https://www.um.edu.mt/library/oar/handle/123456789/814 2026-09-10T05:13:37Z https://www.um.edu.mt/library/oar/handle/123456789/148791 Title: Intrahepatic cholestasis of pregnancy : a single‐centre whole‐exome sequencing study in a Maltese cohort Authors: Spiteri, Dorianne; Grech, Laura; Savona-Ventura, Charles; Pace, Nikolai Paul Abstract: Intrahepatic cholestasis of pregnancy (ICP) has a multifactorial pathophysiology involving genetic, endocrine, and environmental factors. It is associated with maternal distress and adverse foetal outcomes. The monogenic aetiology of ICP remains unexplored in the Maltese population. We apply whole exome sequencing in 20 unrelated index cases to assess the molecular spectrum of variants in genes linked to bile acid transport. We shortlisted five unique heterozygous variants. Three ABCB4 variants, including a novel likely pathogenic stop-gain variant were detected. Three genealogically unrelated cases carried an ABCB4 p.Asn510Ser variant, suggestive of a founder through shared haplotype analysis. This study provides preliminary insight into the monogenic aetiology of ICP from an unstudied population. It expands the spectrum of genetic variants associated with ICP and provides evidence for a founder effect in the Maltese population. 2025-01-01T00:00:00Z https://www.um.edu.mt/library/oar/handle/123456789/148790 Title: Investigating the inflammatory link between vitamin D and hidradenitis suppurativa : a systematic review and causal inference analysis Authors: Spiteri, Jasmine; Grech, Laura; Mintoff, Dillon; Pace, Nikolai Paul Abstract: An inverse correlation between serum vitamin D levels and hidradenitis suppurativa (HS) severity is frequently reported, yet the causal nature and direction of this association remain unresolved. A systematic review was conducted following PRISMA guidelines, identifying 12 relevant studies. A two-sample Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW) method was subsequently performed using genetic instruments for vitamin D from the UK Biobank (n = 417,580) and HS summary statistics from FinnGen (n = 1420). The systematic review confirmed a high prevalence of vitamin D deficiency (<20 ng mL−1) among HS patients (weighted mean 17.90 ng mL−1) and identified inverse correlations between vitamin D levels and disease severity, active lesions, and C-reactive protein (CRP), while supplementation improved clinical outcomes. A null MR estimate consistent with the absence of a detectable average linear causal effect of lifelong genetically predicted 25(OH)D levels on HS risk in the analyzed population was observed. Sensitivity analyses yielded consistent null results with no significant horizontal pleiotropy. The results suggest that hypovitaminosis D is likely a marker of the systemic inflammatory state rather than a direct causative factor. The observed clinical benefits of vitamin D supplementation warrant further interventional studies to define its potential therapeutic role. 2026-01-01T00:00:00Z https://www.um.edu.mt/library/oar/handle/123456789/148788 Title: Rethinking scale in AI-driven genomic medicine – the role of small biobanks Authors: Grech, Laura; Pace, Nikolai Paul Abstract: Artificial intelligence is rapidly advancing genomic medicine, but its clinical trustworthiness cannot be secured by larger datasets alone. This perspective argues that small biobanks, including national, regional, hospital-linked and disease-focused collections provide essential stress tests for AI-driven genomic medicine because they expose failures in population calibration, rare-variant interpretation, phenotype realism, privacy protection, and governance. Rather than serving primarily as substrates for training general-purpose models, small biobanks are most valuable as environments for external validation, local calibration, interpretability, federated analysis, and accountable deployment. Their local representativeness, clinical linkage, and governance structures can help determine whether AI predictions remain valid and clinically useful outside the large datasets on which they were developed. Trustworthy AI-powered genomic medicine will therefore depend not only on larger models and larger datasets, but also on smaller, well-governed biobanks that force those models to prove their validity in real-world settings. 2026-01-01T00:00:00Z https://www.um.edu.mt/library/oar/handle/123456789/148787 Title: Frequency and spectrum of actionable secondary findings in the Maltese population Authors: Grech, Laura; Grech, Celine Ann; Spiteri, Jasmine; Mintoff, Dillon; Pace, Nikolai Paul Abstract: Background: The identification of actionable secondary findings (SFs) through clinical exome sequencing has become increasingly relevant with the integration of genomics into routine healthcare. The frequency and spectrum of these findings vary across populations.; Methods: We analyzed exome sequencing data from 350 unrelated Maltese individuals, comprising 320 pseudonymised controls and 30 participants from the pilot sequencing phase of the national biobank DwarnaBio, to assess the prevalence of pathogenic or likely pathogenic (P/LP) variants in the ACMG SF v3.2 gene list. All samples underwent uniform sequencing, rigorous quality control, and variant interpretation according to ACMG/AMP guidelines.; Results: Actionable P/LP variants were identified in 12 individuals (3.4%) across autosomal dominant genes, predominantly associated with inherited cardiac conditions and cancer predisposition syndromes. These findings highlight the importance of including underrepresented populations in genomic research and emphasize the need to establish provisions for the return of clinically actionable results to biobank participants, supported by access to genetic counseling.; Conclusion: Our results advocate for the integration of population-specific genomic data into national precision medicine frameworks, particularly for small or isolated populations where tailored approaches to variant curation and clinical translation are required. This study provides the first baseline estimate of actionable SFs in the Maltese population and offers insights for advancing precision medicine frameworks. 2025-01-01T00:00:00Z