Screening for Rare Mitochondrial Genome Variants Reveals a Potentially Novel Association between MT-CO1 and MT-TL2 Genes and Diabetes Phenotype.

Variations in several nuclear genes predisposing humans to the development of MODY diabetes have been very well characterized by modern genetic diagnostics. However, recent reports indicate that variants in the mtDNA genome may also be associated with the diabetic phenotype. As relatively little research has addressed the entire mitochondrial genome in this regard, the aim of the present study is to evaluate the genetic variations present in mtDNA among individuals susceptible to MODY diabetes. In total, 193 patients with a MODY phenotype were tested with a custom panel with mtDNA enrichment. Heteroplasmic variants were selected for further analysis via further sequencing based on long-range PCR to evaluate the potential contribution of frequent NUMTs (acronym for nuclear mitochondrial DNA) insertions. Twelve extremely rare variants with a potential damaging character were selected, three of which were likely to be the result of NUMTs from the nuclear genome. The variant m.3243A>G in MT-TL1 was responsible for 3.5% of MODY cases in our study group. In addition, a novel, rare, and possibly pathogenic leucine variant m.12278T>C was found in MT-TL2. Our findings also found the MT-CO1 gene to be over-represented in the study group, with a clear phenotype-genotype correlation observed in one family. Our data suggest that heteroplasmic variants in MT-COI and MT-TL2 genes may play a role in the pathophysiology of glucose metabolism in humans.

Case report: Neonatal diabetes mellitus with congenital hypothyroidism as a result of biallelic heterozygous mutations in GLIS3 gene.

Neonatal diabetes mellitus with congenital hypothyroidism (NDH) syndrome (MIM# 610199) is a rare disease caused by autosomal recessive mutations in the GLIS3 gene. GLIS3 is an important transcription factor that might acts as both a repressor and activator of transcription. To date, 22 cases of NDH syndrome from 16 families and 11 countries have been described. Herein, we report a child who developed diabetes during the first week of age. Additionally, she suffered from congenital hypothyroidism, cardiac abnormalities, and polycystic kidney disease. Genetic analysis revealed that patient is a carrier of two novel heterozygous mutations, p.Pro444fsdelG (c.1330delC) and p.His647Arg (c.1940A > G) in the GLIS3 gene. Each was inherited from clinically healthy father and mother, respectively. Bioinformatic tools (SIFT, PolyPhen2, PROVEAN and SWISS-MODEL) declared that the p.His647Arg (c.1940A > G) variant has strong detrimental effect and disturbs Kruppel-like zinc finger domain. All but one so far described cases of NDH syndrome have been caused by homozygous of GLIS3, making the described case the second case of pathogenic, compound heterozygosity of GLIS3 worldwide posing substantial clinical novelty and detailing an interesting interplay between the observed variants and GLIS3 expression, which seems to be autoregulated. Hence, the damaging missense mutation may further reduce the expression of any remaining functional alleles. This case report expands our understanding of the clinical phenotype, treatment approaches, and outcome of infants with GLIS3 mutations and indicates the need for further research to deepen our understanding of the role of GLIS3.

Transient Neonatal Diabetes Mellitus with an Unknown Cause in a 1-Month-Old Infant: A Case Report.

Transient neonatal diabetes mellitus (TNDM) is a genetically heterogeneous form of neonatal diabetes characterized by hyperglycemia that remits during infancy with a tendency to recur in later life. This case report presents the history of a male infant with transient neonatal diabetes mellitus. The patient was treated with a continuous subcutaneous insulin infusion (CSII) and a continuous glucose monitoring (CGM) system until the age of 2 months, when the normoglycemia connected with a withdrawal of treatment was noted. The genetic test results excluded the majority of known mutations related to TNDM. This case report focuses on various genetic mutations and the clinical features connected with them that cause TNDM and highlights the difficulties in the diagnostic and therapeutic processes of this disease. CSII and CGM systems seem to be a safe and effective treatment option in TNDM and may be used in the therapy.

Wolfram-like syndrome - another face of a rare disease in children.

OBJECTIVES: The presence of two pathogenic variants in the WFS1 gene leads to the occurrence of a rare genetic disease in children - Wolfram syndrome (WFS), which includes insulin-dependent diabetes mellitus (DM), optic atrophy (OA), diabetes insipidus (DI), and deafness (D). However, the presence of a single mutation in the WFS1 gene results in a number of other autosomal dominant inherited diseases, including Wolfram-like syndrome (WFS-like). CASE PRESENTATION: A 10-year-old boy was referred to the Genetic Outpatient Clinic with suspected WFS based on the coexistence of D, type 1 DM, short stature, and abnormalities in ophthalmologic examination (astigmatism and OA due to the optical coherence tomography result). The genetic analysis did not confirm WFS syndrome in the boy but identified a single likely pathogenic de novo variant in the WFS1 gene, which confirmed WFS-like syndrome. CONCLUSIONS: Currently, the patient is under the care of an endocrinologist, diabetologist, ophthalmologist, audiologist, and also psychologist because of mood disorders.