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Intellectual disability
Gene: YARS

YARS (tyrosyl-tRNA synthetase)
EnsemblGeneIds (GRCh38): ENSG00000134684
EnsemblGeneIds (GRCh37): ENSG00000134684
OMIM: 603623, Gene2Phenotype
YARS is in 5 panels

5 reviews

Ida Ertmanska (Genomics England Curator)

Green List (high evidence)

Comment on phenotypes: OMIM phenotype updated 8th Oct 2026.
Created: 8 Oct 2026, 2:32 p.m. | Last Modified: 8 Oct 2026, 2:32 p.m.

Panel Version: 11.41

Comment on list classification: There are now at least 5 unrelated probands reported in literature with biallelic YARS (new name YARS1) variants and a multisystem disorder including significant developmental delays. Hence, this gene can be promoted to Green at the next update.
Created: 8 Oct 2026, 2:28 p.m. | Last Modified: 8 Oct 2026, 2:28 p.m.

Panel Version: 11.38

PMID: 38125821 Kuan et al., 2023
Report of a Hispanic individual with dysmorphic facies and neurological issues. Admitted in the neonatal period due to seizure-like activity, vomiting, and poor feeding. Brain MRI yielded no significant findings. An abdominal ultrasound revealed an echogenic liver. He had hearing loss in his left ear. Subsequently diagnosed with microcephaly, hypotonia, nystagmus, and significant developmental delays.
A microarray conducted shortly after birth revealed 47, XXY. WES uncovered a paternally inherited YARS: c.1099C > T, p.Arg367Trp variant & a maternally inherited YARS: c.782T > G, p.Leu261Arg. Father has history of hearing loss and neurological symptoms; mother was unaffected.

PMID: 34536092 Averdunk et al., 2021
Study identified 12 individuals from 6 families with the recurrent homozygous missense variant c.1099C > T;p.(Arg367Trp) in YARS. Patients presented with a multisystem disorder with developmental delay (12/12), microcephaly (12/12), failure to thrive, short stature, muscular hypotonia (9/12), ataxia, brain anomalies, microcytic anemia (8/8 assessed), hepatomegaly (7/7 assessed), and hypothyroidism. Seq method: exome sequencing. Haplotype analysis showed that the haplotype of individuals originating from Saudi Arabia (C-I) differs from the haplotypes of individuals A + B (from Turkey) and L (from Puerto Rico) - supportive of a recurrent rather than a founder variant. 2 unrelated individuals had hearing loss.

PMID 30304524 Williams et al., 2019
Report of 7 related Amish children homozygous for YARS, c.499C>A, p.Pro167Thr (seq method: WES). Phenotype: poor growth, developmental delay, brain dysmyelination, sensorineural hearing loss, nystagmus, progressive cholestatic liver disease, pancreatic insufficiency, hypoglycemia, anemia, intermittent proteinuria, recurrent bloodstream infections and chronic pulmonary disease. Bilateral sensorineural hearing loss and cholestatic liver disease were present in 7/7 affected individuals. Related adult het carriers were asymptomatic.

PMID: 29232904 Tracewska-Siemiątkowska et al., 2017
Report of a Swedish proband homozygous for YARS: c.806T>C, p.(F269S). Method: Trio WES. Phenotype of the proband: progressive retinal degeneration with congenital nystagmus, profound congenital hearing impairment, primary amenorrhea, agenesis of the corpus callosum, and liver disease. Het parents unaffected.
Created: 8 Oct 2026, 2:26 p.m. | Last Modified: 8 Oct 2026, 2:26 p.m.

Panel Version: 11.38

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2, OMIM:619418; neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2, MONDO:0030375

Publications

Created: 8 Oct 2026, 2:26 p.m.
Last Modified: 8 Oct 2026, 2:26 p.m.
Panel version: 11.38

Achchuthan Shanmugasundram (Genomics England Curator)

I don't know

As reviewed by Sarah Leigh, none of the previously reported cases presented with intellectual disability, although the family reported in PMID:30304524 had expressive language delay and the older brother reported in PMID:27633801 had mild delays.

As reviewed by Dmitrijs Rots, all 12 patients from six families identified with homozygous p.Arg367Trp variant had neurodevelopmental phenotype including intellectual disability. As all these families were identified with the same homozygous variant, the rating should remain amber.
Created: 9 Jan 2024, 10:21 a.m. | Last Modified: 9 Jan 2024, 10:21 a.m.

