Journal/Magazine Articles

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This collection contains original research articles, review articles and case reports published in local and international peer reviewed journals by the staff members of the Faculty of Medicine

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Author: search.filters.author.de Silva, D.

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    RB1 screening of retinoblastoma patients in Sri Lanka using targeted next generation sequencing (NGS) and gene ratio analysis copy enumeration PCR (GRACE-PCR)
    (BioMed Central, 2023) Kugalingam, N.; de Silva, D.; Abeysekera, H.; Nanayakkara, S.; Tirimanne, S.; Ranaweera, D.; Suravajhala, P.; Chandrasekharan, V.
    BACKGROUND: Retinoblastoma (RB) a tumour affecting those under 5 years, has a prevalence of 1 in 20,000, with around twenty new diagnoses per year in Sri Lanka. Unilateral and bilateral RB presents around 24 and 15 months respectively. Approximately 10% are familial. Systematic genetic testing for germline pathogenic variants of RB1, the only gene associated with an inherited risk of RB, is unavailable in Sri Lanka. Genetic testing optimizes management of affected children and at-risk siblings. This study aimed to develop accessible genetic testing to identify children with a germline pathogenic variant of RB1 in Sri Lanka. METHODS: Targeted next generation sequencing (NGS) for detecting pathogenic sequence variants and Gene Ratio Analysis Copy Enumeration PCR (GRACE-PCR) for detecting RB1 copy number variations (CNVs) were performed for 49 consecutive RB patients treated between 2016 and 2020 at the designated RB care unit, Lady Ridgway hospital, Colombo. Patients (bilateral RB (n = 18; 37%), unilateral n = 31) were recruited following ethical clearance and informed consent. RESULTS: There were 26 (53%) females. Mean age at diagnosis was 18 months. Thirty-five patients (71%) had undergone enucleation. Germline pathogenic variants of RB1 identified in 22/49 (45%) patients including 18 (37%; 12 bilateral and 6 unilateral) detected by targeted NGS (2 missense, 7 stop gained, 1 splice donor, 8 frameshift variants). Six were previously undescribed, likely pathogenic frameshift variants. Four bilateral RB patients had GRACE-PCR detected CNVs including one whole RB1, two intragenic deletions (exon 12/13; exon 11 and 23) and a partial duplication of exon 27. The only familial case (affected mother and child) shared the duplication. Only 2 of 4 CNVs and 10 of 18 pathogenic variants were confirmed by whole exome sequencing and Sanger sequencing respectively, due to funding limitations. CONCLUSIONS: The study identified pathogenic or likely pathogenic germline RB1 sequence variants and copy number variants in 16/18 (89%) bilateral and 6/31(19%) unilateral cases, which is comparable to worldwide data (10-15% unilateral, 80-85% bilateral). Targeted NGS combined with GRACE-PCR significantly reduce the cost of RB1 testing in Sri Lanka, and may widen access for genetic diagnosis of RB patients in other low and middle income countries.
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    Human resources for health in Sri Lanka over the post-independence period: key issues
    (Sri Lanka Medical Association, 2023) de Silva, D.; Chandratilake, M.; de Silva, N.
    No abstract available
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    Arterial tortuosity syndrome: A rare inherited form of connective tissue disorder with SLR2A10 gene mutation
    (Sri Lanka College of Paediatricians, 2022) Wijesinghe, S.; de Silva, D.; Samarasinghe, D.; Irugalbandara, S.
    No abstract available
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    Nail-patella syndrome: Clinical importance of diagnosis
    (Sri Lanka College of Paediatricians, 2021) Kaleel, F.; Gunasekera, R.; de Silva, D.
    No abstract available
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    Correction:Arterial tortuosity syndrome: 40 new families and literature review
    (Nature Publishing Group, 2019) Beyens, A.; Albuisson, J.; Boel, A.; Al-Essa, M.; Al-Manea, W.; Bonnet, D.; Bostan, O.; Boute, O.; Busa, T.; Chanham, N.; Cil, E.; Couke, P.J.; Cousin, M.A.; Dasouki, M.; Da Backer, J.; De Paepe, A.; de Schepper, S.; de Silva, D.; Devriendt, K.; De Wandele, I.; Deyle, D.R.; Dietz, H.; Dupuis-Giroid, S.; Fontenot, E.; Fischer-Zirnsak, B.; Gezdirici, A.; Ghoumid, J.; Giuliano, F.; Baena, N.; Haider, M.Z.; Hardin, J.S.; Jeunemaitre, X.; Klee, E.W.; Kornak, U.; Landecho, M.F.; Legrand, A.; Loeys, B.; Lyonnet, S.; Michael, H.; Moceri, P.; Mohammed, S.; Muino-Mosquera, L.; Nampoothiri, S.; Picher, K.; Prescott, K.; Rajeb, A.; Ramos-Arroyo, M.; Rossi, M.; Salih, M.; Seidahmed, M.Z.; Schaefer, E.; Steichen-Gersdorf, E.; Temel, S.; Uysal, F.; Vanhomwegen, M.; Van Laer, L.; Van Maldergem, L.; Warner, D.; Willaert, A.; Collins, T.R.; Taylor, A.; Davis, E.C.; Zarate, Y.; Callewaert, B.
