

Brain MRI often shows reduced brain volume with enlarged ventricles and/or subarachnoid space, thinning of the corpus callosum, hypomyelination or delayed myelination, and cystic changes in periventricular white matter (see Figure 1 and Figure 2) [Nowaczyk et al 2017, Tracewska-Siemiątkowska et al 2017, Williams et al 2019, Averdunk et al 2021, Estève et al 2021, Zeiad et al 2021].

Figure 1.

Coronal MRI of the head of an individual with YARS1 deficiency at age seven years showing cystic changes in periventricular white matter (green arrows) Reproduced with permission from Nowaczyk et al [2017]

Figure 2.

(A) Axial sequences (head MRI) of three different individuals with YARS1 deficiency showing wide lateral ventricles as a sign of diffuse cerebral volume loss due to periventricular white matter loss. (B) Sagittal sequences (head MRI) of the same three (more...)

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of YARS1 deficiency is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in YARS1 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variant" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic YARS1 variants of uncertain significance (or of one known YARS1 pathogenic variant and one YARS1 variant of uncertain significance) does not establish nor rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determines which gene(s) are likely involved, whereas comprehensive genomic testing does not.

Note: Single-gene testing (sequence analysis of YARS1, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• A multigene panel that includes YARS1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. To date, most YARS1 pathogenic variants reported (e.g., missense, nonsense) are within the coding region and are likely to be identified on exome sequencing.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

YARS1 encodes tyrosine-tRNA ligase, cytoplasmic (also called tyrosyl-tRNA synthetase 1; YARS1), a member of the aminoacyl-tRNA synthase family of cytoplasmic enzymes that link amino acids with the correct nucleotide triplets, ensuring the correct translation of the protein code during protein synthesis. Thus, the multisystem clinical manifestations of deficiency of YARS1, like deficiency of all other members of the aminoacyl-tRNA synthase family, typically vary from individual to individual [Estève et al 2021].

YARS1 deficiency is characterized by developmental delay / intellectual disability, poor prenatal and postnatal growth, gastrointestinal (GI) involvement (feeding difficulties, recurrent vomiting, GI bleeding, chronic diarrhea, pancreatic insufficiency), liver involvement (increased transaminases, cholestasis, steatosis, fibrosis, episodes of hepatic failure), chronic anemia, endocrine involvement (hypothyroidism, hypoglycemia), lung disease (cystic disease, interstitial fibrosis), retinitis pigmentosa, and sensorineural hearing loss. Other less frequent findings include kidney disease and primary amenorrhea.

To date, more than 30 individuals with YARS1 deficiency have been reported: 17 individuals (from seven families) with a range of biallelic YARS1 pathogenic variants [Nowaczyk et al 2017, Tracewska-Siemiątkowska et al 2017, Shaheen et al 2019, Williams et al 2019, Estève et al 2021, Zeiad et al 2021, Kuan et al 2023, Lenz et al 2024] and 14 individuals (from seven families) homozygous for the YARS1 pathogenic variant p.Arg367Trp [Averdunk et al 2021, Nasser Samra et al 2023]. The following description of the phenotypic features associated with YARS1 deficiency is based on these reports.

Pregnancy and preterm birth. Some infants were born preterm (before 29 weeks' gestation). Preterm birth was variably associated with decreased fetal movements, placental abruption, and premature rupture of membranes [Williams et al 2019, Estève et al 2021].

Intrauterine growth restriction was reported in some infants [Shaheen et al 2019, Williams et al 2019, Estève et al 2021, Zeiad et al 2021].

None of the individuals homozygous for the p.Arg367Trp pathogenic variant were born prematurely or had intrauterine growth restriction [Averdunk et al 2021, Nasser Samra et al 2023].

Growth. All children had linear growth failure (with weight proportional to height) (ranging to a z score of −10) and most had microcephaly of prenatal or postnatal onset (ranging to a z score of −10) [Tracewska-Siemiątkowska et al 2017, Williams et al 2019, Estève et al 2021, Kuan et al 2023].

