Etiological investigation of genetic cause in autism spectrum disorder

Keywords: Autism Spectrum Disorder, Neurodevelopmental Disorders, Genetic Testing

Abstract

AIMS: The aims of this study were to characterize the etiological investigation of genetic cause in the autism spectrum disorder and to determine the factors related to its identification.
METHODS: A retrospective descriptive study, with an analytical component, included children and adolescents with autism spectrum disorder followed in consultation at a level 2 hospital, between November 2017 and October 2019. The following variables were analyzed: age, sex, age at the first consultation, family history, objective examination, cognitive assessment, etiological investigation of genetic cause and etiological diagnosis of genetic cause. Statistical analysis was performed using the SPSS®v23 program (significance level 0.05).
RESULTS: We identified 153 children with autism spectrum disorder, of which 48 underwent a genetic cause investigation: 45 performed microarray analysis (15.6% pathogenic); 42 carried out a molecular study of the Fragile X syndrome (one altered); two performed sequencing of the methyl CpG binding protein 2 (MECP2) gene (one altered). The diagnosis of genetic cause was made in 18.8% of the sample. The identification of the etiology of a genetic cause was related to global development delay/ intellectual disability (p = 0.04) and the presence of relevant family history (p = 0.005).
CONCLUSIONS: The diagnostic yield of the genetic study was higher in patients with a global development delay /intellectual disability and in patients with relevant family history.

Downloads

Download data is not yet available.

Author Biographies

Carla Andreia Esteves Fernandes, Centro Hospitalar e Universitário de Coimbra (CHUC), Coimbra, Portugal

Resident of Pediatrics, Centro Hospitalar e Universitário de Coimbra (CHUC), Coimbra, Portugal.

Ana Francisca Henriques Cardoso, Centro Hospitalar de Leiria (CHL), Leiria, Portugal.

Resident of Pediatrics, Centro Hospitalar de Leiria (CHL), Leiria, Portugal.

Caroline Reis Lopes, Centro Hospitalar de Leiria (CHL), Leiria, Portugal.

Resident of Pediatrics, Centro Hospitalar de Leiria (CHL), Leiria, Portugal.

Margarida Maria Videira Henriques, Centro Hospitalar de Leiria (CHL), Leiria, Portugal.

Graduated Hospitalar Assistant of Pediatrics, Centro Hospitalar de Leiria (CHL), Leiria, Portugal

Ester Preciosa Maio Nunes Pereira, Centro Hospitalar de Leiria (CHL), Leiria, Portugal.

Hospitalar Assistant of Pediatrics, Centro Hospitalar de Leiria (CHL), Leiria, Portugal.

References

Kanner L. Autistic disturbances of affective contact. Acta Paedopsychiatr. Acta Paedopsychiatr. 1968;35(4):100-36.

Al-Dewik N, Al-Jurf R, Styles M, Tathamouni S, Alsharshani D, Alsharshani M, et al. Overview and introduction to Autism Spectrum Disorder (ASD). Adv Neurobiol. 2020;24:3-42. https://doi.org/10.1007/978-3-030-30402-7_1.

Chaste P, Roeder K, Devlin B. The Yin and Yang of autism genetics: how rare de novo and common variations affect liability. Annu Rev Genomics Hum Genet. 2017;18:167-87. https://doi.org/10.1146/annurev-genom-083115-022647.

American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th Edition Washington DC: American Psychiatric Association; 2013

Baumer N, Spence SJ. Evaluation and management of the child with autism spectrum disorder. Continuum. 2018;24(1):248-75. https://doi.org/10.1212/CON.0000000000000578

World Health Organization. Regional Office for South-East Asia. WHO South-East Asia regional strategy on autism spectrum disorders [Internet]. New Delhi: World Heath House, 2017 [cited 2021 Apr 15]. Available from: https://apps.who.int/iris/bitstream/handle/10665/259505/9789290225454-en.pdf?sequence=1&isAllowed=y

Wiśniowiecka-Kowalnik B, Nowakowska BA. Genetics and epigenetics of autism spectrum disorder-current evidence in the field. J Appl Genet. 2019;60(1):37-47. https://doi.org/10.1007/s13353-018-00480-w

Busch RM, Srivastava S, Hogue O, Frazier TW, Klaas P, Hardan A, et al. Neurobehavioral phenotype of autism spectrum disorder associated with germline heterozygous mutations in PTEN. Transl Psychiatry. 2019;9(1):253. https://doi.org/10.1038/s41398-019-0588-1

Al-Dewik N, Alsharshani M. New horizons for molecular genetics diagnostic and research in autism spectrum disorder. Adv Neurobiol. 2020;24:43-81. https://doi.org/10.1007/978-3-030-30402-7_2

Bitar T, Hleihel W, Marouillat S, Vonwill S, Vuillame ML, Soufia M, et al. Identification of rare copy number variations reveals PJA2, APCS, SYNPO, and TAC1 as novel candidate genes in autism spectrum disorders. Mol Genet Genomic Med. 2019;7(8):e786. https://doi.org/10.1002/mgg3.786

Toma C. Genetic Variation across phenotypic severity of autism. Trends Genet. 2020;36(4):228-31 https://doi.org/10.1016/j.tig.2020.01.005

McDiarmid TA, Belmadani M, Liang J, Meili F, Mathews EA, Mullen GP, et al. Systematic phenomics analysis of autism-associated genes reveals parallel networks underlying reversible impairments in habituation. Proc Natl Acad Sci USA. 2020;117(1):656-67. https://doi.org/10.1073/pnas.1912049116

