Evidence asserting this gene-disease relationship includes case-level data, segregation data, and experimental data. Summary of case-level and experimental data: 1.5 points. *KLF11 *was first reported in relation to autosomal dominant monogenic diabetes in 2005 (Neve et al., 2005, PMID: 15774581). One of the original variants reported, p.Thr220Met (rs34336420), is now known to have a MAF of 0.04 in Africans (gnomAD) and is classified as benign/likely benign in ClinVar, and the second one p.Ala347Ser (rs121912645) has MAFs of 0.0005 and 0.0001 in Latino and European populations respectively. A common variant p.Gln62Arg (rs35927125, MAF in Europeans 0.12) was modestly associated with T2D in the original publication, but this is not borne out in the AMP T2D Portal (ExTexT2D exome chip Pval 0.08; type2diabetesgenetics.org). A rare variant (p.His418Gln) in this gene segregated with antibody negative childhood onset diabetes in 3 family members; a fourth carrier was said to be unaffected with limited information available (PMID: 31124255), reducing evidence for segregation. A rare variant (p.Pro193Thr) was found in a father and son with early onset (32 and 13 years) diabetes with metabolic syndrome features (PMID: 36241199). Variants have shown in vitro effects on transcription and/or cofactor binding (PMIDs: 15774581, 31124255, 36241199).
Laver et al (PMID: 35108381) reported a lack of enrichment of ultra-rare (MAF<6x10-6) protein-truncating and missense variants in BLK, PAX4, and KLF11 in a large cohort of cases with suspected MODY (n=1227) compared to population cohort (UK Biobank =185,898), gnomADv2 and gnomADv3. They also showed a similar lack of enrichment of protein-truncating variants of any frequency in BLK, PAX4, and KLF11 in the MODY cohort.
In summary, there is limited evidence to support, and there appears to be strong evidence to contradict the KLF11-monogenic diabetes relationship that warrants refuting the association (originally asserted as maturity-onset diabetes of the young 7, MODY7, MIM: 610508).
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