All individuals homozygous for the p.Arg367Trp pathogenic variant had linear growth failure (weight proportional to height) ranging to 5.6 standard deviations below the mean and postnatal onset of microcephaly (ranging to a z score of −7) [Averdunk et al 2021, Nasser Samra et al 2023].

Development / cognitive ability. Cognitive function ranged from normal (some individuals) [Nowaczyk et al 2017, Tracewska-Siemiątkowska et al 2017, Lenz et al 2024] to severe intellectual disability (most individuals) [Shaheen et al 2019, Williams et al 2019, Averdunk et al 2021, Estève et al 2021, Zeiad et al 2021, Kuan et al 2023, Nasser Samra et al 2023].

Individuals homozygous for the p.Arg367Trp pathogenic variant required assistance in feeding and dressing but were able to follow simple commands (e.g., help setting the table). Most learned to use single words by age three to six years or to speak in simple two- to three-word sentences.

Fine and gross motor skills and muscular hypotonia. Most individuals had muscular hypotonia and delayed gross motor development. One individual walked without support at age 13 months, but with poor balance [Tracewska-Siemiątkowska et al 2017]. Most individuals homozygous for the p.Arg367Trp pathogenic variant learned to sit without support, walk by age four years, and climb stairs with assistance [Averdunk et al 2021, Nasser Samra et al 2023]. Some individuals with other YARS1 genotypes learned to walk by age four years [Williams et al 2019].

Deceased velocity of motor and sensory nerve conduction was reported in one individual [Nasser Samra et al 2023].

Speech development was delayed in all individuals who had impaired cognitive function. Some learned to speak in two- to three-word sentences and to use signs to communicate; some learned to use letters and numbers [Williams et al 2019].

Gastrointestinal. Many children experienced gastroesophageal reflux disease, slowed gastric emptying, and recurrent vomiting [Williams et al 2019, Kuan et al 2023]. Some required gastrostomy tube placement for nutritional support [Tracewska-Siemiątkowska et al 2017, Williams et al 2019, Estève et al 2021, Zeiad et al 2021, Kuan et al 2023]. One child had an episode of pancreatitis [Averdunk et al 2021].

Exocrine pancreatic insufficiency was observed in some individuals [Williams et al 2019].

Chronic diarrhea, observed in some individuals, was mostly associated with exocrine pancreatic insufficiency [Williams et al 2019].

Liver disease, which typically was evident by age 12 months, ranged from stable hepatomegaly, mild steatosis, and mild fibrotic changes with transient increase of liver transaminases to severe and chronic cholestatic liver failure and cirrhosis [Williams et al 2019, Estève et al 2021, Zeiad et al 2021]. Individuals with more severe liver disease had variants other than homozygosity for p.Arg367Trp. Some children with severe liver disease had coagulopathy and hyperammonemia.

In surviving infants, liver function usually stabilized after age two to three years [Nowaczyk et al 2017, Tracewska-Siemiątkowska et al 2017, Williams et al 2019, Averdunk et al 2021]. Findings in some of these children included splenomegaly and transient increases in plasma triglycerides and/or transient or persisting hypoalbuminemia [Nowaczyk et al 2017, Estève et al 2021].

Microcytic, hypochromic anemia is present in most individuals; some critically ill or severely affected children required blood transfusion [Williams et al 2019, Estève et al 2021] and/or treatment with erythropoietin [Williams et al 2019]. Some individuals developed iron deficiency.

