La evolución tecnológica en genómica tiene una velocidad muy rápida y las guías clínicas se quedan obsoletas respecto a la práctica clínica habitual, de forma que los profesionales frecuentemente nos encontramos con preguntas difíciles de responder.

Mucho ha llovido desde las guías de la AAN de 2003, en las que se propuso como primer escalón para el estudio del retraso global del desarrollo y los trastornos del espectro del autismo la utilización del cariotipo y el X-fragil, actualmente retiradas , tras la revisión realizada en 2011 por los mismos autores .

Las guías de 2012 de la academia americana de pediatría, introdujeron por primera vez el uso sistemático del aCGH . Una consecuencia no inesperada, ha sido la progresiva decadencia de las técnicas de citogenética tradicionales (cariotipo), hasta el punto de que se está perdiendo el “know how”, y el número de profesionales capaces de realizar la técnica está en riesgo de extinción.

Desde entonces, la aparición de los estudios de secuenciación del exoma ha significado una revolución desde el punto de vista del incremento de la rentabilidad diagnóstica (diagnostic yield). En particular, la aparición de sistemas bioinformáticos de detección de CNV a partir de los datos obtenidos en la secuenciación del exoma, ha permitido cuestionar seriamente la utilidad de realizar un aCGH previo.

En las últimas guías de la ACMG de 2021, se ha analizado si el exoma debería ser el 1º escalón en el estudio diagnóstico de los pacientes con malformaciones congénitas múltiples y discapacidad intelectual, proponiendo un cambio en el paradigma actual.

No obstante, continua existiendo discusión en el campo respecto a cuál debe ser la actual secuencia de decisiones desde el punto de vista de la práctica clínica, cuestionandose tímidamente si realmente es rentable continuar realizando X-fragil a toda la población, dada la disminución de prevalencia identificada en las últimas décadas .

1.
Specchio N, Wirrell EC, Scheffer IE, Nabbout R, Riney K, Samia P, et al. International League Against Epilepsy classification and definition of epilepsy syndromes with onset in childhood: Position paper by the ILAE Task Force on Nosology and Definitions. Epilepsia [Internet]. 2022 [cited 2022 Oct 22];63(6):1398–442. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/epi.17241
1.
Kang B, Kwon YS. Benign convulsion with mild gastroenteritis. Korean J Pediatr [Internet]. 2014 [cited 2022 Oct 22];57(7):304. Available from: http://www.e-cep.org/journal/view.php?doi=10.3345/kjp.2014.57.7.304
1.
Lee YS, Lee GH, Kwon YS. Update on benign convulsions with mild gastroenteritis. Clin Exp Pediatr [Internet]. 2021 Dec 27 [cited 2022 Oct 22];65(10):469–75. Available from: http://www.e-cep.org/journal/view.php?doi=10.3345/cep.2021.00997
1.
Verity C, Baker E, Maunder P, Pal S, Winstone AM. Differential diagnosis of progressive intellectual and neurological deterioration in children. Dev Med Child Neurol [Internet]. 2021 Mar [cited 2022 Oct 15];63(3):287–94. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891454/
1.
Hoffmann K, Müller JS, Stricker S, Megarbane A, Rajab A, Lindner TH, et al. Escobar Syndrome Is a Prenatal Myasthenia Caused by Disruption of the Acetylcholine Receptor Fetal γ Subunit. The American Journal of Human Genetics [Internet]. 2006 Aug 1 [cited 2022 Oct 15];79(2):303–12. Available from: https://www.sciencedirect.com/science/article/pii/S0002929707631371
1.
Hacohen Y, Jacobson LW, Byrne S, Norwood F, Lall A, Robb S, et al. Fetal acetylcholine receptor inactivation syndrome: A myopathy due to maternal antibodies. Neurology - Neuroimmunology Neuroinflammation [Internet]. 2015 Feb 1 [cited 2022 Oct 15];2(1). Available from: https://nn.neurology.org/content/2/1/e57
1.
Polyak A, Kubina RM, Girirajan S. Comorbidity of intellectual disability confounds ascertainment of autism: implications for genetic diagnosis. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics [Internet]. 2015 [cited 2022 Oct 15];168(7):600–8. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1002/ajmg.b.32338
1.
Moore CA, Staples JE, Dobyns WB, Pessoa A, Ventura CV, Fonseca EB da, et al. Characterizing the Pattern of Anomalies in Congenital Zika Syndrome for Pediatric Clinicians. JAMA Pediatrics [Internet]. 2017 Mar 1 [cited 2022 Oct 15];171(3):288–95. Available from: https://doi.org/10.1001/jamapediatrics.2016.3982
1.