Schaefer GB, Mendelsohn NJ; Professional Practice and Guidelines Committee. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med. 2013;15(5):399-407. https://doi.org/10.1038/gim.2013.32

Monteiro S, Pinto J, Mira Coelho A, Leão M, Dória S. Identification of copy number variation by Array-CGH in Portuguese children and adolescents diagnosed with autism spectrum disorders. Neuropediatrics. 2019;50(6):367-77. https://doi.org/10.1055/s-0039-1694797

Riggs ER, Andersen EF, Cherry AM, Kantarci S, Kearney H, Patel A, et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020;22(2):245-57. https://doi.org/10.1038/s41436-019-0686-8

Woodbury-Smith M, Scherer SW. Progress in the genetics of autism spectrum disorder. Dev Med Child Neurol. 2018;60(5):445-51. https://doi.org/10.1111/dmcn.13717

Loomes R, Hull L, Mandy WPL. What is the male-to-female ratio in autism spectrum disorder? A systematic review and meta-analysis. J Am Acad Child Adolesc Psychiatry. 2017;56(6):466-74. https://doi.org/10.1016/j.jaac.2017.03.013

Jacquemont S, Coe BP, Hersch M, Duyzend MH, Krumm N, Bergmann S, et al. A higher mutational burden in females supports a “female protective model” in neurodevelopmental disorders. Am J Hum Genet. 2014;94(3):415-25. https://doi.org/10.1016/j.ajhg.2014.02.001

Zhang Y, Li N, Li C, Zhang Z, Teng H, Wang Y, et al. Genetic evidence of gender difference in autism spectrum disorder supports the female-protective effect. Transl Psychiatry. 2020;10(1):4. https://doi.org/10.1038/s41398-020-0699-8.

Baron-Cohen S. The extreme male brain theory of autism. Trends Cogn Sci. 2002;6(6):248-54. https://doi.org/10.1016/s1364-6613(02)01904-6.

Shen Y, Dies KA, Holm IA, Bridgemohan C, Sobeih MM, Caronna EB, et al. Clinical genetic testing for patients with autism spectrum disorders. Pediatrics. 2010;125(4):e727-e735. https://doi.org/10.1542/peds.2009-1684.

Tammimies K, Marshall CR, Walker S, Kaur G, Thiruvahindrapuram B, Lionel AC, et al. Molecular diagnostic yield of chromosomal microarray analysis and whole-exome sequencing in children with autism spectrum disorder. JAMA. 2015;314(9):895-903. https://doi.org/10.1001/jama.2015.10078.

Kalsner L, Twachtman-Bassett J, Tokarski K, Stanley C, Dumont-Mathieu T, Cotney J, et al. Genetic testing including targeted gene panel in a diverse clinical population of children with autism spectrum disorder: Findings and implications. Mol Genet Genomic Med. 2018;6(2):171-85. https://doi.org/10.1002/mgg3.354.

Schaefer GB, Starr L, Pickering D, Skar G, Dehaai K, Sanger WG. Array comparative genomic hybridization findings in a cohort referred for an autism evaluation. J Child Neurol. 2010;25(12):1498-503. https://doi.org/10.1177/0883073810370479.

Vicari S, Napoli E, Cordeddu V, Menghini D, Alesi V, Loddo S, et al. Copy number variants in autism spectrum disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2019;92:421-27. https://doi.org/10.1016/j.pnpbp.2019.02.012.

Nisar S, Hashem S, Bhat AA, Syed N, Yadav S, Azeem MW, et al. Association of genes with phenotype in autism spectrum disorder. Aging. 2019;11(22):10742-70. https://doi.org/10.18632/aging.102473.

Sanders SJ, He X, Willsey AJ, Ercan-Sencicek AG, Samocha KE, Cicek AE, et al. Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci. Neuron. 2015;87(6):1215-33. https://doi.org/10.1016/j.neuron.2015.09.016.

Bourgeron, T. From the genetic architecture to synaptic plasticity in autism spectrum disorder. Nat Rev Neurosci. 2015;16(9):551–63. https://doi.org/10.1038/nrn3992.

Capkova Z, Capkova P, Srovnal J, Staffova K, Becvarova V, Trkova M, et al. Differences in the importance of microcephaly, dysmorphism, and epilepsy in the detection of pathogenic CNV in ID and ASD patients. PeerJ. 2019;7:e7979 https://doi.org/10.7717/peerj.7979.

Portugal. Ministério da Saúde. Serviço Nacional de Saúde. Direção Geral de Saúde. Norma nº 002/2019. Abordagem diagnóstica e intervenção na perturbação do espetro do autismo em idade pediátrica e no adulto [Internet]. Lisboa: Direção Geral de Saúde; 2019 [Cited 2021 Apr 15]. Available from: https://normas.dgs.min-saude.pt/wp-content/uploads/2019/09/Abordagem-Diagnostica-e-Intervencao-na-Perturbacao-do-Espetro-do-Autismo-em-Idade-Pediatrica-e-no-Adulto_2019.pdf

Published
2021-05-27
How to Cite
Fernandes, C. A. E., Cardoso, A. F. H., Lopes, C. R., Henriques, M. M. V., & Pereira, E. P. M. N. (2021). Etiological investigation of genetic cause in autism spectrum disorder. Scientia Medica, 31(1), e39581. https://doi.org/10.15448/1980-6108.2021.1.39581