Neonatal diabetes

Gene: TARS2

I don't know

Comment on list classification: Out of more than 30 individuals reported in literature with biallelic TARS2 variants and Combined oxidative phosphorylation deficiency 21, only 4 patients presented with the additional phenotype of neonatal diabetes. 4/4 of those patients were homozygous for the same missense variant p.(Arg327Gln) - 3 families had a shared haplotype (PMID:39509107, Donis et al., 2025). An additional patient with TARS2-related COXPD-21 and diabetes was reported in PMID: 37454282 Accogli et al., 2023 - age of onset unknown. Based on the available evidence, this gene should be rated Amber for Neonatal diabetes until more evidence emerges.

Importantly, ID/DD and axial hypotonia are the main features reported in COXPD-21 patients (92% and 85% of individuals respectively - PMID: 39509107). TARS2 is already rated Green / tagged for promotion on other panels in PanelApp which cover the most common symptoms, including: Intellectual disability; Childhood onset dystonia, chorea or related movement disorder; Mitochondrial disorders .

Created: 17 Nov 2025, 12:12 p.m. | Last Modified: 17 Nov 2025, 12:12 p.m.

Panel Version: 5.6

PMID: 24827421 Diodato et al., 2014
P2 &P3 - Italian sibs presenting with axial hypotonia and limb hypertonia, psychomotor delay, and high levels of blood lactate; no diabetes - compound heterozygous for c.845C>T, p.(Pro282Leu) and g.4255A>G; c.695+3A>G.

PMID: 34508595 Zheng et al., 2022
Report of five unrelated patients with TARS2-related mitochondrial disease; phenotype: epilepsy, dystonia, hyperhidrosis and severe hearing impairment. Patients were of Danish, Syrian, and Indian ethnicity. 6 variants reported: 1 splice (c.695+3A>G) and 5 missense. No diabetes reported.

PMID: 37454282 Accogli et al., 2023
18 individuals with biallelic TARS2 variants from 15 unrelated families. Only 1 case - Female of Latin ancestry (family 15) - was reported to have Non-autoimmune diabetes (age of onset unknown) together with COXPD-21 related features. She was homozygous for c.1010C>T p.(Ala337Val). This variant is rare (2 alleles reported in gnomAD v.4.1.0, no homozygotes); Revel score = 0.07 - Benign Moderate.

PMID: 39394138 Zhang et al., 2024
4 individuals from three unrelated Chinese families with mitochondrial encephalomyopathy caused by pathogenic variants in TARS2 - diabetes not reported.

PMID: 39509107 Donis et al., 2025
Four individuals diagnosed with diabetes (3 neonatal and 1 at 52 weeks) shared a rare homozygous missense variant c.980G>A, p.(Arg327Gln), in TARS2 - founder effect? On haplotype analysis, individuals 1, 3 and 4 shared a 1.8 Mb region (including TARS2), indicating inheritance from a common ancestor. Individual 2 did not share a haplotype.
The reported variant is rare (9 alleles in gnomAD v4.1.0, no homozygotes); Revel score = 0.32, Uncertain.
One proband had epilepsy, one had development delay and two had both. Authors hypothesise that homozygous missense variants specifically in the TARS2 301‐381aa region may impair binding of TARS2 to Rag GTPases and disrupt the mTORC1 signalling pathway, leading to β‐cell dysfunction.
Method: WGS. Targeted NGS previously excluded pathogenic variants in 35 known Neonatal diabetes mellitus genes in all patients.

TARS2 is associated with AR Combined oxidative phosphorylation deficiency 21, MIM:615918 (accessed 17th Nov 2025).

Created: 17 Nov 2025, 11:59 a.m. | Last Modified: 17 Nov 2025, 11:59 a.m.

Panel Version: 5.6

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Combined oxidative phosphorylation deficiency 21, OMIM:615918; combined oxidative phosphorylation defect type 21, MONDO:0014398

Publications

• 24827421
• 34508595
• 37454282
• 39394138
• 39509107

Green List (high evidence)

Donis et al 2024 (PMID: 39509107) performed WGS on 27 neonatal diabetes patients who also had epilepsy and/or developmental delay. 3 individuals were found to be homozygous for a TARS2 missense variant, c.980G>A, p.(Arg327Gln). A replication cohort identified 1 additional individual who is also homozygous for this variant. An additional patient with diabetes (age of diagnosis not provided) and COXPD-21 related features has been reported with compound heterozygous TARS2 variants (Accogli et al 2023, PMID: 37454282). Biallelic TARS2 variants cause Combined Oxidative Phosphorylation Deficiency-21(COXPD-21, 21;OMIM: 615918) and neonatal diabetes is a reported feature of this disorder. Evidence shows that the p.(Arg327Gln) variant disrupts TARS2's regulation of the mTORC1 pathway which is essential for pancreatic beta-cells.
Sources: Literature

Created: 4 Nov 2025, 12:22 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neonatal diabetes; developmental delay; epilepsy

Publications

• PMID: 39509107 and PMID: 37454282

Mode of pathogenicity
Other