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Biallelic loss-of-function variants in SLC2A2 have been identified as a rare cause of permanent neonatal diabetes mellitus (PNDM) in highly consanguineous populations. In a Qatari cohort of nine patients with PNDM, whole‐genome sequencing revealed seven distinct pathogenic variants across six genes, including SLC2A2 in one proband, corresponding to an incidence of 1:22 938 live births ([PMID:31441606]). In northwest Saudi Arabia, 17 PNDM patients from 11 consanguineous families were studied; sequencing of 9 genes uncovered one novel homozygous SLC2A2 variant among six disease-causing alleles, with an incidence of 1:21 196 live births ([PMID:22060631]).
SLC2A2-related PNDM follows an autosomal recessive inheritance pattern, with at least two unrelated probands reported. One homozygous nonsense mutation, c.901C>T (p.Trp420Ter), has been modeled in patient-derived iPSCs, demonstrating complete GLUT2 deficiency and defective glucose release in β-cell precursors ([PMID:34171785]). GLUT2 is essential for glucose‐stimulated insulin secretion, and its absence impairs neonatal glycemic homeostasis.
SLC2A2 should be included in genetic testing panels for autosomal recessive PNDM, particularly in consanguineous populations, although further segregation and functional data are required to establish definitive clinical validity.
Gene–Disease AssociationLimited2 probands with biallelic variants in consanguineous cohorts; no extended segregation; minimal PNDM-specific functional confirmation Genetic EvidenceLimitedBiallelic SLC2A2 variants in two unrelated probands; autosomal recessive pattern; no segregation beyond index cases Functional EvidenceLimitediPSC modeling shows GLUT2 deficiency impairs glucose release, but PNDM-specific rescue/segregation data are lacking |