Hülya MARAŞ GENÇ, Yasemin KENDİR DEMİRKOL, Hande BEKLEN, Büşra KUTLUBAY, Ozlem AKGUN-DOGAN, Gülhan SÖZEN

Nörogelişimsel Geriliği Olan ve Mikrodizin Analizinda Patojenik Kopya Sayısı Değişikliği Saptanan Çocukların Klinik Özellikleri

Amaç: Bu çalışmada, nörogelişimsel geriliği olan ve kromozomal mikrodizin analizinde patojenik kopya sayısı değişikliği saptanan çocukların klinik özelliklerini tanımlamayı amaçladık. Gereç ve Yöntem: Üçüncü basamak bir hastanenin pediatrik genetik ve pediatrik nöroloji polikliniğinde Ağustos 2017-Mart 2021 tarihleri arasında nörogelişimsel gecikme açısından değerlendirilen ve patojenik kopya sayısı değişikliği saptanan 0-18 yaş arası çocuklar retrospektif olarak analiz edildi. Bulgular: Çalışmaya 24 hasta dahil edildi, 15’i (%62,5) kızdı. Ortalama tanı yaşı 47.0±42.0 ay (yaş aralığı: 4-133 ay). Çocukların çoğunda (n=17, %70,8) iyi tanımlanmış OMIM mikrodelesyon/mikroduplikasyon sendromları saptandı. Yirmi dört hastada saptanan 28 kopya sayısı değişikliklerinin 21’i (%75) delesyon, 7’si (%25) duplikasyondu. On beş hastada (%62,5) global gelişme geriliği, 7 hastada (%29.2) zihinsel yetersizlik ve 3 hastada (%12.5) otizm spektrum bozukluğu vardı. Sırasıyla 4 ve 5 çocukta erken doğum öyküsü ve gestasyonel yaşa göre düşük doğum ağırlığı mevcuttu. Nörogörüntüleme 2 çocukta hipoksik-iskemik hasar ve 1 çocukta hipoglisemik sekel ile uyumluydu. Fasiyal dismorfizm 19 (%79.2), hipotoni 14 (%58.3), epilepsi 8 (%33,3), mikrosefali 7 (%29.2), makrosefali 2 (%8.3), görme bozukluğu 3 (%12,5) ve işitme kaybı 2 (%8,3) hastada saptandı. Sonuç: Kromozomal mikrodizin analizi, açıklanamayan nörogelişimsel gecikmesi olan hastalarda değerli bir tanısal araçtır. Perinatal asfiksi ve neonatal hipoglisemiye sekonder beyin hasarı olan çocuklarda bile, eşlik eden dismorfizm ve/veya multisistem tutulumu olan olgularda mikroarray analizi yapılmalıdır.

Anahtar Kelimeler:

Nörogelişimsel gerilik, zihinsel yetersizlik, global gelişme geriliği, otizm spektrum bozukuğu, kromozomal mikroarray, kopya sayısı değişikliği

Clinical Characteristics of Children with Neurodevelopmental Delay and Pathogenic Copy Number Variations in Chromosomal Microarray Analysis

Objective: In this study, we report the clinical characteristics of a small cohort of children with neurodevelopmental delay and pathogenic copy number variations (CNV) in chromosomal microarray. Materials and Methods: We retrospectively analyzed children aged 0-18 years with neurodevelopmental delay and a pathogenic CNV in the chromosomal microarray analysis, who had been evaluated in the pediatric genetics and pediatric neurology outpatient clinics of a tertiary hospital between August 2017 and March 2021. Results: Twenty-four patients were included, 15 (62.5%) of them were girls. The mean age at diagnosis was 47.0±42.0 months (age range: 4-133 months). Most of the children (n=17, 70.8%) were diagnosed with welldefined microdeletion/microduplication syndromes. Of 28 CNVs in 24 patients; 21 (75%) were deletions, 7 (25%) were duplications. Fifteen (62.5%) of them had GDD, seven (29.2%) had ID, and three (12.5%) had ASD. A history of preterm birth and small birth weight for gestational age were present in four and five children, respectively. Neuroimaging was compatible with hypoxic-ischemic injury in two children and hypoglycemic sequel in one child. Facial dysmorphism was present in 19 (79.2%), hypotonicity in 14 (58.3%), epilepsy in eight (33.3%), microcephaly in seven (29.2%), macrocephaly in two (8.3%), hearing impairment in two (8.3%), and visual impairment in three (12.5%) children. Conclusion: Chromosomal microarray analysis is a valuable tool in patients with unexplained neurodevelopmental delay. Even in children with brain injury secondary to perinatal asphyxia and neonatal hypoglycemia, microarray analysis should be performed in cases with concomitant dysmorphism and/or multisystem involvement.