Adebanjo T. Update: Interim Guidance for the Diagnosis, Evaluation, and Management of Infants with Possible Congenital Zika Virus Infection — United States, October 2017. MMWR Morb Mortal Wkly Rep [Internet]. 2017 [cited 2022 Oct 15];66. Available from: https://www.cdc.gov/mmwr/volumes/66/wr/mm6641a1.htm
1.
Koens LH, Tijssen MAJ, Lange F, Wolffenbuttel BHR, Rufa A, Zee DS, et al. Eye movement disorders and neurological symptoms in late‐onset inborn errors of metabolism. Mov Disord [Internet]. 2018 Dec [cited 2022 Oct 10];33(12):1844–56. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587951/
1.
Brodsky MC. Pediatric Neuro-Ophthalmology [Internet]. New York, NY: Springer; 2010 [cited 2022 Oct 10]. Available from: http://link.springer.com/10.1007/978-0-387-69069-8
1.
Ozonoff S, Young GS, Carter A, Messinger D, Yirmiya N, Zwaigenbaum L, et al. Recurrence Risk for Autism Spectrum Disorders: A Baby Siblings Research Consortium Study. Pediatrics [Internet]. 2011 Sep [cited 2022 Oct 10];128(3):e488–95. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164092/
1.
Yoo J. Differential diagnosis and management of hyperpigmentation. Clinical and Experimental Dermatology [Internet]. 2022 [cited 2022 Oct 8];47(2):251–8. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/ced.14747
1.
Kopanos C, Tsiolkas V, Kouris A, Chapple CE, Albarca Aguilera M, Meyer R, et al. VarSome: the human genomic variant search engine. Bioinformatics [Internet]. 2019 Jun 1 [cited 2022 Oct 3];35(11):1978–80. Available from: https://doi.org/10.1093/bioinformatics/bty897
1.
Tornese G, Pellegrin MC, Barbi E, Ventura A. Pediatric endocrinology through syndromes. European Journal of Medical Genetics [Internet]. 2020 [cited 2022 Oct 3];63(1):103614. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1769721218303161
1.
Annual Health Checks for People with Intellectual Disabilities in General Practice [Internet]. [cited 2022 Oct 3]. Available from: http://www.intellectualdisability.info/how-to-guides/articles/annual-health-checks-for-people-with-intellectual-disabilities-in-general-practice
1.
Lagorio I, Brunelli L, Striano P. Paroxysmal Nonepileptic Events in Children: A Video Gallery and a Guide for Differential Diagnosis. Neurology: Clinical Practice [Internet]. 2022 Aug 1 [cited 2022 Oct 3];12(4):320–7. Available from: https://cp.neurology.org/content/12/4/320
1.
de Freitas FD, Pimenta S, Soares S, Gonzaga D, Vaz-Matos I, Prior C. El papel de los cannabinoides en los trastornos del neurodesarrollo de niños y adolescentes. Rev Neurol. :9.
1.
Marwaha S, Knowles JW, Ashley EA. A guide for the diagnosis of rare and undiagnosed disease: beyond the exome. Genome Medicine [Internet]. 2022 Feb 28 [cited 2022 Oct 3];14(1):23. Available from: https://doi.org/10.1186/s13073-022-01026-w
1.
Patel RA, Hall DA, Eichenseer S, Bailey M. Movement Disorders and Hematologic Diseases. Mov Disord Clin Pract [Internet]. 2020 Dec 29 [cited 2022 Oct 3];8(2):193–207. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853188/
1.
Girirajan S, Rosenfeld JA, Coe BP, Parikh S, Friedman N, Goldstein A, et al. Phenotypic Heterogeneity of Genomic Disorders and Rare Copy-Number Variants. New England Journal of Medicine [Internet]. 2012 Oct 4 [cited 2022 Oct 3];367(14):1321–31. Available from: https://doi.org/10.1056/NEJMoa1200395
1.
Bharath R, Unnikrishnan AG, Thampy MV, Anilkumar A, Nisha B, Praveen VP, et al. Turner syndrome and its variants. Indian J Pediatr [Internet]. 2010 [cited 2022 Sep 24];77(2):193–5. Available from: http://link.springer.com/10.1007/s12098-009-0226-7
1.
Liehr T. Cytogenetically visible copy number variations (CG-CNVs) in banding and molecular cytogenetics of human; about heteromorphisms and euchromatic variants. Mol Cytogenet [Internet]. 2016 Jan 22 [cited 2022 Sep 24];9:5. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724132/
1.
Nothing’s for sure, that’s for sure: Evaluating variants of uncertain significance | Beyond the Ion Channel [Internet]. [cited 2022 Sep 22]. Available from: http://epilepsygenetics.net/2016/08/11/nothings-for-sure-thats-for-sure-evaluating-variants-of-uncertain-significance/
1.
Vaz-Drago R, Custódio N, Carmo-Fonseca M. Deep intronic mutations and human disease. Hum Genet [Internet]. 2017 [cited 2020 May 3];136(9):1093–111. Available from: http://link.springer.com/10.1007/s00439-017-1809-4
1.
