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| Neonatal diabetes v5.17 | PAX4 | Ida Ertmanska changed review comment from: 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 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.; to: 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neonatal diabetes v5.17 | PAX4 | Ida Ertmanska Phenotypes for gene: PAX4 were changed from neonatal diabetes; learning disorder; small for gestational age to Diabetes mellitus, type 2, OMIM:125853; type 2 diabetes mellitus,MONDO:0005148 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neonatal diabetes v5.16 | PAX4 | Ida Ertmanska Publications for gene: PAX4 were set to PMID: 40614820 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neonatal diabetes v5.15 | PAX4 | Ida Ertmanska edited their review of gene: PAX4: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neonatal diabetes v5.15 | PAX4 | Ida Ertmanska Classified gene: PAX4 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neonatal diabetes v5.15 | PAX4 | Ida Ertmanska Gene: pax4 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neonatal diabetes v5.14 | PAX4 | Ida Ertmanska commented on gene: PAX4: 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 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neonatal diabetes v5.14 | PAX4 | Ida Ertmanska reviewed gene: PAX4: Rating: AMBER; Mode of pathogenicity: None; Publications: 11723072, 25951767, 36595822, 40614820, 41475885; Phenotypes: Diabetes mellitus, type 2, OMIM:125853; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neonatal diabetes v5.14 | PAX4 |
Amy Cann gene: PAX4 was added gene: PAX4 was added to Neonatal diabetes. Sources: Literature Mode of inheritance for gene: PAX4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PAX4 were set to PMID: 40614820 Phenotypes for gene: PAX4 were set to neonatal diabetes; learning disorder; small for gestational age Penetrance for gene: PAX4 were set to Complete Mode of pathogenicity for gene: PAX4 was set to Other Review for gene: PAX4 was set to GREEN Added comment: 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 |
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