Genetic Findings in Children with Unexplained Developmental Delay Dr Dipti Deshmukh Neurodevelopmental Consultant, St. George's Hospital, London Mayu Uemura 4th year MBBS4, St George s University of London 11th September 2018 Introduction Global developmental delay (GDD) affects 1% 3% of children under 5 1 acgh is widely accepted as a first line investigation 3 Diagnostic yield is variable based on cohort and study size Examples: o Children with Autism - 3.3% 5-9% 6 o Children with intellectual disability 5.1% - 16.7% 7,11 o Intellectual disability, dysmorphism, congenital anomalies, ASD, learning difficulties 10.4-20 % 4,8 What is the yield in a community developmental service? Is there any correlation with clinical findings or clinical diagnosis? 1
To determine what proportion of children investigated for global developmental delay had chromosomal imbalances on acgh Aims To assess what percentage of these imbalances were actually known to be pathological To assess whether there is any correlation between genetic findings and clinical findings To compare the yield of genetic findings in our study to similar published data Retrospective case note study of children who had an acgh for the investigation of global developmental delay in the Neurodevelopmental service at St George's Hospital, London o June 2011 - December 2017 o 288 children Methods Recorded clinical findings: 1. Clinical diagnosis 2. Dysmorphic features 3. Neurocutaneous makers 4. Neurological examination 5. Family history of developmental disorders (immediate and distant relatives) 2 proportions test on statistical software 2
n=59 Results 59 out of 288 - Abnormal acgh results (20.5%) 12 out of 59 - known pathological CNVs 6 out of 59 - possibly pathological CNVs 39 out of 59 - Copy number variants of unknown clinical significance (CNVoUCS) 2 out of 59 - Uncertain results Results 12 Children with pathological CNVs Table 1. acghresults and clinical findings of 12 patients with pathological copy number variants. CNVoUCS copy number variants of unknown clinical significance, LD=learning difficulties, ADHD = attention deficit hyperactivity disorder, SCD = social communication difficulties, SLD = speech and language disorder, GDD = global developmental delay, SPD = sensory processing difficulties, ASD = autism spectrum disorder Sex acgh Result acgh description Diagnosis 1 F arr 17p11.2(16,720,901 20,294,009)x1 Smith Magenis syndrome 2 M 3 M arr Xp21.2(29,388,825 29,420,548)x1,2p21(44,539,987 44,618,912)x1 arryp11.31q11.23(2,654,861 28,629,864)x2, arr(x)x1,(y)x2 4 M arr[hg19] 16p11.2( 29,673,984 30,190,539)x1 SCD, moderate LD, behavioural difficulties 16p12.1 microdeletion syndrome and possible Hypotonia Cystinuria syndrome (CNVoUCS) Severe ADHD, LD, sleep disorder XYY syndrome and CNVoUCS ADHD and LD Proximal 16p11.2 microdeletion syndrome ASD 5 F arr(x) x3[0.7] Triple X LD, SLD 6 M arr(x)x1,(y)x2 XYY syndrome SLD and LD 7 M arr(x)x2~3 Klinefelter syndrome LD and behavioral difficulties 8 M arr[grch37] 17q11.2(28146310_30315540)x1 17q11 microdeletion syndrome GDD, ASD 17q21.31 deletion syndrome (Koolen 9 F arr[hg19] 17q21.31(43,655,777 44,476,664)x1 de Vries syndrome) SLD, GDD 10 M 11 M 12 M arr[hg19] 7q11.23(72,766,343 74,133,303)x1, 16q23.1(75,042,190 75,673,739)x1 arr[hg19] 9p24.3p23(204,221 12,196,172)x1,10p11.21(35,004,858 35,803,147)x3 William syndrome and another CNVoUCS GDD 9p deletion syndrome and 1 CNVoUCS Significant SCD and fine motor difficulties arr16p13.3(3,878,449 3,924,979)x1,22q11.21(18,818,399 21,561,492)x3 Rubinstein Taybi syndrome GDD, SPD, SCD Extra M arr[grch37] 16p12.2(21959950_22466948)x1 Inherited from his mother, 16p12.1 microdeletion syndrome SLD, SCD, attention difficulty and hyperactivity Suspected genetic diagnosis 3
Results 6 children with possibly pathogenic CNVs Table 2. acgh results and clinical findings of 6 patients with possibly pathological copy number variants. CNVoUCS copy number variants of unknown clinical significance, LD=learning difficulties, ADHD = attention deficit hyperactivity disorder, SCD = social communication disorder, SLD = speech and language disorder, ASD = autism spectrum disorder ADD = attention difficulty disorder Sex acgh result acgh description Diagnosis Suspected diagnosis 1 M arr[grch37] 22q11.21(207 54408_21457552)x1 2 F arr[hg19] 2p21p16.3(46,29 5,757 48,546,132)X3, 20q11.21(2 9,462,074 30,971,525)x3 3 M arr[grch37] 15q11.2(22729340_23086 260)x3 4 F arr[grch37] 15q11.2(22765636_23300 254)x1 5 M arr[grch37] 2q13(111368816_1130656 80)x3 6 M arr 15q11.1q11.2(20,686,219 23,146,103)x1 Extra M arr 15q11.1q11.2(20,686,219 23,146,103)x1 Atypical 22q11.21 deletion Possible Borhing Opitz syndrome (copy number gain) and CNVoUCS Copy number gain in neurosusceptible locus BP1 BP2 microdeletion syndrome SLD and LD SLD, orofacial dyspraxia, SCD, hypermobility ASD, Tics, Anxiety?ADHD Duplication of 2q13?ADD Possible association with Prader Willi / Angelman syndrome 15q13.3 microdeletion syndrome neurosusceptible locus GDD ASD and SLD Results: Clinical findings in normal vs. abnormal acgh groups Figure 1. Presence of clinical findings and family history of developmental/mental disorders in percentage, compared between patients with normal and abnormal acghresults. 4
