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Cytogenetic Studies of Rwandan Pediatric Patients Presenting with Global Developmental Delay, Intellectual Disability And/Or Multiple

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Cytogenetic Studies of Rwandan Pediatric Patients Presenting with Global Developmental Delay, Intellectual Disability And/Or Multiple Journal of Tropical Pediatrics, 2016, 62, 38–45 doi: 10.1093/tropej/fmv065 Advance Access Publication Date: 27 October 2015 Original Paper Cytogenetic Studies of Rwandan Pediatric Patients Presenting with Global Developmental Delay, Intellectual Disability and/or Multiple Congenital Anomalies Downloaded from by Annette Uwineza,1,2 Janvier Hitayezu,1 Mauricette Jamar,2 Jean-Hubert Caberg,2 Seraphine Murorunkwere,1 1 2 1 Ndinkabandi Janvier, Vincent Bours, and Leon Mutesa http://tropej.oxfordjournals.org/ 1Center for Medical Genetics, College of Medicine and Health Sciences, University of Rwanda, Huye, Rwanda 2Center for Human Genetics, Centre Hospitalier Universitaire Sart-Tilman, University of Liege, Liege, Belgium Correspondence: Leon Mutesa, Center for Medical Genetics, College of Medicine and Health Sciences, University of Rwanda, Huye, Rwanda. Tel: (þ250) 788451013. E-mail <[email protected]> or <[email protected]> ABSTRACT Global developmental delay (GDD) is defined as a significant delay in two or more developmental at McMaster University Library on April 8, 2016 domains: gross or fine motor, speech/language, cognitive, social/personal and activities of daily liv- ing. Many of these children will go on to be diagnosed with intellectual disability (ID), which is most commonly defined as having an IQ <75 in addition to impairment in adaptive functioning. Cytogenetic studies have been performed in 664 Rwandan pediatric patients presenting GDD/ID and/or multiple congenital abnormalities (MCA). Karyotype analysis was performed in all patients and revealed 260 chromosomal abnormalities. The most frequent chromosomal abnormality was Down syndrome and then Edward syndrome and Patau syndrome. Other identified chromosomal abnormalities included 47,XX,þdel(9)(q11), 46,XY,del(13)(q34) and 46,XX,der(22)t(10;22) (p10;p10)mat. In conclusion, our results highlight the high frequency of cytogenetically detectable abnormalities in this series, with implications for the burden on the healthcare. This study demon- strates the importance of cytogenetic analysis in patients with GDD/ID and MCA. KEYWORDS: global developmental delay, intellectual disability, multiple congenital anomalies, karyotype, chromosomal abnormality, Rwandan pediatric patients INTRODUCTION motor, speech/language, cognitive, social/personal Global developmental delay and intellectual disabil- and activities of daily living [2]. Many of these ity (GDD/ID) are common clinical conditions and children would later be diagnosed with ID, which affect 1–3% of children worldwide [1]. is most commonly defined as having an IQ <75 GDD is defined as significant delay in two in addition to impairment in adaptive functioning or more developmental domains: gross or fine [3]. VC The Author [2015]. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected] 38 Cytogenetic studies of Rwandan pediatric patients 39 To date, there is little or no data on the incidence hundred thirty-six (80%) were aged <5 years and of GDD/ID and cytogenetic studies in Sub-Saharian presented GDD while 128 children (20%) were aged Africa. The birth prevalence of congenital anomalies >5 years and presented ID. In 128 children diag- in the developing world is underestimated by defi- nosed with ID, the majority had moderate ID ciencies in diagnostic capabilities and lack of reliabil- (n ¼ 63), while 26 had mild ID, 32 severe ID and 7 ity of medical records and health statistics [4]. Birth profound ID (Table 1). defect registry allows more reliable estimates of the In addition, a blood sample was taken for karyo- prevalence at birth of congenital anomalies in a type analysis and for DNA extraction for further mo- population. However, cytogenetics analysis in indi- lecular cytogenetic testing. This study was approved viduals with various congenital abnormalities, dys- morphic features, GDD and/or ID is generally Downloaded from considered as an essential component in the overall Table 1. Clinical characteristics of the 664 evaluation process [5]. Chromosomal disorders are Rwandan pediatric patients with ID/GDD and/ recognized as one of the major causes of childhood or MCA morbidity and mortality in developed countries [6]. Characteristics Number (percentage) However, these disorders have not received much at- http://tropej.oxfordjournals.org/ tention in developing countries, because the main Gender priority health problems responsible for childhood Total cohort 664 morbidity and mortality are caused by socioeco- Gender nomic and environmental factors rather than genetic Male 360 (54%) aetiologies [7]. The present study aimed at deter- Female 304 (46%) mining the prevalence and pattern of microscopically Mean age 2.6 years visible chromosomal abnormalities among children Global development 536 (80%) referred to our clinical department for diagnosis and delay (child with at McMaster University