Browsing by Author "Mičule, Ieva"

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    Altered Splicing of LAMP2 in a Multigenerational Family from Latvia Affected by Danon Disease
    (2024-01) Stavusis, Janis; Mičule, Ieva; Grīnfelde, Ieva; Zdanovica, Anna; Pudulis, Janis; Valeina, Sandra; Sepetiene, Svetlana; Lace, Baiba; Inashkina, Inna
    Background and Objectives: Danon disease is a multisystemic disorder associated with variants in the LAMP2 gene, mainly affecting the cardiac muscle. Here, we report a multigenerational family from Latvia with two male patients, hemizygous for a novel splice-affecting variant c.928+3A>G. Affected patients exhibit a cardiac phenotype, moderate mental disability, and mild retinal changes. Materials and Methods: Both patients underwent either exome or hypertrophic cardiomyopathy gene panel next-generation sequencing. The pathogenic variant effect was determined using reverse transcription, Sanger sequencing, and high-resolution electrophoresis. Results: Evaluation of the splicing process revealed that approximately 80% of the transcripts exhibited a lack of the entire exon 7. This alteration was predicted to cause a shift of the reading frame, consequently introducing a premature stop codon downstream in the sequence. Conclusions: Based on our data, we propose that c.928+3A>G is a pathogenic variant associated with Danon disease.
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    Epilepsiju ģenētiskā diagnostika Latvijā
    (Rīgas Stradiņa universitāte, 2023) Mašinska, Madara; Mičule, Ieva; Rezidentūras studiju fakultāte; Faculty of Residency
    Mērķis: Iegūt raksturojumu par pārmantojamo epilepsiju ģenētisko struktūru Latvijā. Apraksts: Pētījums tika veikts BKUS Medicīnas ģenētikas un Prenatālās diagnostikas klīnikā un Neiroloģijas un Neiroķirurģijas klīnikā Metodes: Pacientu atlase - pacienti tika atlasīti slimnīcas iekšējā elektroniskajā sistēmā. Atlasē tika iekļauti dati par pacientiem ar ģenētisku sindromu un simptomu epilepsija, kas konsultēti BKUS no 01.01.2019. līdz 31.12.2021. Retrospektīvi tika izvērtētas ambulatorās kartes un elektroniski pieejamie aprūpes dati. Pacientu dati kodēti, piešķirot pacientiem identifikācijas numuru un kodētā veidā apkopoti Excel tabulā. Dati tiks uzglabāti ierobežotas pieejas (piekļuve tikai pētījuma vadītājam un pētniekiem) mapē BKUS serverī. Tika reģistrēti tādi pacientu dati kā – dzimums, vecums (slimības manifestācijas brīdī), atklātās ģenētiskās saslimšanas. Rezultāti: Pētījuma periodā BKUS tika reģistrēti 1196 bērni ar diagnozi epilepsija, no tiem 120 pacientiem (56 siev. un 64 vīr.) bija ģenētiska diagnoze, no tiem 81 monogēnas epilepsijas, 8 ar iedzimtiem vielmaiņas traucējumiem, 29 ar hromosomu aberācijām, 2 ar vairāk nekā vienu ģenētisku diagnozi. Visbiežāk sastopamā monogēnā epilepsija bija tuberozās sklerozes (21) izraisīta, otra biežākā patoloģija SCN1A (13) mutācija. Visbiežākās hromosomu aberācijas bija 15q11.2del (6) un 16p11.2del (4).
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    Impact of the genes UGT1A1, GSTT1, GSTM1, GSTA1, GSTP1 and NAT2 on acute alcohol-toxic hepatitis
    (2014-02) Piekuse, Linda; Lace, Baiba; Kreile, Madara; Sadovska, Lilite; Kempa, Inga; Daneberga, Zanda; Mičule, Ieva; Sondore, Valentina; Keiss, Jazeps; Krumina, Astrida; Scientific Laboratory of Molecular Genetics
    Alcohol metabolism causes cellular damage by changing the redox status of cells. In this study, we investigated the relationship between genetic markers in genes coding for enzymes involved in cellular redox stabilization and their potential role in the clinical outcome of acute alcohol-induced hepatitis. Study subjects comprised 60 patients with acute alcohol-induced hepatitis. The control group consisted of 122 healthy non-related individuals. Eight genetic markers of the genes UGT1A1, GSTA1, GSTP1, NAT2, GSTT1 and GSTM1 were genotyped. GSTT1 null genotype was identified as a risk allele for alcohol-toxic hepatitis progression (OR 2.146, P=0.013). It was also found to correlate negatively with the level of prothrombin (β= -11.05, P=0.037) and positively with hyaluronic acid (β=170.4, P=0.014). NAT2 gene alleles rs1799929 and rs1799930 showed opposing associations with the activity of the biochemical markers γ-glutamyltransferase and alkaline phosphatase; rs1799929 was negatively correlated with γ-glutamyltransferase (β=-261.3, P=0.018) and alkaline phosphatase (β= -270.5, P=0.032), whereas rs1799930 was positively correlated with Γ-glutamyltransferase (β=325.8, P=0.011) and alkaline phosphatase (β=374.8, P=0.011). Enzymes of the glutathione S-transferase family and NAT2 enzyme play an important role in the detoxification process in the liver and demonstrate an impact on the clinical outcome of acute alcohol-induced hepatitis.
