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Aia Elise Jønch , Elise Douard , Clara Moreau , Anke Van Dijck , Marzia Supplementary material J Med Genet Jønch et al. ESTIMATING THE EFFECT SIZE OF THE 15Q11.2 BP1-BP2 DELETION AND ITS CONTRIBUTION TO NEURODEVELOPMENTAL SYMPTOMS: RECOMMENDATIONS FOR PRACTICE Aia Elise Jønch1,2,3, Elise Douard4,5, Clara Moreau4,5, Anke Van Dijck6, Marzia Passeggeri7, R. Frank Kooy6, Jacques Puechberty8, Carolyn Campbell9, Damien Sanlaville10,11, Henrietta Lefroy12, Sonia Richetin7, Aurélie Pain7,13, David Genevieve8,14,15, Usha Kini12,16, Cédric Le Caignec17,18, James Lespinasse19, Anne-Bine Skytte20,21, Bertrand Isidor17, Christiane Zweier22, Jean-Hubert Caberg23, Marie-Ange Delrue4,5, 15q11.2 Working Group, Anders Bojesen24, Helle Hjalgrim25, Charlotte Brasch-Andersen1,2, Emmanuelle Lemyre4,5, Lilian B. Ousager1,2* & Sébastien Jacquemont4,5,7* Supplementary information 1 Jønch AE, et al. J Med Genet 2019; 0:701–710. doi: 10.1136/jmedgenet-2018-105879 Supplementary material J Med Genet Jønch et al. Table of Contents Members of the 15q11.2 working group ......................................................................................................................... 5 Supplementary Materials and Methods .......................................................................................................................... 7 S1.1. Participants and Data Sources ............................................................................................................................................................ 7 S1.2. Cognitive Assessments ......................................................................................................................................................................... 9 S1.3. Microarray platforms .......................................................................................................................................................................... 9 S1.4. Additional pathogenic variants ........................................................................................................................................................... 9 S1.5. Conversion of odds-ratios to a shift in IQ ........................................................................................................................................ 10 S1.6. Logistic Regression Models ............................................................................................................................................................... 11 S1.7. The Probability of Loss-of-Function Intolerance (pLI) .................................................................................................................. 12 Supplementary Results ................................................................................................................................................... 13 S1.1. Neurological symptoms ...................................................................................................................................................................... 13 S1.2. Magnetic resonance image (MRI) ..................................................................................................................................................... 13 S1.3. Major Malformation .......................................................................................................................................................................... 13 S1.4. Major Medical Conditions ................................................................................................................................................................. 14 S1.5. Dysmorphism ...................................................................................................................................................................................... 14 Supplementary Figures ................................................................................................................................................... 15 Figure S1. Distribution of CNVs based on pLI score and classification in the SJCHU database ....................................................... 15 2 Jønch AE, et al. J Med Genet 2019; 0:701–710. doi: 10.1136/jmedgenet-2018-105879 Supplementary material J Med Genet Jønch et al. Figure S2. Estimation of the probability to be de novo in function of the pLI score of a CNV ........................................................... 17 Figure S3. Contour-shaded funnel plot of 20 15q11.2 deletion studies included in our meta-analyses .............................................. 18 Figure S4. Contour-shaded funnel plot of 7 15q11.2 duplication studies included in our meta-analyses ........................................... 19 Figure S5. Additional CNVs detected in 15q11.2 deletion and duplication probands from the clinically referred group and their distribution by size (A), number of genes (B) and pLI score (C) ............................................................................................................ 20 Supplementary Tables .................................................................................................................................................... 22 Table S1. Characteristics of published 15q11.2 deletion studies investigating neurodevelopmental disorders and congenital heart disease ........................................................................................................................................................................................................... 22 Table S2. Characteristics of published 15q11.2 duplication studies investigating neurodevelopmental disorders ........................... 25 Table S3. Cognitive and behavioral results for 15q11.2 CNV carriers from the clinically referred group ........................................ 26 Table S4. Comparing frequencies of additional pathogenic CNVs in 15q11.2 deletion and duplication carriers from the clinically referred group .............................................................................................................................................................................................. 28 Table S5. Characteristics of additional pathogenic CNVs detected in 15q11.2 deletion and duplication probands from the clinically referred group ............................................................................................................................................................................. 29 Table S6. Additional genetic variants identified in 15q11.2 deletion and duplication probands from the clinically referred group ....................................................................................................................................................................................................................... 45 Table S7. Transmission and de novo frequency in previous published 15q11.2 deletion studies and case series .............................. 47 Table S8. Transmission and de novo frequency of the 15q11.2 CNVs in the DECIPHER database .................................................. 53 3 Jønch AE, et al. J Med Genet 2019; 0:701–710. doi: 10.1136/jmedgenet-2018-105879 Supplementary material J Med Genet Jønch et al. Table S9. Comparing frequencies of ASD in 15q11.2 deletion and duplication probands from the clinically referred group ........ 54 Table S10. Comparing frequencies of epilepsy in 15q11.2 CNV carriers from the clinically referred group .................................... 55 Table S11. Neurological features in 15q11.2 deletion carriers from the clinically referred group according to ascertainment ...... 56 Table S12. Neurological features in 15q11.2 duplication carriers from the clinically referred group according to ascertainment 58 Table S13. Comparing frequencies of congenital heart disease in 15q11.2 CNV carriers from the clinically referred group ......... 60 Table S14. Malformation and medical conditions in 15q11.2 deletion carriers from the clinically referred group according to ascertainment ............................................................................................................................................................................................... 61 Table S15. Malformation and medical conditions in 15q11.2 duplication carriers from the clinically referred group according to ascertainment ............................................................................................................................................................................................... 64 Table S16. Comparing frequencies of ID in 15q11.2 deletion and duplication probands from the clinically referred group .......... 67 Supplementary References ............................................................................................................................................. 68 4 Jønch AE, et al. J Med Genet 2019; 0:701–710. doi: 10.1136/jmedgenet-2018-105879 Supplementary material J Med Genet Jønch et al. Members of the 15q11.2 working group Andrieux Joris, Institut de Génétique Médicale, Hôpital Jeanne de Flandre, CHRU de Lille, Lille, France; Barnicoat Angela, Department of Clinical Genetics, Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom; Blanchet Patricia, Département de Génétique Médicale, Hôpital Arnaud de Villeneuve, CHU de Montpellier, Montpellier, France; Blesson Sophie, Service de Génétique, CHRU de Tours, Tours, France; Bütschi Florence Niel, Service de Médecine Génétique, CHUV Lausanne, Lausanne Switzerland; Campeau Philippe M., Department of Pediatrics, University
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