Neonatal diabetes

Gene: PAX4

I don't know

Comment on list classification: As reviewed by Amy Cann, there are 2 unrelated individuals reported in literature with biallelic PAX4 LoF variants and transient neonatal diabetes. Other reports link heterozygous variants in PAX4 to Maturity-onset diabetes of the young type 9 (onset in adulthood). The association between PAX4 and monogenic diabetes has been classified as REFUTED by ClinGen. Based on available evidence, this gene can only be rated Amber for Neonatal diabetes, until more evidence emerges.

Created: 11 Feb 2026, 5:42 p.m. | Last Modified: 12 Feb 2026, 9:24 a.m.

Panel Version: 5.17

PMID: 11723072 Shimajiri et al. 2001
Analysed he PAX4 gene in 200 unrelated Japanese probands with type 2 diabetes and identified the mutation p.R121W in 6 heterozygous patients and 1 homozygous patient (mutant allele frequency 2.0%) - risk factor? Age at onset was 25-49 years.

PMID: 25951767 Sujjitjoon et al., 2016
Thai family with MODY9 and early-onset renal complications, harbouring a PAX4 IVS7-1G>A splice mutation, resulting in p.Q250del protein change. Age at diagnosis: 30-40yrs.

PMID: 36595822 Zhang et al., 2022
Chinese 19 month old boy with c.487C>T mutation in PAX4 gene and MODY9. 43 alleles present in gnomADv4, MAF = 0.00004007.

PMID: 41475885 Chen et al., 2025
Report of 3 unrelated individuals with Maturity-onset diabetes of the young (MODY). Age of diabetes onset: 2 'pediatric' patients and 1 with onset in early adulthood.
Three novel PAX4 variants (c.83delA; p.Gln28ArgfsTer6, c.35T>C; p.Leu12Pro, and c.488G>C; p.Arg163Pro) were identified. Expression of p.Gln28ArgfsTer6 was undetectable, likely due to NMD; p.Leu12Pro and p.Arg163Pro resulted in markedly reduced protein levels.
Variant p.Leu12Pro segregated with disease - it was present in both the affected father and daughter. However, variants p.Gln28ArgfsTer6 and p.Arg163Pro were present in unaffected family members as well as the probands.

PAX4 is linked to AD Diabetes mellitus, type 2, OMIM:125853 (OMIM accessed 11th Feb 2026). The association between PAX4 and monogenic diabetes has been classified as REFUTED by ClinGen (Monogenic Diabetes Expert Panel, Dec 2022), highlighting that 'PAX4 variants may play a role in susceptibility to polygenic type 2 diabetes (MIM: 125853)'.

Created: 11 Feb 2026, 5:37 p.m. | Last Modified: 11 Feb 2026, 5:37 p.m.

Panel Version: 5.14

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Diabetes mellitus, type 2, OMIM:125853

Publications

• 11723072
• 25951767
• 36595822
• 40614820
• 41475885

Green List (high evidence)

Russ-Silsby et al. 2025 (PMID: 40614820) report two homozygous PAX4 loss-of-function variants in two unrelated individuals with neonatal diabetes (NDM) diagnosed aged 6.5 and 9 weeks. In both cases diabetes was transient, remitting in early infancy and relapsing at the ages of 2.4 and 6.7 years. The authors performed genome sequencing on a cohort of 43 consanguineous individuals with NDM, where all the known genetic causes had been previously excluded. The two homozygous PAX4 loss-of-function variants identified were nonsense variant c.376C>T p.(Arg126Ter), and a c.-352_104del deletion affecting the first 4 PAX4 exons. Both variants were predicted to result in complete loss of PAX4 mRNA and the p.(Arg126Ter) variant was confirmed to cause nonsense-mediated decay in CRISPR-edited human induced pluripotent stem cell-derived pancreatic endoderm cells. The parents of the two probands were confirmed to be heterozygous for the respective familial PAX4 variants and did not have diabetes at the time of recruitment. No further recessive PAX4 loss-of-function variants were identified in a replication cohort of 6,087 individuals with suspected monogenic diabetes, including 476 individuals with NDM diagnosed before 6 months, suggesting the loss of PAX4 is a rare cause of monogenic diabetes. The diabetes remission observed in the two patients with complete PAX4 loss, suggests that pancreatic beta cells can develop in the absence of PAX4. However, functional profiling of PAX4 in human beta cell models support its role in the regulation of islet development and glucose-sensitive insulin secretion.
Sources: Literature

Created: 2 Feb 2026, 1:06 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
neonatal diabetes; learning disorder; small for gestational age

Publications

• PMID: 40614820

Mode of pathogenicity
Other