    In the published version of this paper the author Neus Baena's name was incorrectly given as Neus Baena Diez. This has now been corrected in both the HTML and PDF versions of the paper. Erratum for:Arterial tortuosity syndrome: 40 new families and literature review. Beyens A. et al. [Genet Med. 2018;20(10):1236-1245. doi: 10.1038/gim.2017.253] .
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    Confirmation of mosaic trisomy 22 in an infant with failure to thrive
    (Sri Lanka College of Paediatricians, 2018) Dayasiri, K.C.; de Silva, D.; Weerasekara, K.
    No Abstract available
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    Characteristic dental pattern with hypodontia and short roots in Fraser Syndrome
    (Wiley-Liss, 2020) Kunz, F.; Kayserili, H.; Midro, A.; de Silva, D.; Basnayake, S.; Güven, Y.; Borys, J.; Schanze, D.; Stellzig-Eisenhauer, A.; Bloch-Zupan, A.; Zenker, M.
    ABSTRACT:Fraser syndrome (FS) is a rare autosomal recessive multiple congenital malformation syndrome characterized by cryptophthalmos, cutaneous syndactyly, renal agenesis, ambiguous genitalia, and laryngotracheal anomalies. It is caused by biallelic mutations of FRAS1, FREM2, and GRIP1 genes, encoding components of a protein complex that mediates embryonic epithelial-mesenchymal interactions. Anecdotal reports have described abnormal orodental findings in FS, but no study has as yet addressed the orodental findings of FS systematically. We reviewed dental radiographs of 10 unrelated patients with FS of different genetic etiologies. Dental anomalies were present in all patients with FS and included hypodontia, dental crowding, medial diastema, and retained teeth. A very consistent pattern of shortened dental roots of most permanent teeth as well as altered length/width ratio with shortened dental crowns of upper incisors was also identified. These findings suggest that the FRAS1-FREM complex mediates critical mesenchymal-epithelial interactions during dental crown and root development. The orodental findings of FS reported herein represent a previously underestimated manifestation of the disorder with significant impact on orodental health for affected individuals. Integration of dentists and orthodontists into the multidisciplinary team for management of FS is therefore recommended. KEYWORDS: Fraser syndrome; dental roots; hypodontia; orodental health; taurodontism.
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    Gillespie syndrome in a South Asian child: a case report with confirmation of a heterozygous mutation of the ITPR1 gene and review of the clinical and molecular features
    (BioMed Central, 2018) de Silva, D.; Williamson, K.A.; Dayasiri, K.C.; Suraweera, N.; Quinters, V.; Abeysekara, H.; Wanigasinghe, J.; de Silva, D.; de Silva, H.
    BACKGROUND: Gillespie syndrome is a rare, congenital, neurological disorder characterized by the association of partial bilateral aniridia, non-progressive cerebellar ataxia and intellectual disability. Homozygous and heterozygous pathogenic variants of the ITPR1 gene encoding an inositol 1, 4, 5- triphosphate- responsive calcium channel have been identified in 13 patients recently. There have been 22 cases reported in the literature by 2016, mostly from the western hemisphere with none reported from Sri Lanka. CASE PRESENTATION: A 10-year-old girl born to healthy non-consanguineous parents with delayed development is described. She started walking unaided by 9 years with a significantly unsteady gait and her speech was similarly delayed. Physical examination revealed multiple cerebellar signs. Slit lamp examination of eyes revealed bilateral partial aniridia. Magnetic resonance imaging of brain at the age of 10 years revealed cerebellar (mainly vermian) hypoplasia. Genetic testing confirmed the clinical suspicion and demonstrated a heterozygous pathogenic variant c.7786_7788delAAG p.(Lys2596del) in the ITPR1 gene. CONCLUSION: The report of this child with molecular confirmation of Gillespie syndrome highlights the need for careful evaluation of ophthalmological and neurological features in patients that enables correct clinical diagnosis. The availability of genetic testing enables more accurate counseling of the parents and patients regarding recurrence risks to other family members.
