Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: LY9

Green List (high evidence)

Comment on list classification: As reviewed by Boaz Palterer, there is sufficient evidence available (three unrelated cases and functional evidence) for the association of LY9 gene with this panel. Hence, this gene can be promoted to green rating in the next GMS update.

Created: 30 Jul 2026, 7:26 p.m. | Last Modified: 30 Jul 2026, 7:26 p.m.

Panel Version: 9.46

PMID:40446017 (2025) reported the identification of two different homozygous loss-of-function frameshift variants in four individuals from three unrelated families (c.182del, p.(G61Vfs*3) - three individuals from 2 families of Moroccan descent (patients 1-3); c.1052_1053del, p.(H351Rfs*22) - one unrelated individual of Turkish descent (patient 4). Three of these individuals were reported with active tuberculosis (infant pulmonary TB, adult pulmonary TB, mediastinal tuberculous lymphadenitis). Patient 2 (uncle of patient 1) was clinically asymptomatic, despite having the same homozygous variant suggesting incomplete penetrance.

The gene-disease association is statistically robust (adjusted OR 81.7, P=0.00012 for pLOF enrichment in TB patients vs. controls) and extensively functionally validated — loss of surface LY9 expression, impaired ERK signaling, and selectively impaired IFN-γ production by TH1* memory CD4+ T cells, with rescue via wild-type LY9 transduction. Both variants are rare in gnomAD (MAF 9.9×10⁻⁵ and 2.6×10⁻⁴ respectively; biallelic pLOF genotype frequency ~3.6×10⁻⁶).

This gene has not yet been associated with relevant phenotypes in OMIM or ClinGen (last accessed 30 July 2026).

Created: 30 Jul 2026, 7:22 p.m. | Last Modified: 30 Jul 2026, 7:22 p.m.

Panel Version: 9.44

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
inborn error of immunity, MONDO:0003778; Mycobacterium tuberculosis, susceptibility, MONDO:0000070

Publications

• 40446017

Green List (high evidence)

Ogishi et al. described 3 subjects from 3 kindreds with homozygous LOF mutations in LY9 presenting with tuberculosis in a large TB cohort, notably no homozygous LOF was found in a large control cohort. Extensive ex-vivo and in vivo functional validation.
Sources: Literature

Created: 24 Jun 2026, 1:32 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Tubercolosis

Publications

• 40446017