Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: KARS

Added new-gene-name tag, new approved HGNC gene symbol for KARS is KARS1.

Created: 7 Aug 2026, 3:58 p.m. | Last Modified: 7 Aug 2026, 3:58 p.m.

Panel Version: 9.86

Comment on list classification: As reviewed by Boaz Palterer & Luke Stuart, this gene should be promoted to green rating in the next GMS update.

Created: 31 Jul 2026, 4:30 p.m. | Last Modified: 31 Jul 2026, 4:30 p.m.

Panel Version: 9.57

Green List (high evidence)

As reviewed by Boaz Palterer, accumulating evidence supports immuno-haematological manifestations as part of the KARS1-related disorder spectrum.

Cappuccio et al. 2021 (PMID 33942428) reported three unrelated individuals with biallelic KARS1 variants and immuno-haematological abnormalities. Clinical features included anaemia, neutropenia, hypogammaglobulinaemia, coagulopathy, and requirement for immunoglobulin replacement therapy. The pathogenicity of the reported missense variants was supported by functional studies in yeast.

Saettini et al. 2023 (PMID 37770806) described an additional unrelated individual with biallelic KARS1 variants (p.Phe291Val/p.Pro499Leu) who presented with hypogammaglobulinaemia, recurrent infections, and impaired B-cell function. Functional characterisation in patient-derived B cells demonstrated reduced mitochondrial number and activity, consistent with previous yeast studies showing impaired mitochondrial protein synthesis associated with these variants (Cappuccio et al. 2021 (PMID 33942428)). A subsequent review of 17 published individuals with KARS1-related disorder (including those reported by Cappuccio et al.) identified recurrent/severe infections (9/17) and B cell abnormalities (either B cell lymphopenia [3/9], hypogammaglobulinemia [either IgG, IgA or IgM; 6/15] or impaired vaccine responses [4/7]). Immunoglobulin replacement therapy was administered in 5/13 cases where treatment information was available.

Conclusion: Immuno-haematological abnormalities, particularly hypogammaglobulinaemia, recurrent infections, and B-cell dysfunction, have been reported in at least three unrelated individuals with biallelic KARS1 variants, supported by functional evidence. Given the presence of >3 unrelated cases with a compatible phenotype, promotion to Green is recommended at the next review.

Created: 31 Jul 2026, 4:01 p.m. | Last Modified: 31 Jul 2026, 4:01 p.m.

Panel Version: 9.54

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Hypogammaglobulinemia; antibody deficiency

Publications

• 33942428
• 37770806

Green List (high evidence)

KARS1 encodes lysyl-tRNA synthetase, an enzyme crucial for protein translation in both the cytoplasm and mitochondria.

Classically associated with a multisystemic condition involving progressive leukoencephalopathy, peripheral neuropathy, and deafness, recent evidence establishes KARS1 defects as an Inborn Error of Immunity (IEI) characterized by B cell metabolic impairment and antibody deficiency.

Saettini et al. identified 1 patient from 1 family carrying pathogenic biallelic KARS1 variants (p.Phe291Val/p.Pro499Leu) presenting with hypogammaglobulinemia, recurrent infections, and impaired B cell activity.
From literature review 17 patients with KARS-related diseases were identified. Recurrent/severe infections (9/17) and B cell abnormalities (either B cell lymphopenia [3/9], hypogammaglobulinemia [either IgG, IgA or IgM; 6/15] or impaired vaccine responses [4/7]) were frequently reported.
Sources: Literature

Created: 17 Jun 2026, 3:47 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
progressive leukoencephalopathy; peripheral neuropathy; deafness; antibody deficiency; hypogammaglobulinemia

Publications

• 37770806