Barros FS, Marussi VHR, Amaral LLF, da Rocha AJ, Campos CMS, Freitas LF, et al. The Rare Neurocutaneous Disorders: Update on Clinical, Molecular, and Neuroimaging Features. Topics in Magnetic Resonance Imaging [Internet]. 2018 [cited 2019 Apr 28];27(6):433–62. Available from: http://Insights.ovid.com/crossref?an=00002142-201812000-00004
1.
Gabriele M, Lopez Tobon A, D’Agostino G, Testa G. The chromatin basis of neurodevelopmental disorders: Rethinking dysfunction along the molecular and temporal axes. Progress in Neuro-Psychopharmacology and Biological Psychiatry [Internet]. 2018 Jun 8 [cited 2019 Oct 5];84:306–27. Available from: http://www.sciencedirect.com/science/article/pii/S0278584617305389
1.
Guerra J, Cacabelos R. Genomics of speech and language disorders. JTGG [Internet]. 2019 [cited 2020 Sep 25]; Available from: https://jtggjournal.com/article/view/3118
1.
Truty R, Paul J, Kennemer M, Lincoln SE, Olivares E, Nussbaum RL, et al. Prevalence and properties of intragenic copy-number variation in Mendelian disease genes. Genet Med [Internet]. 2019 [cited 2019 Sep 3];21(1):114–23. Available from: http://www.nature.com/articles/s41436-018-0033-5
1.
Garone G, Capuano A, Travaglini L, Graziola F, Stregapede F, Zanni G, et al. Clinical and Genetic Overview of Paroxysmal Movement Disorders and Episodic Ataxias. IJMS [Internet]. 2020 May 20 [cited 2021 Sep 2];21(10):3603. Available from: https://www.mdpi.com/1422-0067/21/10/3603
1.
Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, et al. A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. Human Mutation [Internet]. 2016 [cited 2022 Sep 22];37(1):127–34. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1002/humu.22918
1.
Beetz C, Bauer P. Dual genetic diagnoses - underappreciated “double trouble.” JBCGenetics [Internet]. 2020 [cited 2022 Sep 13];52–3. Available from: https://www.ejmanager.com/fulltextpdf.php?mno=135141
1.
Posey JE, Harel T, Liu P, Rosenfeld JA, James RA, Coban Akdemir ZH, et al. Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation. New England Journal of Medicine [Internet]. 2017 Jan 5 [cited 2022 Sep 13];376(1):21–31. Available from: https://doi.org/10.1056/NEJMoa1516767
1.
Koutroumanidis M, Arzimanoglou A, Caraballo R, Goyal S, Kaminska A, Laoprasert P, et al. The role of EEG in the diagnosis and classification of the epilepsy syndromes: a tool for clinical practice by the ILAE Neurophysiology Task Force (Part 2). Epileptic Disorders [Internet]. 2017 Dec 1 [cited 2022 Sep 12];19(4):385–437. Available from: http://www.jle.com/fr/revues/epd/e-docs/the_role_of_eeg_in_the_diagnosis_and_classification_of_the_epilepsy_syndromes_a_tool_for_clinical_practice_by_the_ilae_neurophysiology_task_force_part_2__311218/article.phtml?tab=texte
1.
Koutroumanidis M, Arzimanoglou A, Caraballo R, Goyal S, Kaminska A, Laoprasert P, et al. The role of EEG in the diagnosis and classification of the epilepsy syndromes: a tool for clinical practice by the ILAE Neurophysiology Task Force (Part 1). Epileptic Disorders [Internet]. 2017 Sep 1 [cited 2022 Sep 12];19(3):233–98. Available from: http://www.jle.com/fr/revues/epd/e-docs/the_role_of_eeg_in_the_diagnosis_and_classification_of_the_epilepsy_syndromes_a_tool_for_clinical_practice_by_the_ilae_neurophysiology_task_force_part_1__310508/article.phtml?tab=texte
1.
Bronkhorst AJ, Ungerer V, Oberhofer A, Gabriel S, Polatoglou E, Randeu H, et al. New Perspectives on the Importance of Cell-Free DNA Biology. Diagnostics [Internet]. 2022 Sep 3 [cited 2022 Sep 12];12(9):2147. Available from: https://www.mdpi.com/2075-4418/12/9/2147
1.
Friedman JM. Neurofibromatosis 1 [Internet]. University of Washington, Seattle; 2022 [cited 2022 Sep 12]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1109/
1.
Myths of Human Genetics: Introduction [Internet]. [cited 2022 Sep 6]. Available from: https://udel.edu/~mcdonald/mythintro.html
1.