Endocrinologic/Metabolism

• Hypoglycemia. Many individuals, especially those with variants other than homozygosity for p.Arg367Trp, experienced one or more episodes of hypoglycemia especially in the first two years of life [Tracewska-Siemiątkowska et al 2017, Estève et al 2021]. Some had persistent, severe hypoglycemia requiring treatment (see Management).
• Primary hypothyroidism, reported in about half of individuals homozygous for the p.Arg367Trp pathogenic variant, resolved over time [Zeiad et al 2021].
• Less common endocrinologic findings in a few individuals included:
  • Central adrenal insufficiency [A Kwok, personal observation]
  • Hypogonadotropic hypogonadism (manifesting in females as primary amenorrhea) [Tracewska-Siemiątkowska et al 2017, Lenz et al 2024]
  • Low growth hormone levels in one individual who did not experience linear growth acceleration following treatment with recombinant growth hormone [Averdunk et al 2021]

Cystic lung disease, manifesting on chest radiographs in some children as diffuse interstitial prominence involving the lower lobes by age 8-12 months (see Figure 3) [Nowaczyk et al 2017], did not progress to need for home ventilation.

Figure 3.

Computerized tomography of the chest of an individual with YARS1 deficiency age ten years showing cystic lesions in the lower lobes bilaterally Reproduced with permission from Nowaczyk et al [2017]

Kidney involvement included intermittent proteinuria [Williams et al 2019, Kuan et al 2023] and transient hydronephrosis in some [Williams et al 2019, Averdunk et al 2021], and the following in single individuals: acute kidney failure during intercurrent illness [Zeiad et al 2021], intermittent hyperkalemia [Kuan et al 2023], and recurrent episodes of hypovolemic hypernatremia, probably caused by dehydration [L Averdunk, personal observation].

Ophthalmologic involvement in some individuals included:

• Neonatal nystagmus [Tracewska-Siemiątkowska et al 2017, Williams et al 2019, Kuan et al 2023]
• Retinal dystrophy / retinitis pigmentosa with reduced central vision, constricted visual fields, and loss of night vision. Retinal findings included macular pigmentation, degeneration, and atrophy [Tracewska-Siemiątkowska et al 2017, Lenz et al 2024].

Sensorineural hearing loss was present in some individuals [Tracewska-Siemiątkowska et al 2017, Williams et al 2019, Averdunk et al 2021, Kuan et al 2023]. Delayed auditory brain stem response testing was reported in one individual [Nasser Samra et al 2023].

Recurrent infections. Some individuals experienced life-threatening recurrent infections (including bacteriemia, enterovirus meningitis, peritonitis, and bacterial pneumonia [Williams et al 2019, Zeiad et al 2021].

Occasional seizures were reported in two individuals "with focal sites of hyperexcitability" [Tracewska-Siemiątkowska et al 2017, Kuan et al 2023].

Sparse hair was observed in many individuals [Williams et al 2019, Averdunk et al 2021, Kuan et al 2023, Nasser Samra et al 2023].

Prognosis. Seven children with severe liver disease died between ages 10 and 25 months due to their liver disease and multiorgan failure, most commonly in the setting of systemic infections [Williams et al 2019, Estève et al 2021, Zeiad et al 2021].

One individual homozygous for the p.Arg367Trp pathogenic variant died at age 15 years; the cause of death is unknown [Averdunk et al 2021].

Given that the oldest reported individuals were born around 2002, to date no data on the life expectancy of these individuals are available.

Brain MR spectroscopy revealed a nonspecific lactate peak of the basal ganglia in one individual [Zeiad et al 2021] and increase in the myoinositol peak in another individual [Estève et al 2021].

Histologic findings

• Brain. Neuronal loss with gliosis and vacuoles in gray and white matter was observed in an individual age 10 months [Williams et al 2019] and noninflammatory leukodystrophy, periventricular gliosis, and foci of necrosis with mineralization in the cerebellum was observed in an individual age 8 months [Zeiad et al 2021].
• Liver. Biopsy findings included [Nowaczyk et al 2017, Tracewska-Siemiątkowska et al 2017, Williams et al 2019, Estève et al 2021, Zeiad et al 2021]:
  • Micro- and macrovesicular hepatic steatosis with or without steatohepatitis
  • Minor to severe portal and periportal fibrosis with or without either cholestasis or bile duct proliferation in more progressive stages of liver disease
  • Regenerative nodules indicative of cirrhosis in one individual

Genotype-Phenotype Correlations

Homozygosity for the pathogenic variant p.Arg367Trp is associated with a relatively consistent phenotype [Averdunk et al 2021, Nasser Samra et al 2023].