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    Arterial tortuosity syndrome: 40 new families and literature review
    (Nature Publishing Group, 2018) Beyens, A.; Albuisson, J.; Boel, A.; Al-Essa, M.; Al-Manea, W.; Bonnet, D.; Bostan, O.; Boute, O.; Busa, T.; Chanham, ,N.; Cil, E.; Couke, P.J.; Cousin, M.A.; Dasouki, M.; Da Backer, J.; De Paepe, A.; de Schepper, S.; de Silva, D.; Devriendt, K.; De Wandele, I.; Deyle, D.R.; Dietz, H.; Dupuis-Giroid, S.; Fontenot, E.; Fischer-Zirnsak, B.; Gezdirici, A.; Ghoumid, J.; Giuliano, F.; Baena, N; Haider, M.Z.; Hardin, J.S.; Jeunemaitre, X.; Klee, E.W.; Kornak, U.; Landecho, M.F.; Legrand, A.; Loeys, B.; Lyonnet, S.; Michael, H.; Moceri, P.; Mohammed, S.; Muino-Mosquera, L.; Nampoothiri, S.; Picher, K.; Prescott, k.; Rajeb, A.; Ramos-Arroyo, M.; Rossi, M.; Salih, M.; Seidahmed, M.Z.; Schaefer, E.; Steichen-Gersdorf, E.; Temel, S.; Uysal, F.; Vanhomwegen, M.; Van Laer, L.; Van Maldergem, L.; Warner, D.; Willaert, A.; Collins, T.R.; Taylor, A.; Davis, E.C.; Zarate, Y.; Callewaert, B.
    PurposeWe delineate the clinical spectrum and describe the histology in arterial tortuosity syndrome (ATS), a rare connective tissue disorder characterized by tortuosity of the large and medium-sized arteries, caused by mutations in SLC2A10.MethodsWe retrospectively characterized 40 novel ATS families (50 patients) and reviewed the 52 previously reported patients. We performed histology and electron microscopy (EM) on skin and vascular biopsies and evaluated TGF-β signaling with immunohistochemistry for pSMAD2 and CTGF.ResultsStenoses, tortuosity, and aneurysm formation are widespread occurrences. Severe but rare vascular complications include early and aggressive aortic root aneurysms, neonatal intracranial bleeding, ischemic stroke, and gastric perforation. Thus far, no reports unequivocally document vascular dissections or ruptures. Of note, diaphragmatic hernia and infant respiratory distress syndrome (IRDS) are frequently observed. Skin and vascular biopsies show fragmented elastic fibers (EF) and increased collagen deposition. EM of skin EF shows a fragmented elastin core and a peripheral mantle of microfibrils of random directionality. Skin and end-stage diseased vascular tissue do not indicate increased TGF-β signaling.ConclusionOur findings warrant attention for IRDS and diaphragmatic hernia, close monitoring of the aortic root early in life, and extensive vascular imaging afterwards. EM on skin biopsies shows disease-specific abnormalities. In the published version of this paper the author Neus Baena's name was incorrectly given as Neus Baena Diez. This has now been corrected in both the HTML and PDF versions of the paper.(Baena N)Genetics in Medicine 2018; Sep 10
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    Noncoding copy-number variations are associated with congenital limb malformation
    (Nature Publishing Group, 2018) Flöttmann, R.; Kragesteen, B.K.; Geuer, S.; Socha, M.; Allou, L.; Sowińska-Seidler, A.; Bosquillon de Jarcy, L.; Wagner, J.; Jamsheer, A.; Oehl-Jaschkowitz, B.; Wittler, L.; de Silva, D.; Kurth, I.; Maya, I.; Santos-Simarro, F.; Hülsemann, W.; Klopocki, E.; Mountford, R.; Fryer, A.; Borck, G.; Horn, D.; Lapunzina, P.; Wilson, M.; Mascrez, B.; Duboule, D.; Mundlos, S.; Spielmann, M.
    PurposeCopy-number variants (CNVs) are generally interpreted by linking the effects of gene dosage with phenotypes. The clinical interpretation of noncoding CNVs remains challenging. We investigated the percentage of disease-associated CNVs in patients with congenital limb malformations that affect noncoding cis-regulatory sequences versus genes sensitive to gene dosage effects.MethodsWe applied high-resolution copy-number analysis to 340 unrelated individuals with isolated limb malformation. To investigate novel candidate CNVs, we re-engineered human CNVs in mice using clustered regularly interspaced short palindromic repeats (CRISPR)-based genome editing.ResultsOf the individuals studied, 10% harbored CNVs segregating with the phenotype in the affected families. We identified 31 CNVs previously associated with congenital limb malformations and four novel candidate CNVs. Most of the disease-associated CNVs (57%) affected the noncoding cis-regulatory genome, while only 43% included a known disease gene and were likely to result from gene dosage effects. In transgenic mice harboring four novel candidate CNVs, we observed altered gene expression in all cases, indicating that the CNVs had a regulatory effect either by changing the enhancer dosage or altering the topological associating domain architecture of the genome.Conclusion:Our findings suggest that CNVs affecting noncoding regulatory elements are a major cause of congenital limb malformations.