RESUMO
Ganglioside-monosialic acid (GM1) gangliosidosis (ICD-10: E75.1; OMIM: 230500, 230600, 230650) is a rare autosomal recessive hereditary disease, lysosomal storage disorder caused by mutations in the GLB1 gene that lead to the absence or insufficiency of ß-galactosidase. In this study, we report a case of a Russian family with a history of GM1 gangliosidosis. The family had a child who, from the age of 6 months, experienced a gradual loss of developmental skills, marked by muscle flaccidity, psychomotor retardation, hepatosplenomegaly, and the onset of tonic seizures by the age of 8 months. Funduscopic examination revealed a «cherry red spot¼ in the macula, which is crucial for the diagnosis of lipid storage disorders. To find the pathogenic variants responsible for these clinical symptoms, the next-generation sequencing approach was used. The analysis revealed two variants in the heterozygous state: a frameshift variant c.699delG (rs1452318343, ClinVar ID 928700) in exon 6 and a missense variant c.809A>C (rs371546950, ClinVar ID 198727) in exon 8 of the GLB1 gene. The spouses were advised to plan the pregnancy with assisted reproductive technology (ART), followed by preimplantation genetic testing for monogenic disorder (PGT-M) on the embryos. Trophectoderm biopsy was performed on 8 out of 10 resulting embryos at the blastocyst stage. To perform PGT-M, we developed a novel testing system, allowing for direct analysis of disease-causing mutations, as well as haplotype analysis based on the study of polymorphic markers-short tandem repeats (STR), located upstream and downstream of the GLB1 gene. The results showed that four embryos were heterozygous carriers of pathogenic variants in the GLB1 gene (#1, 2, 5, 8). Two embryos had a compound heterozygous genotype (#3, 4), while the embryos #7 and 9 did not carry disease-causing alleles of the GLB1 gene. The embryo #7 without pathogenic variants was transferred after consideration of its morphology and growth rate. Prenatal diagnosis in the first trimester showed the absence of the variants analyzed in the GLB1 gene in the fetus. The pregnancy resulted in the delivery of a female infant who did not inherit the disease-causing variants in the GLB1 gene.
RESUMO
AIMS: To study the possible association of catechol-O-methyltransferase (COMT) Val158Met polymorphism with multiple and solitary uterine leiomyomas (ULs) and to check whether the COMT Val/Val genotype is associated with MED12 exon 2 mutations in fibroids. METHODS: The COMT Val158Met allele and genotype frequencies were compared between age-matched women with ULs (n=104) and controls (n=59). Patients with UL were subcategorised by diagnosis of solitary (n=59) or multiple (n=45) fibroids and by the presence of somatic MED12 exon 2 mutations in at least one fibroid (n=32) or in neither fibroid (n=26). The association of COMT Val/Val genotype with the presence of any ULs, solitary/multiple ULs and ULs positive/negative for MED12 exon 2 mutations was evaluated by χ2 tests using a dominant genotype model (G/G vs G/A+A/A) and expressed as ORs and 95% CIs. RESULTS: The COMT Val/Val genotype frequency did not differ between the patients with UL and the controls (28.8% vs 18.6%, p=0.149, OR 1.77; CI 0.81 to 3.86). However, it was significantly higher in the patients who had multiple UL compared with the solitary UL (40% vs 20.3%, p=0.028, OR 2.61; CI 1.09 to 6.24) and to the controls (40% vs 18.6%, p=0.016, OR 2.91; CI 1.20 to 7.06). No association of the COMT Val/Val genotype with UL-specific MED12 exon 2 mutations was found (p=0.662, OR 0.77; CI 0.23 to 2.53). CONCLUSIONS: Women with COMT Val/Val genotype are at high risk of developing multiple uterine fibroids either positive or negative for MED12 exon 2 mutations. These data are important to design new strategies for UL prophylaxis and treatment.
Assuntos
Catecol O-Metiltransferase/genética , Leiomioma/genética , Complexo Mediador/genética , Mutação , Polimorfismo de Nucleotídeo Único , Neoplasias Uterinas/genética , Adulto , Análise Mutacional de DNA , Éxons , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Pessoa de Meia-Idade , Adulto JovemRESUMO
Uterine leiomyomas (ULs) are common benign tumors affecting women of different ethnicities. A large proportion of UL has mutations in MED12. Multiple and solitary ULs usually manifest with different severities, suggesting that their origin and growth pattern may be driven by different molecular mechanisms. Here, we compared the frequency and the spectrum of MED12 exon 2 mutations between multiple (n=82) and solitary (n=40) ULs from Russian patients. Overall, we detected MED12 exon 2 mutations in 51.6% (63/122) of ULs. The frequency of MED12 exon 2 mutations was almost two-fold higher in samples from the multiple UL patients than in those from the solitary UL patients - 61% (50/82) versus 32.5% (13/40). The increased MED12 exon 2 mutation frequency in the multiple ULs was not accompanied by significant alterations in the spectrum of mutation categories, which included missense mutations, deletions, splicing defects, and multiple (double/triple) mutations. Each mutation category had a unique mutation set, comprising both frequent and rarely encountered mutations, which did and did not overlap between the studied groups, respectively. We conclude that in contrast to the solitary ULs, the multiple ULs predominantly originate through MED12-associated mechanisms. The nature of these mechanisms seems to be similar in solitary and multiple ULs, as they contain similar mutations. In multiple UL patients, they are likely to be nonsporadic, indicating the existence of specific factors predisposing to multiple UL development. These data suggest that to clearly understand UL pathogenesis, solitary and multiple tumors should probably be analyzed as separate sets.