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    Implication of Genetic Testing and Pregnancy Outcome in a Woman with Unbalanced Translocation t(1;6)
    (2022-02-22) Jurčenko, Marija; Auzenbaha, Madara; Mičule, Ieva; Grīnfelde, Ieva; Dzalbs, Aigars; Mālniece, Ieva; Department of Biology and Microbiology
    BACKGROUND Parental chromosomal structural abnormalities can lead to diverse chromosomal imbalances at meiotic segregation during gametogenesis and subsequent early pregnancy loss or birth of a child with a chromosomal abnormality. The incidence of unbalanced translocations is 1 per 1000 newborns versus 3 per 1000 newborns for balanced rearrangements. Here, we present the case of a mother with an unbalanced chromosomal translocation and her offspring. CASE REPORT Our patient had a 1p36.31 duplication of 0.22 Mb and 6qter deletion of 1.2 Mb. She had 5 pregnancies with different outcomes. Her first child died 24 h after birth due to a congenital heart defect. Her second pregnancy resulted in the birth of a girl who was postnatally diagnosed with 1p36 deletion syndrome. The third and fourth pregnancies ended spontaneously in the first trimester. For her last pregnancy, the patient underwent a diagnostic amniocentesis at the 16th week of gestation. A large 5.4-Mb pathogenic duplication of 1p36.33 was detected in the fetus and the woman decided to terminate the pregnancy. CONCLUSIONS In this case report, we detail the different pregnancy outcomes induced by the mother's unbalanced chromosomal translocation and review the prenatal diagnostic genetic testing. Our report clearly demonstrates the complementary nature of chromosomal microarrays and conventional karyotyping.
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    Newborn Screening for Spinal Muscular atrophy : first results of a Pilot Study in Latvia
    (2021) Kreile, Madara; Isakova, Jekaterina; Isakovs, Aleksejs; Konika, Maija; Mičule, Ieva; Diriks, Mikus; Gailīte, Linda; Scientific Laboratory of Molecular Genetics
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    The phenotypic spectrum of PTCD3 deficiency
    (2024-09) Lāce, Baiba; Faqeih, Eissa; Kaya, Namik; Krūmiņa, Zita; Mayr, Johannes A.; Mičule, Ieva; Wright, Nathan Thompson; Achleitner, Melanie T.; AlQudairy, Hanan; Pajusalu, Sander; Stavusis, Jānis; Zayakin, Pawel; Inashkina, Inna; Department of Biology and Microbiology
    The PTCD3 gene product (protein PTCD3 or MRPS39) forms the entry channel of the mitochondrial small ribosomal subunit and binds to single-stranded mRNA. Here, we expand on the clinical manifestations of PTCD3 pathogenic variants by describing an early-onset patient with Leigh-like syndrome and two patients with milder form of disease, with combined oxidative phosphorylation deficiency. A 34-year-old male and his 33-year-old sister both have horizontal nystagmus, pronounced rough tremor, truncal ataxia, dysmetria, spasticity and hyperreflexia. The basal respiration rate decreased significantly for the male patient and his mother (p < 0.0001) compared to the controls. The whole genome sequencing analysis revealed two heterozygous variants in the PTCD3: c.1182T>A, p.(Tyr394Ter) and c.805C>T, p.(His269Tyr). Tyr394Ter variant ablates the C-terminal half of the protein, including a significant portion of the central fold. In silico modelling for the variant His269Tyr shows that the inclusion of the slightly larger tyrosine sidechain is well tolerated, with no significant change in either the position or the movement of the surrounding area. The third case is a 9-year-old boy, who has a global developmental delay, central hypotonia, hyperreflexia and abnormal MRI. PTCD3 pathogenic variant c.538+4A>G was identified by whole exome sequencing. To test the variant's effect on splicing, an RT-PCR experiment was performed, which revealed skipping of an out-of-frame exon 7.
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    Phenotypic variability and diagnostic characteristics in inherited peripheral neuropathy in Latvia
    (2022) Millere, Elīna; Kupats, Einārs; Mičule, Ieva; Gailīte, Linda; Ķēniņa, Viktorija; Department of Paediatrics; Scientific Laboratory of Molecular Genetics; Department of Doctoral Studies; Department of Biology and Microbiology
    Inherited peripheral neuropathies (IPN) are a clinically and genetically heterogeneous group of disorders. The most common IPN is Charcot-Marie-Tooth (CMT) disease. Here we describe IPN clinical variability and diagnostic characteristics in the Latvian population. A total of 101 patients were enrolled in the study. Genetic testing consisted of PMP22 copy number analysis and whole-exome sequencing (WES). Clinical assessment comprised CMT Neuropathy Score version 2 (CMTNSv2), CMT Examination Score, pain, anxiety and memory/cognitive ability testing. The diagnostic yields for PMP22 copy number detection and WES were 45.8% and 77.8%, respectively. Disease severity assessment indicated high clinical heterogeneity, with CMTNSv2 scores ranging between 0 and 33. More than one-third of patients reported pain, and it was found to be significantly more common in patients with at least a mild anxiety level. From the initial development of symptoms, on average, it took more than 13 years for a diagnosis of IPN to be confirmed. This study updates the IPN genetic and clinical profile of the Latvian population and demonstrates the presence of a high level of heterogeneity. The time to diagnosis for IPN patients needs to be improved by employing multiplex ligation-dependent probe amplification initially followed by WES.