Library on April 8, 2016 evaluation of GDD/ID associated or not with mul- <5 years) tiple congenital abnormalities (MCA). Intellectual disability 128 (20%) (child >5 years) Level of intellectual disability MATERIALS AND METHODS Mild 26 (4%) Moderate 63 (9.5%) Patients Severe 32 (5%) A total number of 664 Rwandan children with Profound 7 (1.5%) GDD/ID and/or MCA were transferred to the de- Facial dysmorphism partment of Medical Genetics at University Absent 173 (26%) Teaching Hospitals of Kigali and Butare (CHUK Present 491 (74%) and CHUB) and the Rwandan Military hospital Congenital heart defect (RMH) for genetic investigations from January 2010 Absent 457 (69%) to December 2014. During consultation, all patients Present 207 (31%) were seen by a geneticist who collected patient’s Hand and limb abnormalities demographic data (age, sex), a complete family his- Absent 629 (95%) tory and performed a physical examination. Patients Present 35 (5%) with GDD/ID but in whom the clinical history and Uro-genital malformations investigations revealed a non-genetic condition such Absent 641 (96.5%) as a history of birth asphyxia, and neonatal/ perinatal Present 23 (3.5%) infection were excluded. Epilepsy Among the patients, 360 were boys (54%) while Absent 607 (91%) 304 where girls (46%). The age of referral ranged be- Present 57 (9%) tween 1 day to 15 years (mean age 2.6). Five 40 Cytogenetic studies of Rwandan pediatric patients by the Rwandan National Ethics Committee In total, abnormal karyotypes were identified in (N394/RNEC/2013). Signed informed consent 260 patients (39%) with GDD/ID associated with or forms and permission for publication of this report without congenital malformation. Numerical abnor- and any accompanying images were obtained from malities were found in 246 (37%) patients whereas the parents or legal guardians of all patients. structural abnormalities were detected in 14 (2%) patients. Cytogenetic analysis Trisomy 21 was the most frequent abnormality A karyotype analysis was performed in each patient. and found in 203 patients (30%). Among these A sample of 5 ml of peripheral blood was obtained cases, 197 were free trisomy 21, five cases were due from each patient and was cultured and harvested ac- to a Robertsonian translocation where the chromo- cording to conventional protocol. Conventional some 21 was associated with another acrocentric Downloaded from chromosome analyses were performed with a reso- chromosome and one trisomy 21 was associated lution of 550 bands (Q-banding) on peripheral with an extra chromosome X (48,XXX,þ21) lymphocytes. At least 20 metaphases were counted (Table 2). Remaining chromosomal abnormalities for each patient and karyotyped. The karyotypes were characterized by free trisomy 18 in 23 patients; were analysed according to guidelines from the http://tropej.oxfordjournals.org/ International System for Human Cytogenetic Table 2. Chromosomal abnormalities in 664 Nomenclature (ISCN 2013). pediatric patients referred for investigation of congenital anomalies, dysmorphic features, DNA extraction GDD and/or ID DNA extraction was performed in order to perform Karyotype Number of further molecular analyses. Ten to five millilitres of children blood sample were collected into EDTA tube. A gen- (n ¼ 664) omic DNA of each patient was extracted from per- at McMaster University Library on April 8, 2016 ipheral lymphocytes using the phenol–chloroform Numerical abnormalities standard method. 47,XY,þ21 114 47,XX,þ21 83 Confirmatory analysis 48,XXX,þ21 1 Multiplex ligation-dependent probe amplification 47,XY,þ18 11 (MLPA) was performed to confirm the results of 47,XX,þ18 12 karyotype at the Center for Human Genetics at the 47,XY,þ13 6 University of Liege/Belgium. MLPA analysis was car- 47,XX,þ13 14 ried out according to the manufacturer’s instructions 45,X0 4 (MRC Holland, Amsterdam, Netherlands), using the 47,XXX 1 SALSA probe mix P036 and P070 Human Telomere Structural chromosomal abnormalities and SALSA probe mix P245 Microdeletion 46,XX,þ21,rob(21;21)(q10;q10) 2 Syndrome. Amplification products were analyzed 46,XY,þ21,rob(21;21)(q10;q10) 2 using capillary electrophoresis on ABI PRISM 3100 46,XX,þ21,rob(21;22)(q10;q10) 1 Genetic Analyzer. The obtained data were analyzed 47,XX,þdel(9)(q11) 1 using the Sequence Pilot software (JSI medical sys- 46,XX,der(22)t(10;22)(p10;p10)mat 1 tems, Kippenheim, Germany). (46,XX,dup (1)(p35p31) 1 46,XY,del(13)(q34) 1 47,XX,þmar (chr18) 1 RESULTS 47,XX,þmar (chr 22) 2 During the period of January 2010 to December 46, XX,r(15)(p10q26) 1 2014, 664 children were referred to the department 47,XX,þ18,t(5,6)(p10;p10) 1 of Medical Genetics at the University of Rwanda for Total 260 diagnostic investigation of GDD/ID (Table 1). Cytogenetic studies of Rwandan pediatric patients 41 Downloaded from http://tropej.oxfordjournals.org/ at McMaster University Library on April 8, 2016 Fig. 1. Karyotype results. one patient had trisomy 18 associated with a unbal- karyotypes, including 46,XX,r(15)(p10q26) and dupli- anced translocation 47,XX,þ18,t(5,6)(p10;p10). In cation (46,XX,dup (1) (p35p31), were confirmed by addition, 20 patients presented free trisomy 13, four array-CGH [8].
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