Genetic characterization of suspected MODY patients in Tunisia by targeted next-generation sequencing

Abstract

Aims Maturity Onset Diabetes of the Young (MODY) is a monogenic form of diabetes with autosomal dominant inheritance pattern. The diagnosis of MODY and its subtypes is based on genetic testing. Our aim was investigating MODY by means of next-generation sequencing in the Tunisian population. Methods We performed a targeted sequencing of 27 genes known to cause monogenic diabetes in 11 phenotypically suspected Tunisian patients. We retained genetic variants passing filters of frequency in public databases as well as their probable effects on protein structures and functions evaluated by bioinformatics prediction tools. Results Five heterozygous variants were found in four patients. They include two mutations in HNF1A and GCK that are the causative genes of the two most prevalent MODY subtypes described in the literature. Other possible mutations, including novel frameshift and splice-site variants were identified in ABCC8 gene. Conclusions Our study is the first to investigate the clinical application of targeted next-generation sequencing for the diagnosis of MODY in Africa. The combination of this approach with a filtering/prioritization strategy made a step towards the identification of MODY mutations in the Tunisian population.

Identification of Maturity-Onset-Diabetes of the Young (MODY) mutations in a country where diabetes is endemic

“…Similarly, two gene-specific studies conducted in Tunisia identified two variants, one in HNF4A (from 12 patients with diabetes) and the other in the GCK gene (from 23 unrelated patients with diabetes) respectively 17 , 18 . More recently, a third study from Tunisia utilized targeted NGS and identified four variants from 11 patients suspected to have MODY in ABCC8 , HNF1A, and GCK , improving the positive diagnostic rate significantly 19 . There are no studies on MODY published from Kuwait, Bahrain, or Qatar to date.…”

Tunisian Maturity-Onset Diabetes of the Young: A Short Review and a New Molecular and Clinical Investigation

“…Hyperglycemia in F1-III.6 and F1-III.7 probands must be pharmacologically managed according to their genotypes. Furthermore, the c.571C>T mutation has already been reported in another unrelated Tunisian pedigree (20). The main reason for this mutation has never been explained that whether it is due to the gene founder effect or mutational hotspot in Tunisia.…”

“…Overall, 89 unrelated MODY suspected Tunisian participants (including this study) have been investigated using targeted gene panel sequencing, direct/indirect sequencing, or MLPA testing. Only eleven heterozygous pathogenic variants were found in sixteen unrelated patients (~18%) (16,18,20,21). The results of this study support previous observations of Vaxillaire et al (21) such as (i) the severity of the clinical presentation of non-European cases (including those of Tunisian ancestry) with early-onset diabetes (similar to F2-IV.12 and F4-IV.8 index cases), and (ii) low mutation rates despite the heterogeneous clinical inclusion criteria [although strict in our study (Figure 1)].…”

“…Dallali et al. ( 20 ) studied 11 suspected MODY patients and identified five heterozygous pathogenic variants in four patients { GCK p.Arg191Trp, HNF1A c.710A>G, adenosine triphosphate (ATP)-binding cassette, sub-family, member 8 ( ABCC8 ) [(c.2376delC and c.4608+4A>G found at compound heterozygous state) and c.4606G>A]}. Another study has also reported two pathogenic variants in HNF1A (c.476G>A) and HNF4A (c.763C>T) genes ( 21 ).…”

First Report of Diabetes Phenotype due to a Loss-of-Function ABCC8 Mutation Previously Known to Cause Congenital Hyperinsulinism

“…ABCC8 gene mutations also constitute common genetic etiology of Permanent and Transient DM [11]. Recently ABCC8 has been recognized as the MODY12 subtype with an increasing number of relative reports [12–16].…”