Rare copy-number variants as modulators of common disease susceptibility.

BACKGROUND: Copy-number variations (CNVs) have been associated with rare and debilitating genomic disorders (GDs) but their impact on health later in life in the general population remains poorly described. METHODS: Assessing four modes of CNV action, we performed genome-wide association scans (GWASs) between the copy-number of CNV-proxy probes and 60 curated ICD-10 based clinical diagnoses in 331,522 unrelated white British UK Biobank (UKBB) participants with replication in the Estonian Biobank. RESULTS: We identified 73 signals involving 40 diseases, all of which indicating that CNVs increased disease risk and caused earlier onset. We estimated that 16% of these associations are indirect, acting by increasing body mass index (BMI). Signals mapped to 45 unique, non-overlapping regions, nine of which being linked to known GDs. Number and identity of genes affected by CNVs modulated their pathogenicity, with many associations being supported by colocalization with both common and rare single-nucleotide variant association signals. Dissection of association signals provided insights into the epidemiology of known gene-disease pairs (e.g., deletions in BRCA1 and LDLR increased risk for ovarian cancer and ischemic heart disease, respectively), clarified dosage mechanisms of action (e.g., both increased and decreased dosage of 17q12 impacted renal health), and identified putative causal genes (e.g., ABCC6 for kidney stones). Characterization of the pleiotropic pathological consequences of recurrent CNVs at 15q13, 16p13.11, 16p12.2, and 22q11.2 in adulthood indicated variable expressivity of these regions and the involvement of multiple genes. Finally, we show that while the total burden of rare CNVs-and especially deletions-strongly associated with disease risk, it only accounted for ~ 0.02% of the UKBB disease burden. These associations are mainly driven by CNVs at known GD CNV regions, whose pleiotropic effect on common diseases was broader than anticipated by our CNV-GWAS. CONCLUSIONS: Our results shed light on the prominent role of rare CNVs in determining common disease susceptibility within the general population and provide actionable insights for anticipating later-onset comorbidities in carriers of recurrent CNVs.

The estimated prevalence of antiphospholipid antibodies and criteria-antiphospholipid syndrome in subjects with renal thrombotic microangiopathy.

BACKGROUND: While the prevalence of antiphospholipid antibodies (aPL) in venous and arterial thrombotic events had already been estimated by previous studies, the prevalence of aPL in subjects with Thrombotic Microangiopathy (TMA) is still not fully elucidated. Thus, we conducted a systematic review to estimate the frequency of aPL in subjects with biopsy-proven renal TMA. METHODS: We conducted in the PubMed database a search for English-language studies investigating the presence of aPL in subjects with biopsy-proven renal TMA from January 1985 to December 2022. Keywords used in the search included: 'antiphospholipid syndrome', 'antiphospholipid antibodies' and 'thrombotic microangiopathy'. Cohorts of HUS patients were excluded due to the risk of over-estimating the prevalence of aPL in these populations. The median frequency for positive aPL including anticardiolipin antibodies (aCL), antibodies against ß2-glycoprotein-I (anti-ß2GPI) and lupus anticoagulant (LA) was then calculated. RESULTS: 522 articles were identified through the literature search. Six studies, assessing the prevalence of aPL in 211 subjects with renal TMA, were retrieved. The overall aPL prevalence was estimated as 24.4% (range 22-56). The estimated prevalence of aCL (IgG/IgM), anti-ß2GPI, (IgG/IgM) and LA was 4.0% (range 3-27), 4.0% (range 3-16) and 18.9% (range 13-25), respectively. APS was diagnosed in 16.3% (range 11-29) of the patients. Of note, a high level of heterogeneity was observed when comparing the reported aPL profiles for each study. CONCLUSIONS: This comprehensive systematic analysis of studies investigating the prevalence of aPL in renal TMA showed that, despite the high heterogeneity of the included studies, aPL are present in about one case out of four renal-TMA cases.

Molecular Basis and Genetic Modifiers of Thalassemia.

Thalassemia syndromes are common monogenic disorders and represent a significant health issue worldwide. In this review, the authors elaborate on fundamental genetic knowledge about thalassemias, including the structure and location of globin genes, the production of hemoglobin during development, the molecular lesions causing α-, ß-, and other thalassemia syndromes, the genotype-phenotype correlation, and the genetic modifiers of these conditions. In addition, they briefly discuss the molecular techniques applied for diagnosis and innovative cell and gene therapy strategies to cure these conditions.

Integrated approaches for precision oncology in colorectal cancer: The more you know, the better.

Colorectal cancer (CRC) is one of the most common human malignancies accounting for approximately 10 % of worldwide cancer incidence and mortality. While early-stage CRC is mainly a preventable and curable disease, metastatic colorectal cancer (mCRC) remains an unmet clinical need. Moreover, about 25 % of CRC cases are diagnosed only at the metastatic stage. Despite the extensive molecular and functional knowledge on this disease, systemic therapy for mCRC still relies on traditional 5-fluorouracil (5-FU)-based chemotherapy regimens. On the other hand, targeted therapies and immunotherapy have shown effectiveness only in a limited subset of patients. For these reasons, there is a growing need to define the molecular and biological landscape of individual patients to implement novel, rationally driven, tailored therapies. In this review, we explore current and emerging approaches for CRC management such as genomic, transcriptomic and metabolomic analysis, the use of liquid biopsies and the implementation of patients' preclinical avatars. In particular, we discuss the contribution of each of these tools in elucidating patient specific features, with the aim of improving our ability in advancing the diagnosis and treatment of colorectal tumors.