Systematic genetic testing for recessively inherited monogenic diabetes: a cross-sectional study in paediatric diabetes clinics

Abstract

Aims/hypothesis Current clinical guidelines for childhood-onset monogenic diabetes outside infancy are mainly focused on identifying and testing for dominantly inherited, predominantly MODY genes. There are no systematic studies of the recessively inherited causes of monogenic diabetes that are likely to be more common in populations with high rates of consanguinity. We aimed to determine the contribution of recessive causes of monogenic diabetes in paediatric diabetes clinics and to identify clinical criteria by which to select individuals for recessive monogenic diabetes testing. Methods We conducted a cross-sectional study of 1093 children from seven paediatric diabetes clinics across Turkey (a population with high rates of consanguinity). We undertook genetic testing of 50 known dominant and recessive causes of monogenic diabetes for 236 children at low risk of type 1 diabetes. As a comparison, we used monogenic diabetes cases from UK paediatric diabetes clinics (a population with low rates of consanguinity). Results Thirty-four children in the Turkish cohort had monogenic diabetes, equating to a minimal prevalence of 3.1%, similar to that in the UK cohort (p = 0.40). Forty-one per cent (14/34) had autosomal recessive causes in contrast to 1.6% (2/122) in the UK monogenic diabetes cohort (p < 0.0001). All conventional criteria for identifying monogenic diabetes (parental diabetes, not requiring insulin treatment, HbA1c ≤ 58 mmol/mol [≤7.5%] and a composite clinical probability of MODY >10%) assisted the identification of the dominant (all p ≤ 0.0003) but not recessive cases (all p ≥ 0.2) in Turkey. The presence of certain non-autoimmune extra-pancreatic features greatly assisted the identification of recessive (p < 0.0001, OR 66.9) but not dominant cases. Conclusions/interpretation Recessively inherited mutations are a common cause of monogenic diabetes in populations with high rates of consanguinity. Present MODY-focused genetic testing strategies do not identify affected individuals. To detect all cases of monogenic paediatric diabetes, it is crucial that recessive genes are included in genetic panels and that children are selected for testing if they have certain non-autoimmune extra-pancreatic features in addition to current criteria. Graphical abstract

Atypical comorbidities in a child considered to have type 1 diabetes led to the diagnosis of SLC29A3 spectrum disorder

“…Development of the abovementioned comorbidities that are unexpected in T1DM, weak positivity of a single diabetes autoantibody, and a low T1DM genetic risk score generated from 30 T1DM-associated common genetic variants (10.4 th centile of T1D reference population) prompted an investigation into monogenic causes of diabetes ( 10 – 12 ). Based on previous work ( 13 ), a custom-designed NGS panel including 53 genes and the NC_012920.1:m.3243A>G mitochondrial DNA variant revealed the presence of two heterozygous variants in the SLC29A3 gene, namely, the novel variant c.890dupC, p.Leu298fs, and the previously reported variant c.1157G>A, p.Arg386Gln, the latter classified as pathogenic according to ACMG/AMP criteria ( 14 ). Sanger sequencing of the SLC29A3 gene in the parents confirmed compound heterozygosity of our patient [Leu298fs] [Arg386Gln], since the father was found to be heterozygous for the p.Leu298fs variant and the mother heterozygous for p.Arg386Gln ( Supplemental Figure 1 ).…”

An update on the diagnosis and management of monogenic diabetes

“…The presence of additional non-diabetic features suggestive of a monogenic syndrome in a patient with diabetes should always prompt genetic testing that includes dominant and recessively inherited genes. 10 About half of patients with NDM have a transient form of the disease, characterised by complete remission of NDM around the age of three months and relapsing diabetes as a teenager/young adult. 11 The diabetes may be non-penetrant in either the neonatal or adult onset phases; transient NDM (TNDM) can therefore be genetically diagnosed in the neonatal period, or rarely in adult clinics when there is a clinical suspicion of MODY in a young adult patient who has no history of neonatal diabetes.…”

“…clinical feature and family history independent) has been a successful strategy to diagnose monogenic diabetes in Turkish paediatric clinics. 10…”

“…life‐threatening liver disease in EIF2AK3 NDM or cerebellar agenesis and developmental delay in PTF1A NDM). The presence of additional non‐diabetic features suggestive of a monogenic syndrome in a patient with diabetes should always prompt genetic testing that includes dominant and recessively inherited genes 10 …”

“…Selecting patients to test based solely on a low T1DM‐GRS and antibody negativity (i.e. clinical feature and family history independent) has been a successful strategy to diagnose monogenic diabetes in Turkish paediatric clinics 10 …”