Novel insights into genetics and clinics of the HNF1A-MODY

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

Comparison of diabetes phenotype in children and their mothers with permanent neonatal diabetes mellitus carrying the same KCNJ11 variants

Objective. Mutations of the KCNJ11 gene are the most common cause of the permanent neonatal diabetes mellitus (PNDM). Majority of people with KNCJ11-PNDM have a de-novo mutation. We aimed to compare diabetes phenotype in two children and their mothers with PNDM carrying the same sulfonylurea-sensitive KCNJ11 variants

Mutations in SURF1 are important genetic causes of Leigh syndrome in Slovak patients

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

ATAD3A-related pontocerebellar hypoplasia: new patients and insights into phenotypic variability

Abstract Background Pathogenic variants in the ATAD3A gene lead to a heterogenous clinical picture and severity ranging from recessive neonatal-lethal pontocerebellar hypoplasia through milder dominant Harel-Yoon syndrome up to, again, neonatal-lethal but dominant cardiomyopathy. The genetic diagnostics of ATAD3A-related disorders is also challenging due to three paralogous genes in the ATAD3 locus, making it a difficult target for both sequencing and CNV analyses. Results Here we report four individuals from two families with compound heterozygous p.Leu77Val and exon 3–4 deletion in the ATAD3A gene. One of these patients was characterized as having combined OXPHOS deficiency based on decreased complex IV activities, decreased complex IV, I, and V holoenzyme content, as well as decreased levels of COX2 and ATP5A subunits and decreased rate of mitochondrial proteosynthesis. All four reported patients shared a strikingly similar clinical picture to a previously reported patient with the p.Leu77Val variant in combination with a null allele. They presented with a less severe course of the disease and a longer lifespan than in the case of biallelic loss-of-function variants. This consistency of the phenotype in otherwise clinically heterogenous disorder led us to the hypothesis that the severity of the phenotype could depend on the severity of variant impact. To follow this rationale, we reviewed the published cases and sorted the recessive variants according to their impact predicted by their type and the severity of the disease in the patients. Conclusion The clinical picture and severity of ATAD3A-related disorders are homogenous in patients sharing the same combinations of variants. This knowledge enables deduction of variant impact severity based on known cases and allows more accurate prognosis estimation, as well as a better understanding of the ATAD3A function

Genetic analysis of single-minded 1 gene in early-onset severely obese children and adolescents

<div><p>Background</p><p>Inactivating mutations of the hypothalamic transcription factor singleminded1 (SIM1) have been shown as a cause of early-onset severe obesity. However, to date, the contribution of <i>SIM1</i> mutations to the obesity phenotype has only been studied in a few populations. In this study, we screened the functional regions of <i>SIM1</i> in severely obese children of Slovak and Moravian descent to determine if genetic variants within <i>SIM1</i> may influence the development of obesity in these populations.</p><p>Methods</p><p>The <i>SIM1</i> promoter region, exons and exon-intron boundaries were sequenced in 126 unrelated obese children and adolescents (2–18 years of age) and 41 adult lean controls of Slovak and Moravian origin. Inclusion criteria for the children and adolescents were a body mass index standard deviation score higher than 2 SD for an appropriate age and sex, and obesity onset at less than 5 years of age. The clinical phenotypes of the <i>SIM1</i> variant carriers were compared with clinical phenotypes of 4 <i>MC4R</i> variant carriers and with 27 unrelated <i>SIM1</i> and <i>MC4R</i> mutation negative obese controls that were matched for age and gender.</p><p>Results</p><p>Seven previously described <i>SIM1</i> variants and one novel heterozygous variant p.D134N were identified. The novel variant was predicted to be pathogenic by 7 <i>in silico</i> software analyses and is located at a highly conserved position of the SIM1 protein. The p.D134N variant was found in an 18 year old female proband (BMI 44.2kg/m²; +7.5 SD), and in 3 obese family members. Regardless of early onset severe obesity, the proband and her brother (age 16 years) did not fulfill the criteria of metabolic syndrome. Moreover, the variant carriers had significantly lower preferences for high sugar (<i>p</i> = 0.02) and low fat, low carbohydrate, high protein (<i>p</i> = 0.02) foods compared to the obese controls.</p><p>Conclusions</p><p>We have identified a novel <i>SIM1</i> variant, p.D134N, in 4 obese individuals from a single pedigree which is also associated with lower preference for certain foods.</p></div