No clinically relevant genotype-phenotype correlations are available to date in individuals with other YARS1 pathogenic variants.

Prevalence

To date, more than 30 individuals with YARS1 deficiency have been reported [Averdunk et al 2021, Nasser-Samra et al 2023].

The YARS1 pathogenic variant p.Pro167Thr is a founder variant in the Amish population [Williams et al 2019]. The carrier frequency in this population is unknown.

The frequency of the pathogenic variant p.Arg367Trp in the Galilee Bedouin population in Israel is 1:24 (based on the genetic carrier screening program) [Singer & Sagi-Dain 2020, Nasser Samra et al 2023].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with YARS1 deficiency, the evaluations summarized in Table 2 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for YARS1 deficiency. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 3).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in Table 4 are recommended.

Agents/Circumstances to Avoid

Avoid the following:

• Catabolism and insufficient protein intake (i.e., less than 1.5-2 g/kg/day)
• Prolonged fasting given the increased risk of hypoglycemia
• Fever

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

YARS1 deficiency belongs to the group of aminoacyl-tRNA synthetase (ARS) deficiencies. Other ARS deficiencies include MARS1, LARS1, IARS1, SARS1, and FARBSB deficiencies.

Kok et al [2021] tested the effect of high-dose supplementation with the respective amino acids (lysine, isoleucine, serine, and phenylalanine) for one individual with LARS1 deficiency, one individual with IARS1 deficiency, one individual with SARS1 deficiency, and one individual with FARBSB deficiency for five to 32 months. The high-dose supplementation of the amino acid was associated with an improvement of oral food intake, decrease in frequency of infections, and improvement of pulmonary function in the individual with LARS1 deficiency; improvement of overall growth including head circumference in the individuals with IARS1, LARS1, and SARS1 deficiencies; improvement of speech development in the individuals with IARS1 and SARS1 deficiencies; and improvement of fine and gross motor functions in the individual with IARS1 deficiency. The individual with FARBSB deficiency had severe underlying liver disease; after initial improvement of liver function and thrombocytes, during phenylalanine supplementation he died of bleeding from preexisting varices of the esophagus.

In three additional studies, treatment with the respective amino acid was associated with an improvement of liver function and/or improved growth and/or reduced frequency of infections in individuals with MARS1 and IARS1 deficiencies [Kopajtich et al 2016, Lenz et al 2020, Hadchouel et al 2022].

Whether tyrosine supplementation improves the course of YARS1 deficiency is unclear at the current stage. Estève et al [2021] reported that in an infant with steatohepatitis there was no clear improvement after initiation of tyrosine supplementation (100 mg/kg/day and then 200 mg/kg/day). However, the authors posited that the lack of effectiveness may be explained by disease severity and late treatment, suggesting that they may have "missed the time window of efficiency."

As high-dose supplementation of the respective amino acid has shown beneficial effects for other ARS deficiencies, it is worth considering treatment with tyrosine (in addition to high-protein diet) for YARS1 deficiency.

Compassionate use treatment of tyrosine supplementation is currently under way in a few individuals with YARS1 deficiency. For further information contact Dr Luisa Averdunk ([email protected]).

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

YARS1 deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are presumed to be heterozygous for a YARS1 pathogenic variant.
• Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a YARS1 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are not at risk of developing YARS1 deficiency. Specific signs consistent with the allelic disorder YARS1-related dominant intermediate Charcot-Marie-Tooth neuropathy have been reported in one heterozygous parent of a child with YARS1 deficiency (see Genetically Related Disorders).

