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YIPF5 has been implicated in neonatal diabetes mellitus through multiple lines of evidence encompassing both case reports and multi‐patient studies. A recent case report illustrated that a patient with a homozygous YIPF5 missense variant presented with stress‑induced transient hyperglycemia and central nervous system manifestations such as developmental delay and epilepsy (PMID:38632213). This report expanded the phenotype associated with YIPF5 mutations and established a clinical link to neonatal diabetes mellitus.
The overall clinical validity of the YIPF5–neonatal diabetes association is best classified as Strong. Multi‑patient studies have identified homozygous mutations in YIPF5 in 6 probands from 5 independent families (PMID:33164986), and the additional case report lends further supportive evidence. Segregation analyses in these families reinforce that the YIPF5 variants co‐segregate with the disease phenotype.
Genetically, the inheritance pattern is autosomal recessive with affected individuals harboring homozygous variants. The multi‑patient study reported several variant types; one representative variant is c.542C>T (p.Ala181Val), a bona fide coding change that meets HGVS criteria. Additionally, familial segregation data in these studies, with demonstrable co‐segregation among affected relatives (PMID:33164986), further support the genetic evidence.
Functional studies have explored the underlying mechanism of pathogenicity. Evidence from cell and stem cell models has demonstrated that loss of YIPF5 function leads to proinsulin retention, marked endoplasmic reticulum stress, and increased β cell susceptibility to stress-induced apoptosis (PMID:33164986). These experimental findings provide a mechanistic explanation for the clinical manifestations observed in affected individuals.
There is consistency among genetic, segregation, and experimental data without any significant conflicting reports. Both the case report and multi‑patient study converge on ER stress due to impaired ER-to-Golgi trafficking as a central mechanism, aligning with the clinical spectrum of neonatal diabetes mellitus and related neurological features.
In conclusion, the integration of multiple independent studies, robust segregation data, and compelling functional evidence support a strong association between YIPF5 mutations and neonatal diabetes mellitus. The established link not only aids diagnostic decision‑making but also informs future research and potential therapeutic interventions.
Key Take‑home: YIPF5 mutation analysis is a valuable tool for diagnosing neonatal diabetes mellitus and guiding personalized patient care.
Gene–Disease AssociationStrongEvidence from 6 probands across 5 families alongside an independent case report demonstrates consistent genotype-phenotype correlation with supportive segregation and functional data (PMID:33164986, PMID:38632213). Genetic EvidenceStrongMultiple homozygous missense variants, including c.542C>T (p.Ala181Val), identified in affected individuals from independent families support an autosomal recessive model with clear segregation patterns. Functional EvidenceModerateFunctional assays in β cell models and stem cell-derived islet cells show that loss of YIPF5 leads to proinsulin retention and ER stress, underscoring the mechanistic basis of the disease. |