Submission Details

Since 2004, RFX6 has been associated with Mitchell-Riley syndrome, an autosomal recessive genetic disorder characterized by neonatal diabetes, pancreatic hypoplasia, intestinal atresia, and gallbladder aplasia or hypoplasia (OMIM #615710). In 2017, truncation variants in RFX6 were first reported to cause autosomal dominant monogenic diabetes with reduced penetrance (PMID: 29026101). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism between the two disorders but observed a difference in inheritance patterns, phenotypic variability, and variant spectrum. Therefore, the curation has been been split into two disease entities The evidence for MItchell-Riley syndrome is being curated separately. The evidence for the split curation for RFX6-related monogenic diabetes is as follows:

The seven variants (one missense, five nonsense, and one frameshift) that have been reported in seven probands in six publications (PMIDs:27185633, 29026101, 31001871, 33721395, 34416793, 34387403) are included in this curation. It should be noted that all variants except one implicated in autosomal dominant monogenic diabetes have been truncation variants. The missense variant segregated with several affected family members in one family, but no functional assays were reported, so it cannot be ruled out that it was tracking an unknown causal regulatory variant. Thus, at present non-truncation variants should be interpreted with caution. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is reported to be heterozygous loss of function variants in the RFX6 gene as responsible for monogenic diabetes. This gene-disease relationship is supported by transcriptional activation assay and subcellular localization assay in HEK293 cells and mouse conditional knockout models (PMIDs: 33721395, 25497096, 3 points). In summary, there is definitive evidence supporting the relationship between RFX6 and autosomal dominant inheritance of monogenic diabetes. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Monogenic diabetes expert panel GCEP on the meeting date March 20, 2024 (SOP Version [#9].)