Keywords:

Nerodevelopmental delay, cognitive impairment, global developmental delay, autism spectrum disorder, chromosomal microarray, copy number variations,

PDF

___

1. Shevell M, Ashwal S, Donley D, Flint J, Gingold M, Hirtz D, et al. Quality Standards Subcommittee of the American Academy of Neurology; Practice Committee of the Child Neurology Society. 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 2003;60:367-80. google scholar
2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th edn. Arlington, VA: American Psychiatric Publishing, 2013. google scholar
3. American Association of Intellectual and Developmental Disabilities. Definition of Intellectual Disability. Access date: 26 March 2022. Available from: https://www.aaidd.org/intellectual-disability/definition google scholar
4. Moeschler JB, Shevell M, American Academy of Pediatrics Committee on Genetics. Clinical genetic evaluation of the child with mental retardation or developmental delays. Pediatrics 2006; 117:2304. google scholar
5. Maulik PK, Mascarenhas MN, Mathers CD, Dua T, Saxena S. Prevalence of intellectual disability: a meta-analysis of population-based studies. Res Dev Disabil 2011; 32:419. google scholar
6. Augustyn M, Voigt RG, Patterson MC. Autism spectrum disorder: Terminology, epidemiology, and pathogenesis. In: UpToDate, Post, TM (Ed), UpToDate, Waltham, MA. Access date 04 March 2022. Available from: https://www.uptodate.com google scholar
7. Michelson DJ, Shevell MI, Sherr EH, Moeschler JB, Gropman AL, Ashwal S. Evidence report: Genetic and metabolic testing on children 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 2011;77:1629-35. google scholar
8. Miller DT, 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;86:749-64. google scholar
9. Kearney HM, Thorland EC, Brown KK, Quintero-Rivera F, South ST; Working Group of the American College of Medical Genetics Laboratory Quality Assurance Committee. American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med 2011;13:680-5. google scholar
10. Wayhelova M, Smetana J, Vallova V, Hladilkova E, Filkova H, Hanakova M, et al. The clinical benefit of array-based comparative genomic hybridization for detection of copy number variants in Czech children with intellectual disability and developmental delay. BMC Med Genomics 2019;12:111. google scholar
11. D’Arrigo S, Gavazzi F, Alfei E, Zuffardi O, Montomoli C, Corso B, et al. The Diagnostic Yield of Array Comparative Genomic Hybridization Is High Regardless of Severity of Intellectual Disability/Developmental Delay in Children. J Child Neurol 2016;3:691-9. google scholar
12. Misra S, Peters G, Barnes E, Ardern-Holmes S, Webster R, Troedson C, et al. Yield of comparative genomic hybridization microarray in pediatric neurology practice. Neurol Genet 2019;5:e367. google scholar
13. Battaglia A, Doccini V, Bernardini L, Novelli A, Loddo S, Capalbo A, et al. Confirmation of chromosomal microarray as a first-tier clinical diagnostic test for individuals with developmental delay, intellectual disability, autism spectrum disorders and dysmorphic features. Eur J Paediatr Neurol 2013;17:589-99. google scholar
14. Ronzoni L, Grassi FS, Pezzani L, Tucci A, Baccarin M, Esposito S, et al. 7p22.1 microduplication syndrome: Refinement of the critical region. Eur J Med Genet 2017; 60:114-7. google scholar
15. Atack E, Fairtlough H, Smith K, Balasubramanian M. A novel (paternally inherited) duplication 13q31.3q32.3 in a 12-year-old patient with facial dysmorphism and developmental delay. Mol Syndromol 2014;5:245-50. google scholar
16. Vergult S, Dauber A, Delle Chiaie B, Van Oudenhove E, Simon M, Rihani A, et al. 17q24.2 microdeletions: a new syndromal entity with intellectual disability, truncal obesity, mood swings and hallucinations. Eur J Hum Genet 2012; 20:534-9. google scholar
17. Chung WK, Roberts TP, Sherr EH, Snyder LG, Spiro JE. 16p11.2 deletion syndrome. Curr Opin Genet Dev 2021;68:49-56. google scholar
18. Carter LB, Battaglia A, Cherry A, Manning MA, Ruzhnikov MR, Bird LM, et al. Perinatal distress in 1p36 deletion syndrome can mimic hypoxic ischemic encephalopathy. Am J Med Genet A 2019;179:1543-46. google scholar
19. Jordan VK, Zaveri HP, Scott DA. 1p36 deletion syndrome: an update. Appl Clin Genet 2015;8:189-200. google scholar
20. Sim JC, White SM, Lockhart PJ. ARID1B-mediated disorders: Mutations and possible mechanisms. Intractable Rare Dis Res 2015;4:17-23. google scholar
21. Stankiewicz P, Khan TN, Szafranski P, Slattery L, Streff H, Vetrini F, et al. Haploinsufficiency of the Chromatin Remodeler BPTF Causes Syndromic Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features. Am J Hum Genet 2017;101:503-515. google scholar
22. Theisen A, Rosenfeld JA, Farrell SA, Harris CJ, Wetzel HH, Torchia BA, et al. aCGH detects partial tetrasomy of 12p in blood from Pallister-Killian syndrome cases without invasive skin biopsy. Am J Med Genet A 2009;149A:914-918. google scholar
23. Rump P, de Leeuw N, van Essen AJ, Verschuuren-Bemelmans CC, Veenstra-Knol HE, Swinkels ME, et al. Central 22q11.2 deletions. Am J Med Genet A 2014;164A:2707-23. google scholar