MODY (Maturity Onset Diabetes of the Young) is a type of diabetes resulting from a pathogenic effect of gene mutations. Up to date, 13 MODY genes are known. Gene HNF1A is one of the most common causes of MODY diabetes (HNF1A-MODY; MODY3). This gene is polymorphic and more than 1200 pathogenic and non-pathogenic HNF1A variants were described in its UTRs, exons and introns. For HNF1A-MODY, not just gene but also phenotype heterogeneity is typical. Although there are some clinical instructions, HNF1A-MODY patients often do not meet every diagnostic criteria or they are still misdiagnosed as type 1 and type 2 diabetics. There is a constant effort to find suitable biomarkers to help with in distinguishing of MODY3 from Type 1 Diabetes (T1D) and Type 2 Diabetes (T2D). DNA sequencing is still necessary for unambiguous confirmation of clinical suspicion of MODY. NGS (Next Generation Sequencing) methods brought discoveries of multiple new gene variants and new instructions for their pathogenicity classification were required. The most actual problem is classification of variants with uncertain significance (VUS) which is a stumbling-block for clinical interpretation. Since MODY is a hereditary disease, DNA analysis of family members is helpful or even crucial. This review is updated summary about HNF1A-MODY genetics, pathophysiology, clinics functional studies and variant classification.
Objectives. Leigh syndrome is a progressive early onset neurodegenerative disease typically presenting with psychomotor regression, signs of brainstem and/or basal ganglia disease, lactic acidosis, and characteristic magnetic resonance imaging findings. At molecular level, deficiency of respiratory complexes and/or pyruvate dehydrogenase complex is usually observed. Nuclear gene SURF1 encodes an assembly factor for cytochrome c-oxidase complex of the respiratory chain and autosomal recessive mutations in SURF1 are one of the most frequent causes of cytochrome c-oxidase-related Leigh syndrome cases. Here, we aimed to elucidate the genetic basis of Leigh syndrome in three Slovak families.
Methods and results. Three probands presenting with Leigh syndrome were selected for DNA analysis. The first proband, presenting with atypical LS onset without abnormal basal ganglia magnetic resonance imaging findings, was analyzed with whole exome sequencing. In the two remaining probands, SURF1 was screened by Sanger sequencing. Four different heterozygous mutations were identified in SURF1: c.312_321delinsAT:p.(Pro104Profs*1), c.588+1G>A, c.823_833+7del:p. (?) and c.845_846del:p.(Ser282Cysfs*9). All the mutations are predicted to have a loss-of-function effect.
Conclusions. We identified disease-causing mutations in all three probands, which points to the important role of SURF1 gene in etiology of Leigh syndrome in Slovakia. Our data showed that patients with atypical Leigh syndrome phenotype without lesions in basal ganglia may benefit from the whole exome sequencing method. In the case of probands presenting the typical phenotype, Sanger sequencing of the SURF1 gene seems to be an effective method of DNA analysis.