Sibs of a proband

• If both parents are known to be heterozygous for a YARS1 pathogenic variant, at conception each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial YARS1 pathogenic variants.
• Heterozygotes (carriers) are not at risk of developing YARS1 deficiency (see also Genetically Related Disorders).

Offspring of a proband. To date, individuals with YARS1 deficiency are not known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a YARS1 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the YARS1 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of individuals known to be carriers of a YARS1 pathogenic variant, particularly if both partners are of the same ancestry. A YARS1 founder variant has been identified in the Amish population (see Table 5).

Prenatal Testing and Preimplantation Genetic Testing

Once the YARS1 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

YARS1 encodes tyrosine-tRNA ligase, cytoplasmic (also called tyrosyl-tRNA synthetase 1; YARS1), which belongs to the family of aminoacyl-tRNA synthetases (ARSs) responsible of the correct coupling of amino acids to their cognate tRNAs (i.e., the amino acid corresponding to the anticodon triplet of the tRNA according to the genetic code). This is an essential step that enables the transport of the amino acid to the lengthening polypeptide chain during protein translation. Each amino acid is loaded by a specific ARS, as reflected in the nomenclature (thus, YARS1 for tyrosyl-tRNA synthetase and IARS1 for isoleucine-tRNA synthetase). Because of this crucial role in protein translation, ARSs are highly conserved and ubiquitously expressed in the cytosol (ARS1) or in the mitochondria (ARS2) [Kalotay et al 2023].

Biallelic pathogenic variants in YARS1 cause reduced activity of tyrosyl-tRNA synthetase 1 (YARS1), and potentially impaired protein translation. However, impaired protein translation may not be the sole mechanism of YARS1 deficiency. Although not essential for aminoacylation, the C-terminal EMAPII-like domain of YARS1 functions as a cytokine and, upon activation by cleavage, has chemotactic and anti-angiogenic activity. In addition, YARS1 is associated with other non-canonical functions including gene regulation of expression and immunomodulation [Wakasugi & Schimmel 1999a, Wakasugi & Schimmel 1999b, Kanaji et al 2018, Turvey et al 2022].

It is likely that YARS1 pathogenic variants in the C-terminal domain also compromise these non-canonical functions of YARS1.

Mechanism of disease causation. Loss of function. Estève et al [2021] observed an 80% reduction in YARS1 protein abundance in cell lines from individuals with YARS1 deficiency, supporting the idea that YARS1 deficiency contributes to the disorder, characterizing it as, in part, a loss-of-function disorder. In addition, recombinant YARS1 p.Pro167Thr showed a reduced ability to homodimerize [Williams et al 2019].

Author Notes

Dr Luisa Averdunk ([email protected]) is actively involved in clinical research regarding individuals with YARS1 deficiency. She would be happy to communicate with persons who have any questions regarding diagnosis of YARS1 deficiency or other considerations such as management recommendations. Dr Averdunk is currently investigating whether peripheral neuropathy is a typical feature of YARS1 deficiency.

Contact Dr Averdunk to inquire about review of YARS1 variants of uncertain significance. To further assess the functional impact / clinical relevance of a variant of uncertain significance, quantification of residual enzyme tyrosyl-tRNA synthase 1 activity can be done in a specialized laboratory (e.g., Laboratory Genetic Metabolic Diseases at Amsterdam UMC; contact Gajja Salomons and Simas Mendes).

Acknowledgments

We thank Dr Karin Konzett (Department of General Pediatrics, Feldkirch, Austria) and Dr Tobias Linden (Department of General Pediatrics, Oldenburg, Germany) for sharing clinical data of their unpublished cases and discussing the clinical presentation.

We also acknowledge the Elterninitiative Kinderkrebsklinik e.V. (Düsseldorf, Germany) and the Junior Clinician Scientist Programmes by the Heinrich-Heine University (#9772792) and by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) (#493659010), which granted Dr Luisa Averdunk protected working time for scientific work and this review.

