Monogenic Causes in the Type 1 Diabetes Genetics Consortium Cohort: Low Genetic Risk for Autoimmunity in Case Selection

Abstract

Hypothesis About 1% of patients clinically diagnosed as type 1 diabetes have non-autoimmune monogenic diabetes. The distinction has important therapeutic implications but, given the low prevalence and high cost of testing, selecting patients to test is important. We tested the hypothesis that low genetic risk for type 1 diabetes can substantially contribute to this selection. Methods As proof of principle, we examined by exome sequencing families with two or more children, recruited by the Type 1 Diabetes Genetics Consortium and selected for negativity for two autoantibodies and absence of risk HLA haplotypes. Results We examined 46 families that met the criteria. Of the 17 with an affected parent, seven (41.2%) had actionable monogenic variants. Of 29 families with no affected parent, 14 (48.3%) had such variants, including five with recessive pathogenic variants of WFS1 but no report of other features of Wolfram syndrome. Our approach diagnosed 55.8% of the estimated number of monogenic families in the entire T1DGC cohort, by sequencing only 11.1% of the autoantibody-negative ones. Conclusions Our findings justify proceeding to large-scale prospective screening studies using markers of autoimmunity, even in the absence of an affected parent. We also confirm that non-syndromic WFS1 variants are common among cases of monogenic diabetes misdiagnosed as type 1 diabetes.

Maturity Onset Diabetes of the Young—New Approaches for Disease Modelling

“…Currently it is suggested that genetic tests for MODY should be performed when paediatric diabetes is diagnosed, together with modest hyperglycaemia and absence of all four islet autoantibodies (antibodies against GAD, insulinoma antigen-2, zinc transporter 8 and insulin), but there is no standardised diagnostic algorithm [ 12 , 132 , 133 ]. At present, genetic tests for MODY are conducted with NGS methodology due to lower costs and increased diagnostic accuracy [ 134 ].…”

Comprehensive genetic screening reveals wide spectrum of genetic variants in monogenic forms of diabetes among Pakistani population

“…One patient was compound heterozygous at WFS1 , the gene mutated in Wolfram syndrome and also responsible for non-syndromic diabetes. WFS1 variants have been reported from India[ 22 ], China[ 12 , 31 ], Korea[ 20 , 32 , 33 ], Russia[ 6 ], and European ancestry[ 34 ]. Finally, one variant was identified in ZBTB20 , a transcription factor that regulates the function of beta cells and glucose homeostasis[ 35 - 37 ].…”

Why all MODY variants are dominantly inherited: a hypothesis

“…OPEN ACCESS of antibody-negative sibling pairs from the T1D Genetics Consortium, selected for low genetic risk for T1D [10], in whom we did not detect disease-causing variants in the known MODY genes.…”

“…In recent 'agnostic' searches in the exomes of autoantibody-negative patients with a clinical diagnosis of T1D, recessive WFS1 variants were found causing diabetes only, with none of the other manifestations of Wolfram syndrome [9,10]. Such nonsyndromic cases had been previously reported but thought to be rare and confined to populations with high consanguinity or endogamy [11,12].…”