Zafar S, Doria J, Karceski S. Should we standardize the EEG classification of mild, moderate, and severe cerebral dysfunction? Epilepsy Behav [Internet]. 2020 Nov 1 [cited 2022 Sep 6];112. Available from: https://www.epilepsybehavior.com/article/S1525-5050%2820%2930511-4/fulltext
1.
Marks K, Coutinho E, Vincent A. Maternal-Autoantibody-Related (MAR) Autism: Identifying Neuronal Antigens and Approaching Prospects for Intervention. JCM [Internet]. 2020 Aug 7 [cited 2022 Aug 31];9(8):2564. Available from: https://www.mdpi.com/2077-0383/9/8/2564
1.
Watkins CE, Litchfield J, Song E, Jaishankar GB, Misra N, Holla N, et al. Chronic granulomatous disease, the McLeod phenotype and the contiguous gene deletion syndrome-a review. Clin Mol Allergy [Internet]. 2011 Nov 23 [cited 2022 Aug 25];9:13. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3267648/
1.
Weaver DD, Christian JC. Familial variation of head size and adjustment for parental head circumference. J Pediatr. 1980 Jun;96(6):990–4.
1.
Pös O, Radvanszky J, Buglyó G, Pös Z, Rusnakova D, Nagy B, et al. DNA copy number variation: Main characteristics, evolutionary significance, and pathological aspects. Biomedical Journal [Internet]. 2021 Oct 1 [cited 2022 Aug 17];44(5):548–59. Available from: https://www.sciencedirect.com/science/article/pii/S2319417021000093
1.
Talukdar S, Hawkes L, Hanson H, Kulkarni A, Brady AF, McMullan DJ, et al. Structural Aberrations with Secondary Implications (SASIs): consensus recommendations for reporting of cancer susceptibility genes identified during analysis of Copy Number Variants (CNVs). Journal of Medical Genetics [Internet]. 2019 Nov 1 [cited 2022 Aug 17];56(11):718–26. Available from: https://jmg.bmj.com/content/56/11/718
1.
Mossink B, Negwer M, Schubert D, Nadif Kasri N. The emerging role of chromatin remodelers in neurodevelopmental disorders: a developmental perspective. Cell Mol Life Sci [Internet]. 2021 Mar 1 [cited 2022 Aug 15];78(6):2517–63. Available from: https://doi.org/10.1007/s00018-020-03714-5
1.
Murphy NA, Elias ER, for the Council on Children With Disabilities. Sexuality of Children and Adolescents With Developmental Disabilities. Pediatrics [Internet]. 2006 Jul 1 [cited 2022 Jul 22];118(1):398–403. Available from: https://doi.org/10.1542/peds.2006-1115
1.
Quint EH, O’Brien RF, COMMITTEE ON ADOLESCENCE, The North American Society for Pediatric and Adolescent Gynecology, Braverman PK, Adelman WP, et al. Menstrual Management for Adolescents With Disabilities. Pediatrics [Internet]. 2016 Jul 1 [cited 2022 Jul 22];138(1):e20160295. Available from: https://doi.org/10.1542/peds.2016-0295
1.
McHugh JC, Daly N, Colfer A. Measuring the effects of pre-test probability on out-patient first EEG investigation in children – A guide to evidence-based EEG triage in a pandemic. Seizure - European Journal of Epilepsy [Internet]. 2021 Mar 1 [cited 2022 Jul 20];86:8–15. Available from: https://www.seizure-journal.com/article/S1059-1311%2821%2900010-8/fulltext
1.
Koutroumanidis M, Arzimanoglou A, Caraballo R, Goyal S, Kaminska A, Laoprasert P, et al. The role of EEG in the diagnosis and classification of the epilepsy syndromes: a tool for clinical practice by the ILAE Neurophysiology Task Force (Part 1). Epileptic Disorders [Internet]. 2017 Sep 1 [cited 2022 Jul 20];19(3):233–98. Available from: http://www.jle.com/fr/revues/epd/e-docs/the_role_of_eeg_in_the_diagnosis_and_classification_of_the_epilepsy_syndromes_a_tool_for_clinical_practice_by_the_ilae_neurophysiology_task_force_part_1__310508/article.phtml?tab=texte
1.
Koutroumanidis M, Arzimanoglou A, Caraballo R, Goyal S, Kaminska A, Laoprasert P, et al. The role of EEG in the diagnosis and classification of the epilepsy syndromes: a tool for clinical practice by the ILAE Neurophysiology Task Force (Part 2). Epileptic Disorders [Internet]. 2017 Dec 1 [cited 2022 Jul 20];19(4):385–437. Available from: http://www.jle.com/fr/revues/epd/e-docs/the_role_of_eeg_in_the_diagnosis_and_classification_of_the_epilepsy_syndromes_a_tool_for_clinical_practice_by_the_ilae_neurophysiology_task_force_part_2__311218/article.phtml?tab=texte
es_ESSpanish