Pärilike haiguste sünnieelne diagnostika: Downi sündroomi sõeluuring Eestis

Eestis on loote kromosoomihaiguste sõeluuringut (rasedate vereseerumi biokeemiliste markerite määramine II trimestril) tehtud vanuseriski tõttu 8 aastat (1995–2002). Selle tulemusel on Downi sündroomiga laste sünnisagedus vähenenud. Riskigrupi selgitamiseks mõeldud skriiningprogrammide laialdasem rakendamine II trimestril ja ultraheliskriiningu juurutamine I trimestril võimaldaks kromosoomihaigustega laste sünnisagedust veelgi vähendada. Eesti Arst 2003; 82 (3): 192–19

Loote kromosoomhaiguste esimese trimestri sõeluuringu tulemused Eestis kahe aasta jooksul

Taust ja eesmärgid. Loote kromosoomhaiguste avastamiseks on Eestis alates 1995. aastast kasutatud erinevaid sõeluuringuid. 2016. aastast kehtinud sünnieelse diagnostika juhendi kohaselt on esimese trimestri kombineeritud sõeluuring kuni praeguseni olnud esmane sünnieelne kromosoomhaiguste sõeluuring. Käesoleva töö eesmärk oli hinnata esimese trimestri kombineeritud sõeluuringu efektiivsust kromosoomhaiguste avastamisel kaheaastase (2017–2018) uuringu alusel.Metoodika. Uuriti rasedaid, kes pöördusid kromosoomhaiguste sõeluuringuks Ida-Tallinna Keskhaiglasse (ITK) või Tartu Ülikooli (TÜ) Kliinikumi. Sõeluuring tehti Eesti sünnieelse diagnostika juhendi standardiseeritud protokolli alusel.Tulemused. Kombineeritud sõeluuring tehti 14 566 rasedal. Sõeltest oli positiivne 3,54%-l naistest. Trisoomia 21 avastamise määr sünni eel oli 94% (95% usaldusvahemik (uv) 84,09–97,98%), trisoomia 18 (95% uv 74,12–100%) ja trisoomia 13 avastati 100% (95% uv 43,85–100%). Valepositiivsuse määr oli 3,12%. Sõeluuringu tundlikkus oli 95,38% (95% uv 86,24–98,80%), spetsiifilisus 96,86% (95% uv 96,56–97,13%), positiivne ennustatav väärtus 11,99% (95% uv 9,38–15,18%), negatiivne ennustatav väärtus 99,97% (95% uv 99,93–99,99%).Järeldused. Esimese trimestri kombineeritud sõeluuring on efektiivne meetod kromosoomhaiguste sünnieelseks avastamiseks. Trisoomia 21 avastamise määr on suurem võrreldes eelmise Eestis korraldatud uuringu tulemustega. Üleminek esimese trimestri kombineeritud sõeluuringule oli Eestis õigustatud.Uuringuks on andnud loa Tartu Ülikooli inimuuringute eetika komitee (protokoll 263/M-19 17.10.2016)

Detection of a balanced translocation carrier through trophectoderm biopsy analysis: a case report

Balanced translocation carriers are burdened with fertility issues due to improper chromosome segregation in gametes, resulting in either implantation failure, miscarriage or birth of a child with chromosomal disorders. At the same time, these individuals are typically healthy with no signs of developmental problems, hence they often are unaware of their condition. Yet, because of difficulties in conceiving, balanced translocation carriers often turn to assisted reproduction, some of whom may also undergo preimplantation genetic testing for aneuploidy (PGT-A) to improve the likelihood of achieving a successful pregnancy.Peer reviewe

Genome sequencing identifies a homozygous inversion disrupting QDPR as a cause for dihydropteridine reductase deficiency

Background: Dihydropteridine reductase (DHPR) is one of the key enzymes for maintaining in the organism the supply of tetrahydrobiopterin (BH4 ), an essential cofactor for aromatic amino acid hydroxylases. Its dysfunction causes the condition of hyperphenylalaninemia together with the lack of neurotransmitters. Methods: We report a patient with biochemically diagnosed DHPR deficiency, with extensive molecular investigations undertaken to detect variations in quinoid dihydropteridine reductase (QDPR) gene. Sanger sequencing of QDPR coding regions, exome sequencing, QDPR mRNA PCR, and karyotyping were followed by trio genome sequencing. Results: Short-read genome sequencing revealed a homozygous 9-Mb inversion disrupting QDPR. Structural variant breakpoints in chromosome 4 were located to intron 2 of QDPR at Chr4(GRCh38):g.17505522 and in intron 8 of the ACOX3 gene, Chr4(GRCh38):g.8398067). Both nonrelated parents carried the variant in heterozygous state. The inversion was not present in gnomAD structural variant database. Conclusion: Identification of the exact breakpoints now allows further straightforward molecular genetic testing of potential carriers of the inversion. This study extends the pathogenic variant spectrum of DHPR deficiency and highlights the role of structural variants in recessive metabolic disorders. To our knowledge, this is the first report on a large, canonical (rather than complex) homozygous pathogenic inversion detected by genome sequencing. Keywords: QDPR gene; dihydropteridine reductase deficiency; genome sequencing; inversion; tetrahydrobiopterin deficiencies

Distinct Nuclear Organization of Telomeres and Centromeres in Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma

Both multiple myeloma (MM) and its precursor state of monoclonal gammopathy of undetermined significance (MGUS) are characterized by an infiltration of plasma cells into the bone marrow, but the mechanisms underlying the disease progression remain poorly understood. Previous research has indicated that 3D nuclear telomeric and centromeric organization may represent important structural indicators for numerous malignancies. Here we corroborate with previously noted differences in the 3D telomeric architecture and report that modifications in the nuclear distribution of centromeres may serve as a novel structural marker with potential to distinguish MM from MGUS. Our findings improve the current characterization of the two disease stages, providing two structural indicators that may become altered in the progression of MGUS to MM

Telomere Architecture Correlates with Aggressiveness in Multiple Myeloma

The prognosis of multiple myeloma (MM), an incurable B-cell malignancy, has significantly improved through the introduction of novel therapeutic modalities. Myeloma prognosis is essentially determined by cytogenetics, both at diagnosis and at disease progression. However, for a large cohort of patients, cytogenetic analysis is not always available. In addition, myeloma patients with favorable cytogenetics can display an aggressive clinical course. Therefore, it is necessary to develop additional prognostic and predictive markers for this disease to allow for patient risk stratification and personalized clinical decision-making. Genomic instability is a prominent characteristic in MM, and we have previously shown that the three-dimensional (3D) nuclear organization of telomeres is a marker of both genomic instability and genetic heterogeneity in myeloma. In this study, we compared in a longitudinal prospective study blindly the 3D telomeric profiles from bone marrow samples of 214 initially treatment-naïve patients with either monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or MM, with a minimum follow-up of 5 years. Here, we report distinctive 3D telomeric profiles correlating with disease aggressiveness and patient response to treatment in MM patients, and also distinctive 3D telomeric profiles for disease progression in smoldering multiple myeloma patients. In particular, lower average intensity (telomere length, below 13,500 arbitrary units) and increased number of telomere aggregates are associated with shorter survival and could be used as a prognostic factor to identify high-risk SMM and MM patients.Medicine, Faculty ofNon UBCMedicine, Department ofReviewedFacult

Genetic Subtypes and Outcome of Patients Aged 1 to 45 Years Old With Acute Lymphoblastic Leukemia in the NOPHO ALL2008 Trial

Peer reviewe