Revision History

• 3 July 2025 (bp) Review posted live
• 22 December 2023 (la) Original submission

Literature Cited

• Averdunk L, Sticht H, Surowy H, Lüdecke HJ, Koch-Hogrebe M, Alsaif HS, Kahrizi K, Alzaidan H, Alawam BS, Tohary M, Kraus C, Endele S, Wadman E, Kaplan JD, Efthymiou S, Najmabadi H, Reis A, Alkuraya FS, Wieczorek D. The recurrent missense mutation p.(Arg367Trp) in YARS1 causes a distinct neurodevelopmental phenotype. J Mol Med (Berl). 2021;99:1755-68. [PMC free article: PMC8599376] [PubMed: 34536092]
• Estève C, Roman C, DeLeusse C, Baravalle M, Bertaux K, Blanc F, Bourgeois P, Bresson V, Cano A, Coste ME, Delteil C, Lacoste C, Loosveld M, De Paula AM, Monnier AS, Secq V, Levy N, Badens C, Fabre A. Novel partial loss-of-function variants in the tyrosyl-tRNA synthetase 1 (YARS1) gene involved in multisystem disease. Eur J Med Genet. 2021;64:104294. [PubMed: 34352414]
• Fuchs SA, Schene IF, Kok G, Jansen JM, Nikkels PGJ, van Gassen KLI, Terheggen-Lagro SWJ, van der Crabben SN, Hoeks SE, Niers LEM, Wolf NI, de Vries MC, Koolen DA, Houwen RHJ, Mulder MF, van Hasselt PM. Aminoacyl-tRNA synthetase deficiencies in search of common themes. Genet Med. 2019;21:319-30. [PMC free article: PMC7091658] [PubMed: 29875423]
• Hadchouel A, Drummond D, Pontoizeau C, Aoust L, Hurtado Nedelec MM, El Benna J, Gachelin E, Perisson C, Vigier C, Schiff M, Lacaille F, Molina TJ, Berteloot L, Renolleau S, Ottolenghi C, Tréluyer JM, de Blic J, Delacourt C. Methionine supplementation for multi-organ dysfunction in MetRS-related pulmonary alveolar proteinosis. Eur Respir J. 2022;59:2101554. [PubMed: 34503986]
• Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519-22. [PubMed: 28959963]
• Kalotay E, Klugmann M, Housley GD, Fröhlich D. Recessive aminoacyl-tRNA synthetase disorders: lessons learned from in vivo disease models. Front Neurosci. 2023;17:1182874. [PMC free article: PMC10234152] [PubMed: 37274208]
• Kanaji T, Vo MN, Kanaji S, Zarpellon A, Shapiro R, Morodomi Y, Yuzuriha A, Eto K, Belani R, Do MH, Yang XL, Ruggeri ZM, Schimmel P. Tyrosyl-tRNA synthetase stimulates thrombopoietin-independent hematopoiesis accelerating recovery from thrombocytopenia. Proc Natl Acad Sci U S A. 2018;115:E8228-E8235. [PMC free article: PMC6126720] [PubMed: 30104364]
• Kok G, Tseng L, Schene IF, Dijsselhof ME, Salomons G, Mendes MI, Smith DEC, Wiedemann A, Canton M, Feillet F, de Koning TJ, Boothe M, Dean J, Kassel R, Ferreira EA, van den Born M, Nieuwenhuis EES, Rehmann H, Terheggen-Lagro SWJ, van Karnebeek CDM, Fuchs SA. Treatment of ARS deficiencies with specific amino acids. Genet Med. 2021;23:2202-7. [PMC free article: PMC8244667] [PubMed: 34194004]