Panel Version: 5.380

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2, OMIM:619418

Created: 9 Jan 2024, 10:21 a.m.
Last Modified: 9 Jan 2024, 10:21 a.m.
Panel version: 5.380

Dmitrijs Rots (Children's Clinical University Hospital)

12 patients with homozygous p.(Arg367Trp) have distinct NDD reported in PMID: 34536092.
Created: 16 Oct 2022, 12:27 a.m. | Last Modified: 16 Oct 2022, 12:27 a.m.

Panel Version: 3.1746

Publications

PMID: 34536092

Created: 16 Oct 2022, 12:27 a.m.
Last Modified: 16 Oct 2022, 12:27 a.m.
Panel version: 3.1746

Sarah Leigh (Genomics England Curator)

Comment on phenotypes: Monoallelic variants are associated with Charcot-Marie-Tooth disease, dominant intermediate C 608323, while biallelic variants are associated with a complex phenotype that may include intellectual disability, hearing loss and liver damage.
Created: 5 Aug 2020, 4:41 p.m. | Last Modified: 5 Aug 2020, 4:41 p.m.

Panel Version: 3.227

Comment on list classification: Biallelic variants in three families with complex clinical conditions including developmental delay. PMID 30304524 reports an extended family with microcephaly, expressive language delay, hearing loss, amongst other features. PMID 29232904 reports a proband whose phenotype included hearing loss, retnititis pigmentosa and hypotonia, but did not include intellectual disability. PMID 27633801 reports two sibblings with hypotionia, the older brother at 15 years of age has mild delays, he attends school on an individualized educational program and functions at a grade 3 level. He speaks and understands English and Polish.
Created: 6 Jul 2020, 6:25 p.m. | Last Modified: 7 Jul 2020, 2:55 p.m.

Panel Version: 3.144

The new gene for YARS is YARS1
Created: 6 Jul 2020, 5:43 p.m. | Last Modified: 6 Jul 2020, 5:43 p.m.

Panel Version: 3.143

Created: 6 Jul 2020, 5:43 p.m.
Last Modified: 7 Jul 2020, 2:55 p.m.
Panel version: 3.143

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Mono-allelic variants are associated with CMT. However, 10 individuals from three unrelated families reported with bi-allelic variants and a severe phenotype, comprising ID, nystagmus, deafness, liver dysfunction and a range of other features.
Sources: Literature
Created: 23 Apr 2020, 3:39 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Intellectual disability; deafness; nystagmus; liver dysfunction

Publications

Variants in this GENE are reported as part of current diagnostic practice

Created: 23 Apr 2020, 3:39 a.m.

Panel version: 3.31

Details

Mode of Inheritance

BIALLELIC, autosomal or pseudoautosomal

Sources

Expert Review Amber

Phenotypes

Infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2, OMIM:619418
neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2, MONDO:0030375

Tags

new-gene-name Q4_26_promote_green

OMIM

603623

Clinvar variants

Variants in YARS

Penetrance

None

Publications

Panels with this gene

History Filter Activity

8 Oct 2026, Gel status: 2

Set Phenotypes

Ida Ertmanska (Genomics England Curator)

Phenotypes for gene: YARS were changed from Infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2, OMIM:619418; neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2, MONDO:0030375 to Infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2, OMIM:619418; neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2, MONDO:0030375

8 Oct 2026, Gel status: 2

Set Phenotypes

Ida Ertmanska (Genomics England Curator)

8 Oct 2026, Gel status: 2

Set Phenotypes

Ida Ertmanska (Genomics England Curator)

Phenotypes for gene: YARS were changed from Charcot-Marie-Tooth disease, dominant intermediate C 608323; Intellectual disability; deafness; nystagmus; liver dysfunction to Infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2, OMIM:619418; neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2, MONDO:0030375

8 Oct 2026, Gel status: 2

Set publications

Ida Ertmanska (Genomics England Curator)

Publications for gene: YARS were set to 30304524; 29232904; 27633801

8 Oct 2026, Gel status: 2

Removed Tag, Added Tag

Ida Ertmanska (Genomics England Curator)

Tag watchlist was removed from gene: YARS. Tag Q4_26_promote_green tag was added to gene: YARS.

5 Aug 2020, Gel status: 2