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RFX6 is implicated in Martinez-Frías syndrome (MFS), a rare autosomal recessive malformation complex characterized by neonatal diabetes, pancreatic hypoplasia, duodenal atresia, gallbladder agenesis, and chronic diarrhea. Sixteen unrelated probands with biallelic RFX6 variants have been reported, all presenting with neonatal diabetes and gastrointestinal anomalies ([PMID:35813646]). Most cases involve homozygous or compound heterozygous missense or nonsense mutations, consistent with autosomal recessive inheritance. One study described a patient meeting full clinical criteria without an identifiable RFX6 mutation, suggesting phenotypic overlap and potential genetic heterogeneity in MFS ([PMID:25421130]).
Genetic evidence is robust: 16 probands across multiple families harboring biallelic RFX6 mutations confirm the gene–disease association. Segregation analyses demonstrate that affected individuals inherit two pathogenic alleles from heterozygous carrier parents, consistent with a recessive model. A recurrent missense variant, c.541C>T (p.Arg181Trp), was identified in homozygosity in two unrelated families ([PMID:35813646]).
Functional assessments support a loss-of-function mechanism. Morpholino knockdown of rfx6 in Xenopus embryos recapitulates pancreatic and foregut malformations, and rescue with wild-type but not patient-derived mutant rfx6 confirms pathogenicity ([PMID:21215266]). In human β-cells, RFX6 knockdown reduces L-type Ca²⁺-channel expression and insulin secretion; the patient-derived p.Val506Gly variant fails to activate insulin transcription or calcium-channel genes ([PMID:25497100]).
No studies have specifically refuted the RFX6–MFS link, though the absence of RFX6 mutations in one clinical MFS case highlights genetic heterogeneity. Overall, the genetic and experimental data converge on haploinsufficiency and loss of transcriptional activity as drivers of MFS.
Key take-home: Biallelic RFX6 mutations cause Martinez-Frías syndrome, and genetic testing of RFX6 is clinically actionable for early diagnosis and management.
Gene–Disease AssociationStrong16 probands with biallelic RFX6 variants across multiple unrelated families, concordant with AR inheritance and functional data Genetic EvidenceStrong16 probands harboring homozygous or compound heterozygous RFX6 mutations, consistent segregation in families Functional EvidenceModerateXenopus morpholino knockdown recapitulates phenotype with rescue assays and human β-cell studies demonstrate impaired insulin secretion |