• Kopajtich R, Murayama K, Janecke AR, Haack TB, Breuer M, Knisely AS, Harting I, Ohashi T, Okazaki Y, Watanabe D, Tokuzawa Y, Kotzaeridou U, Kölker S, Sauer S, Carl M, Straub S, Entenmann A, Gizewski E, Feichtinger RG, Mayr JA, Lackner K, Strom TM, Meitinger T, Müller T, Ohtake A, Hoffmann GF, Prokisch H, Staufner C. Biallelic IARS mutations cause growth retardation with prenatal onset, intellectual disability, muscular hypotonia, and infantile hepatopathy. Am J Hum Genet. 2016;99:414-22. [PMC free article: PMC4974065] [PubMed: 27426735]
• Kuan J, Hansen A, Wang H. Case report: a new case of YARS1-associated autosomal recessive disorder with compound heterozygous and concurrent 47, XXY. Front Pediatr. 2023;11:1282253. [PMC free article: PMC10731953] [PubMed: 38125821]
• Lenz D, Schlieben LD, Shimura M, Bianzano A, Smirnov D, Kopajtich R, Berutti R, Adam R, Aldrian D, Baric I, Baumann U, Bozbulut NE, Brugger M, Brunet T, Bufler P, Burnytė B, Calvo PL, Crushell E, Dalgıç B, Das AM, Dezsőfi A, Distelmaier F, Fichtner A, Freisinger P, Garbade SF, Gaspar H, Goujon L, Hadzic N, Hartleif S, Hegen B, Hempel M, Henning S, Hoerning A, Houwen R, Hughes J, Iorio R, Iwanicka-Pronicka K, Jankofsky M, Junge N, Kanavaki I, Kansu A, Kaspar S, Kathemann S, Kelly D, Kırsaçlıoğlu CT, Knoppke B, Kohl M, Kölbel H, Kölker S, Konstantopoulou V, Krylova T, Kuloğlu Z, Kuster A, Laass MW, Lainka E, Lurz E, Mandel H, Mayerhanser K, Mayr JA, McKiernan P, McLean P, McLin V, Mention K, Müller H, Pasquier L, Pavlov M, Pechatnikova N, Peters B, Petković Ramadža D, Piekutowska-Abramczuk D, Pilic D, Rajwal S, Rock N, Roetig A, Santer R, Schenk W, Semenova N, Sokollik C, Sturm E, Taylor RW, Tschiedel E, Urbonas V, Urreizti R, Vermehren J, Vockley J, Vogel GF, Wagner M, van der Woerd W, Wortmann SB, Zakharova E, Hoffmann GF, Meitinger T, Murayama K, Staufner C, Prokisch H. Genetic landscape of pediatric acute liver failure of indeterminate origin. Hepatology. 2024;79:1075-87. [PMC free article: PMC11020061] [PubMed: 37976411]
• Lenz D, Stahl M, Seidl E, Schöndorf D, Brennenstuhl H, Gesenhues F, Heinzmann T, Longerich T, Mendes MI, Prokisch H, Salomons GS, Schön C, Smith DEC, Sommerburg O, Wagner M, Westhoff JH, Reiter K, Staufner C, Griese M. Rescue of respiratory failure in pulmonary alveolar proteinosis due to pathogenic MARS1 variants. Pediatr Pulmonol. 2020;55:3057-66. [PubMed: 32833345]
• Nam DE, Park JH, Park CE, Jung NY, Nam SH, Kwon HM, Kim HS, Kim SB, Son WS, Choi BO, Chung KW. Variants of aminoacyl-tRNA synthetase genes in Charcot-Marie-Tooth disease: a Korean cohort study. J Peripher Nerv Syst. 2022;27:38-49. [PubMed: 34813128]
• Nasser Samra N, Morani I, Bayan H, Bakry D, Shaalan M, Saadi H, Beni Shrem S, Sawaed A, Kok G, Muffels IJ, Fuchs SA, Shapira-Rootman M, Mor-Shaked H, Mandel H. [Next-generation sequencing performed in patients raising the suspicion of an inborn error of metabolism uncovered a homozygous variant in YARS1 allowing a novel therapeutic trial]. Harefuah. 2023;162:344-51. [PubMed: 37394435]