Results: Diagnosis of rmal vs. Abnormal acgh groups Learning Difficulty: p<0.05 Discussion CNV yield on acgh was similar to past studies 2,5 (20.5%) The diagnostic yield of acgh was 6.25% similar to studies including children with ASD or GDD/ID (3.3% 5, 9% 6 ) lower than studies including children with ID/GDD with associated congenital anomalies (13.2%, 14.2%, 14.7%) 2,9,10 reflective of the baseline cohort of children selected Presence of LD, dysmorphic features and positive family history predictors of chromosomal imbalances on acgh 5
Conclusion Array CGH is a useful initial investigation for unexplained developmental delay Good diagnostic yield even in the absence of significant clinical findings LD can be a good indicator of acgh abnormality Possible future work Clinical outcomes of children with pathological CNV did early diagnosis make a difference? References 1.Shevell, M., Ashwal, S., Donley, D., Flint, J., Gingold, M., Hirtz, D, ey al. Practice parameter: evaluation of the child with global developmental delay: American Academy of Neurology. [internet]. 2003. [cited 2018 Aug 30]; Neurology60, 367 380. Available from: https://doi.org/10.1212/01.wnl.0000031431.81555.16. 2.Shoukier M, Klein N, Auber B, Wickert J, Schröder J, Zoll B, et al. Array CGH in patients with developmental delay or intellectual disability: are there phenotypic clues to pathogenic copy number variants?. Clin Genet [internet]. 2013 [cited 2018 Jul 5];83:53 65. Available from: https://dx.doi.org /10.1111/j.1399 0004.2012.01850.x. 3.Mithyantha R, Kneen R, McCann E, Gladstone M. Current evidence based recommendations on investigating children with global developmental delay. Arch Dis Child [Internet.] 2017 Oct [cited 2018 Jul 4];102:1171 76. Available from: https://dx.doi.org/10.1136/ archdischild 2017 312843. 4.Hochstenbach R, van Binsbergen E, Engelen J, Nieuwint A, Polstra A, Poddighe P, et al. Array analysis and karyotyping: workflow consequences based on a retrospective study of 36,325 patients with idiopathic developmental delay in the Netherlands Eur. J. Med. Genet [internet]. 2009 [Cited Sep 5];52:161 169. Available from: https://dx.doi.org/10.1016/j.ejmg.2009.03.015. 5.B. Bernhard, P. Ellery, S. Ryley, J. Burbridge. Array CGH: what is the diagnostic yield for autism referrals? [Cited 2018 Jul 4]. Available from: https://www.bacdis.org.uk/membership/documents/autism_audit.pdf. 6.E Napoli E, Russo S, Casula L, Alesi V, Amendola FA,Angioni et al. A. Array CGH analysis in a cohort of phenotypically well characterized individuals with essential autism spectrum disorders. J Autism Dev Disord. [internet] 2018. [cited 2018 Aug 31];48(2)442 449. Available from: https://dx.doi.org/10.1007/s10803 017 3329 4. 7. Miller D, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, et al. Consensus statement: chromosomal microarray is a first tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010 [cited 2018 Sep 4];86:749 764. Available from: https//dx.doi.org/10.1016/j.ajhg.2010.04.006. 8.Shevell M, Ashwal S, Donley D, Flint J, Gingold M, Hirtz D, et al. Practice parameter: evaluation of the child with global developmental delay: Report of the Quality Standards Subcommittee of the American Academy of Neurology and The Practice Committee of the Child Neurology Society. Neurology [internet] 2013 [cited 2018 Jul 10];60: 367 380. Available from https://doi.org/10.1212/01.wnl.0000031431.81555.16. 9.Cooper GM, Coe BP, Girirajan S, Rosefield JA, Vu T, Baker C, et al. A copy number variation morbidity map of developmental delay. Nat Genet [Internet]. 2011 [Cited 2018 Jul 4];43(9):838 846. Available from: https://dx.doi.org/10.1038/ng.909. 10.Kaminsky EB, Kaul V, Paschall J, Church DM, Bumke B, Kunig D, et al. An evidence based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities. Genet Med [Internet]. 2011 [Cited 2018 Jul 4]; 13(9):777 784. Available from: https://dx.doi.org/10.1097/gim.0b013e31822c79f9. 11.Sagoo G, Butterworth S, Sanderson S, Shaw Smith C, Higgins J, Burton H. Array CGH in patients with learning disability (mental retardation) and congenital anomalies: updated systematic review and meta analysis of 19 studies and 13,926 subjects Genet. Med., 11 [internet] 2009[Cited 2018 Sep 6];11(3)139 146. Available from: https//dx.doi.org/10.1097/gim.0b013e318194ee8f. 6