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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Item 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.Item 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 availableItem Nail-patella syndrome: Clinical importance of diagnosis(Sri Lanka College of Paediatricians, 2021) Kaleel, F.; Gunasekera, R.; de Silva, D.No abstract availableItem 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 availableItem 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.Item 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.Item Effectiveness of household lockable pesticide storage to reduce pesticide self-poisoning in rural Asia: a community-based, cluster-randomised controlled trial(London : J. Onwhyn, 2017) Pearson, M.; Metcalfe, C.; Jayamanne, S.; Gunnell, D.; Weerasinghe, M.; Pieris, R.; Priyadarshana, C.; Knipe, D.W.; Hawton, K.; Dawson, A.H.; Bandara, P.; de Silva, D.; Gawarammana, I.; Eddleston, M.; Konradsen, F.BACKGROUND: Agricultural pesticide self-poisoning is a major public health problem in rural Asia. The use of safer household pesticidestorage has been promoted to prevent deaths, but there is no evidence of effectiveness. We aimed to test the effectiveness of lockablehousehold containers for prevention of pesticide self-poisoning. METHODS: We did a community-based, cluster-randomised controlled trial in a rural area of North Central Province, Sri Lanka. Clusters of households were randomly assigned (1:1), with a sequence computer-generated by a minimisation process, to intervention or usual practice (control) groups. Intervention households that had farmed or had used or stored pesticide in the preceding agricultural season were given a lockable storage container. Further promotion of use of the containers was restricted to community posters and 6-monthly reminders during routine community meetings. The primary outcome was incidence of pesticide self-poisoning in people aged 14 years or older during 3 years of follow-up. Identification of outcome events was done by staff who were unaware of group allocation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT1146496. FINDINGS: Between Dec 31, 2010, and Feb 2, 2013, we randomly assigned 90 rural villages to the intervention group and 90 to the control group. 27 091 households (114 168 individuals) in the intervention group and 26 291 households (109 693 individuals) in the control group consented to participate. 20 457 household pesticide storage containers were distributed. In individuals aged 14 years or older, 611 cases of pesticide self-poisoning had occurred by 3 years in the intervention group compared with 641 cases in the control group; incidence of pesticide self-poisoning did not differ between groups (293·3 per 100 000 person-years of follow-up in the intervention group vs 318·0 per 100 000 in the control group; rate ratio [RR] 0·93, 95% CI 0·80-1·08; p=0·33). We found no evidence of switching from pesticide self-poisoning to other forms of self-harm, with no significant difference in the number of fatal (82 in the intervention group vs 67 in the control group; RR 1·22, 0·88-1·68]) or non-fatal (1135 vs 1153; RR 0·97, 0·86-1·08) self-harm events involving all methods. INTERPRETATION: We found no evidence that means reduction through improved household pesticide storage reduces pesticide self-poisoning. Other approaches, particularly removal of highly hazardous pesticides from agricultural practice, are likely to be more effective for suicide prevention in rural Asia. FUNDING: Wellcome Trust, with additional support from the American Foundation for Suicide Prevention, Lister Institute of Preventive Medicine, Chief Scientist Office of Scotland, University of Copenhagen, and NHMRC Australia.Item Exploring the genetic basis of 3MC syndrome: Findings in 12 further families:(Wiley-Blackwell, 2016) Urquhart, J.; Roberts, R.; de Silva, D.; Shalev, S.; Chervinsky, E.; Nampoothiri, S.; Sznajer, Y.; Revencu, N.; Gunasekera, R.; Suri, M.; Ellingford, J.; Williams, S.; Bhaskar, S.; Clayton-Smith, J.The 3MC syndromes are a group of rare autosomal recessive disorders where the main clinical features are cleft lip and palate, hypertelorism, highly arched eyebrows, caudal appendage, postnatal growth deficiency, and genitourinary tract anomalies. Ophthalmological abnormalities, most notably anterior chamber defects may also be seen. We describe the clinical and molecular findings in 13 individuals with suspected 3MC syndrome from 12 previously unreported families. The exclusion of the MASP1 and COLEC11 Loci in two individuals from different consanguineous families and the absence of mutations in four further individuals sequenced for both genes raises the possibility that that there is further genetic heterogeneity of 3MC syndrome. © 2016 Wiley Periodicals, Inc.