Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: GINS4

Green List (high evidence)

Comment on list classification: There are five unrelated families reported with biallelic GINS4 variants and with NK cell deficiency and neutropenia. This includes three unrelated patients with the same recurrent potentially founder variant (p.Val171Met) and two additional families reported with compound heterozygous variants (and one variant in both these families is p.Val171Leu). There is also extensive functional evidence available.

Hence, this gene can be promoted to green rating in the next GMS update.

Created: 6 Aug 2026, 2:19 p.m. | Last Modified: 6 Aug 2026, 2:19 p.m.

Panel Version: 9.71

PMID:36345943 (2022) reported two siblings from a family with NK cell deficiency (NKD) and neutropenia in the absence of other immune system abnormalities. They also presented with growth restriction, and developed severe herpesvirus and other infections. They were identified with compound heterozygous variants in GINS4 gene (c.511G>C/p.Val171Leu & c.571C>T/p.Gln191Ter). There is extensive functional evidence available.

PMID:40510848 (2025) reported a 60-patient congenital neutropenia cohort in which 4 new independent families were identified with biallelic GINS4 variants, including a recurrent homozygous variant (c.511G>A/ p.Val171Met) in three families with the same geographic origin suggesting that it might be a founder allele. This variant is found in homozygous state in an individual in gnomAD v4.1.1. The fourth patient was identified with compound heterozygous variants in GINS4 gene (c.511G>C/p.Val171Leu & c.282_287del/ p.Cys95_Arg96del). All four GINS4 probands presented with congenital neutropenia, with growth retardation noted in two of four families. Reduced NK cell/lymphocyte subsets were a shared feature across the immunodeficiency-gene subgroup in this cohort. No new functional studies reported.

PMID:40768335 (2025) re-studied the same two siblings with compound heterozygous GINS4 variants (p.Val171Leu/p.Gln191*) originally reported by PMID:36345943 (2022), using patient-derived iPSCs and NK cells to investigate why the siblings had different disease severity despite identical genotypes. They found that NK cells (but not hematopoietic stem/progenitor cells) show allelic expression bias—each sibling's NK cells preferentially expressed a different one of the two mutant alleles—revealing lineage-specific allelic bias as a novel mechanism driving variable penetrance/severity in GINS4-associated NK cell deficiency.

This gene has not yet been associated with relevant phenotypes in OMIM or ClinGen (last accessed 06 August 2026).

Created: 6 Aug 2026, 11:43 a.m. | Last Modified: 6 Aug 2026, 11:43 a.m.

Panel Version: 9.63

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
combined immunodeficiency, MONDO:0015131

Publications

• 36345943
• 40510848
• 40768335

Red List (low evidence)

Conte et al. described a familial NKD case in which 2 siblings had a substantive NKD and neutropenia in the absence of other immune system abnormalities. Exome sequencing identified compound heterozygous variants in Go-Ichi-Ni-San (GINS) complex subunit 4 (GINS4, also known as SLD5), an essential component of the human replicative helicase, which we demonstrate to have a damaging impact upon the expression and assembly of the GINS complex.

Cells derived from affected individuals and a GINS4-knockdown cell line demonstrate delayed cell cycle progression, without signs of improper DNA synthesis or increased replication stress.
Sources: Literature

Created: 17 Jun 2026, 3:33 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
NK cell deficiency; neutropenia; viral infections

Publications

• 36345943