Medicine
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This repository contains the published and unpublished research of the Faculty of Medicine by the staff members of the faculty
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Item Genome sequencing in families with congenital limb malformations(Springer-Verlag., 2021) Elsner, J.; Mensah, M.A.; Holtgrewe, M.; Hertzberg, J.; Bigoni, S.; Busche, A.; Coutelier, M.; de Silva, D.C.; Elçioglu, N.; Filges, I.; Gerkes, E.; Girisha, K.M.; Graul-Neumann, L.; Jamsheer, A.; Krawitz, P.; Kurth, I.; Markus, S.; Megarbane, A.; Reis, A.; Reuter, M.S.; Svoboda, D.; Teller, C.; Tuysuz, B.; Türkmen, S.; Wilson, M.; Woitschach, R.; Vater, I.; Caliebe, A.; Hülsemann, W.; Horn, D.; Mundlos, S.; Spielmann, M.ABSTRACT: The extensive clinical and genetic heterogeneity of congenital limb malformation calls for comprehensive genome-wide analysis of genetic variation. Genome sequencing (GS) has the potential to identify all genetic variants. Here we aim to determine the diagnostic potential of GS as a comprehensive one-test-for-all strategy in a cohort of undiagnosed patients with congenital limb malformations. We collected 69 cases (64 trios, 1 duo, 5 singletons) with congenital limb malformations with no molecular diagnosis after standard clinical genetic testing and performed genome sequencing. We also developed a framework to identify potential noncoding pathogenic variants. We identified likely pathogenic/disease-associated variants in 12 cases (17.4%) including four in known disease genes, and one repeat expansion in HOXD13. In three unrelated cases with ectrodactyly, we identified likely pathogenic variants in UBA2, establishing it as a novel disease gene. In addition, we found two complex structural variants (3%). We also identified likely causative variants in three novel high confidence candidate genes. We were not able to identify any noncoding variants. GS is a powerful strategy to identify all types of genomic variants associated with congenital limb malformation, including repeat expansions and complex structural variants missed by standard diagnostic approaches. In this cohort, no causative noncoding SNVs could be identified.Item Biallelic variants in DNA2 cause microcephalic primordial dwarfism.(Wiley-Liss, 2019) Tarnauskaitė, Z.; Bicknell, L.S.; Marsh, J.A.; Murray, J.E.; Parry, D.A.; Logan, C.V.; Bober, M.B.; de Silva, D.C.; Duker, A.L.; Sillence, D.; Wise, C.; Jackson, A.P.; Murina, O.; Reijns, M.A.M.Microcephalic primordial dwarfism (MPD) is a group of rare single-gene disorders characterised by extreme reduction in brain and body size from early development onwards. Proteins encoded by MPD-associated genes play important roles in fundamental cellular processes, notably genome replication and repair. Here we report identification of four MPD individuals with biallelic variants in DNA2, which encodes an ATP-dependent helicase/nuclease involved in DNA replication and repair. We demonstrate that the two intronic variants (c.1764-38_1764-37ins(53) and c.74+4A>C) found in these individuals substantially impair DNA2 transcript splicing. Additionally we identify a missense variant (c.1963A>G), affecting a residue of the ATP-dependent helicase domain that is highly conserved between humans and yeast, with the resulting substitution (p.Thr655Ala) predicted to directly impact ATP/ADP binding by DNA2. Our findings support pathogenicity of these variants as biallelic hypomorphic mutations, establishing DNA2 as an MPD-disease gene. This article is protected by copyright. All rights reserved.Item Soto syndrome: a rare overgrowth disorder(Sri Lanka Medical Association, 2013) de Silva, D.C.; de Leeuw, N.; Gunasekera, R.This is a case report of a boy with an overgrowth syndrome called Soto syndrome (cerebral gigantism).