• Nowaczyk MJ, Huang L, Tarnopolsky M, Schwartzentruber J, Majewski J, Bulman DE; FORGE Canada Consortium, Care4Rare Canada Consortium; Hartley T, Boycott KM. A novel multisystem disease associated with recessive mutations in the tyrosyl-tRNA synthetase (YARS) gene. Am J Med Genet A. 2017;173:126-34. [PubMed: 27633801]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Shaheen R, Maddirevula S, Ewida N, Alsahli S, Abdel-Salam GMH, Zaki MS, Tala SA, Alhashem A, Softah A, Al-Owain M, Alazami AM, Abadel B, Patel N, Al-Sheddi T, Alomar R, Alobeid E, Ibrahim N, Hashem M, Abdulwahab F, Hamad M, Tabarki B, Alwadei AH, Alhazzani F, Bashiri FA, Kentab A, Şahintürk S, Sherr E, Fregeau B, Sogati S, Alshahwan SAM, Alkhalifi S, Alhumaidi Z, Temtamy S, Aglan M, Otaify G, Girisha KM, Tulbah M, Seidahmed MZ, Salih MA, Abouelhoda M, Momin AA, Saffar MA, Partlow JN, Arold ST, Faqeih E, Walsh C, Alkuraya FS. Genomic and phenotypic delineation of congenital microcephaly. Genet Med. 2019;21:545-52. [PMC free article: PMC6986385] [PubMed: 30214071]
• Singer A, Sagi-Dain L. Impact of a national genetic carrier-screening program for reproductive purposes. Acta Obstet Gynecol Scand. 2020;99:802-8. [PubMed: 32242916]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207. [PMC free article: PMC7497289] [PubMed: 32596782]
• Tracewska-Siemiątkowska A, Haer-Wigman L, Bosch DGM, Nickerson D, Bamshad MJ; University of Washington Center for Mendelian Genomics; van de Vorst M, Rendtorff ND, Möller C, Kjellström U, Andréasson S, Cremers FPM, Tranebjærg L. An expanded multi-organ disease phenotype associated with mutations in YARS. Genes (Basel). 2017;8:381. [PMC free article: PMC5748699] [PubMed: 29232904]
• Turvey AK, Horvath GA, Cavalcanti ARO. Aminoacyl-tRNA synthetases in human health and disease. Front Physiol. 2022;13:1029218. [PMC free article: PMC9623071] [PubMed: 36330207]
• Wakasugi K, Schimmel P. Highly differentiated motifs responsible for two cytokine activities of a split human tRNA synthetase. J Biol Chem. 1999a;274:23155-9. [PubMed: 10438485]
• Wakasugi K, Schimmel P. Two distinct cytokines released from a human aminoacyl-tRNA synthetase. Science. 1999b;284:147-51. [PubMed: 10102815]
• Williams KB, Brigatti KW, Puffenberger EG, Gonzaga-Jauregui C, Griffin LB, Martinez ED, Wenger OK, Yoder MA, Kandula VVR, Fox MD, Demczko MM, Poskitt L, Furuya KN, Reid JG, Overton JD, Baras A, Miles L, Radhakrishnan K, Carson VJ, Antonellis A, Jinks RN, Strauss KA. Homozygosity for a mutation affecting the catalytic domain of tyrosyl-tRNA synthetase (YARS) causes multisystem disease. Hum Mol Genet. 2019;28:525-38. [PMC free article: PMC6360277] [PubMed: 30304524]
• Zeiad RKHM, Ferren EC, Young DD, De Lancy SJ, Dedousis D, Schillaci LA, Redline RW, Saab ST, Crespo M, Bhatti TR, Ackermann AM, Bedoyan JK, Wood JR. A Novel Homozygous Missense Mutation in the YARS gene: expanding the phenotype of YARS multisystem disease. J Endocr Soc. 2021;5:bvaa196. [PMC free article: PMC7806200] [PubMed: 33490854]