Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder
Abstract Background Neurogenetics investigations and diagnostic yield in patients with autism spectrum disorder (ASD) have significantly improved over the last few years. Yet, many patients still fail to be systematically investigated. Methods To improve access to services, an ambulatory team has be...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-08-01
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| Series: | Molecular Autism |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13229-019-0284-2 |
| _version_ | 1828489675621269504 |
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| author | Arnold Munnich Caroline Demily Lisa Frugère Charlyne Duwime Valérie Malan Giulia Barcia Céline Vidal Emeline Throo Claude Besmond Laurence Hubert Gilles Roland-Manuel Jean-Pierre Malen Mélanie Ferreri Sylvain Hanein Jean-Christophe Thalabard Nathalie Boddaert Moïse Assouline |
| author_facet | Arnold Munnich Caroline Demily Lisa Frugère Charlyne Duwime Valérie Malan Giulia Barcia Céline Vidal Emeline Throo Claude Besmond Laurence Hubert Gilles Roland-Manuel Jean-Pierre Malen Mélanie Ferreri Sylvain Hanein Jean-Christophe Thalabard Nathalie Boddaert Moïse Assouline |
| author_sort | Arnold Munnich |
| collection | DOAJ |
| description | Abstract Background Neurogenetics investigations and diagnostic yield in patients with autism spectrum disorder (ASD) have significantly improved over the last few years. Yet, many patients still fail to be systematically investigated. Methods To improve access to services, an ambulatory team has been established since 1998, delivering on-site clinical genetics consultations and gradually upgrading services to 502 children and young adults with ASD in their standard environment across 26 day-care hospitals and specialized institutions within the Greater Paris region. The evaluation included a clinical genetics consultation, screening for fragile X syndrome, metabolic workup, chromosomal microarray analysis, and, in a proportion of patients, next-generation sequencing of genes reported in ASD and other neurodevelopmental disorders. Results Fragile X syndrome and pathogenic copy number variants (CNVs) accounted for the disease in 10% of cases, including 4/312 (1.3%) with fragile X syndrome and 34/388 (8.8%) with pathogenic CNVs (19 de novo and 4 inherited). Importantly, adding high-throughput resequencing of reported intellectual disability/ASD genes to the screening procedure had a major impact on diagnostic yield in the 141 patients examined most recently. Pathogenic or likely pathogenic sequence variants in 27 disease genes were identified in 33/141 patients (23.4%; 23 were de novo and 10 inherited, including five X-linked and five recessive compound heterozygous variants). Diagnosed cases presented atypical and/or syndromic ASD with moderate to severe intellectual disability. The diagnostic yield of fragile X syndrome and array CGH testing combined with next-generation sequencing was significantly higher than fragile X syndrome and array CGH alone (p value 0.009). No inborn errors of metabolism were detected with the metabolic screening. Conclusion Based on the diagnostic rate observed in this cohort, we suggest that a stepwise procedure be considered, first screening pathogenic CNVs and a limited number of disease genes in a much larger number of patients, especially those with syndromic ASD and intellectual disability. |
| first_indexed | 2024-12-11T10:30:11Z |
| format | Article |
| id | doaj.art-82edb3badd9e428b9096501733b083a1 |
| institution | Directory Open Access Journal |
| issn | 2040-2392 |
| language | English |
| last_indexed | 2024-12-11T10:30:11Z |
| publishDate | 2019-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Autism |
| spelling | doaj.art-82edb3badd9e428b9096501733b083a12022-12-22T01:10:59ZengBMCMolecular Autism2040-23922019-08-0110111010.1186/s13229-019-0284-2Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorderArnold Munnich0Caroline Demily1Lisa Frugère2Charlyne Duwime3Valérie Malan4Giulia Barcia5Céline Vidal6Emeline Throo7Claude Besmond8Laurence Hubert9Gilles Roland-Manuel10Jean-Pierre Malen11Mélanie Ferreri12Sylvain Hanein13Jean-Christophe Thalabard14Nathalie Boddaert15Moïse Assouline16Fédération de Génétique Médicale, Institute Imagine, Inserm, Université Paris-Descartes, Hôpital Necker Enfants-Malades, Fondation Elan RetrouvéCentre de Reference Maladies Rares GénoPsy, Centre Hospitalier le Vinatier, Institut Marc JeannerodHôpital Necker Enfants-Malades, Fondation Elan RetrouvéHôpital Necker Enfants-Malades, Fondation Elan RetrouvéFédération de Génétique Médicale, Institute Imagine, Inserm, Université Paris-Descartes, Hôpital Necker Enfants-MaladesFédération de Génétique Médicale, Institute Imagine, Inserm, Université Paris-Descartes, Hôpital Necker Enfants-MaladesInstitute Imagine, Inserm, Université Paris-Descartes, Hôpital Necker Enfants-Malades, Fondation Elan RetrouvéInstitute Imagine, Inserm, Université Paris-Descartes, Hôpital Necker Enfants-Malades, Fondation Elan RetrouvéInstitute Imagine, Inserm, Université Paris-Descartes, Hôpital Necker Enfants-MaladesInstitute Imagine, Inserm, Université Paris-Descartes, Hôpital Necker Enfants-MaladesFondation Elan RetrouvéFondation Elan RetrouvéFondation Elan RetrouvéInstitute Imagine, Inserm, Université Paris-Descartes, Hôpital Necker Enfants-MaladesMAP5, CNRS, Université Paris-DescartesDepartment of Pediatric Radiology, Institute Imagine, Inserm, Université Paris-Descartes, Hôpital Necker Enfants-MaladesFondation Elan RetrouvéAbstract Background Neurogenetics investigations and diagnostic yield in patients with autism spectrum disorder (ASD) have significantly improved over the last few years. Yet, many patients still fail to be systematically investigated. Methods To improve access to services, an ambulatory team has been established since 1998, delivering on-site clinical genetics consultations and gradually upgrading services to 502 children and young adults with ASD in their standard environment across 26 day-care hospitals and specialized institutions within the Greater Paris region. The evaluation included a clinical genetics consultation, screening for fragile X syndrome, metabolic workup, chromosomal microarray analysis, and, in a proportion of patients, next-generation sequencing of genes reported in ASD and other neurodevelopmental disorders. Results Fragile X syndrome and pathogenic copy number variants (CNVs) accounted for the disease in 10% of cases, including 4/312 (1.3%) with fragile X syndrome and 34/388 (8.8%) with pathogenic CNVs (19 de novo and 4 inherited). Importantly, adding high-throughput resequencing of reported intellectual disability/ASD genes to the screening procedure had a major impact on diagnostic yield in the 141 patients examined most recently. Pathogenic or likely pathogenic sequence variants in 27 disease genes were identified in 33/141 patients (23.4%; 23 were de novo and 10 inherited, including five X-linked and five recessive compound heterozygous variants). Diagnosed cases presented atypical and/or syndromic ASD with moderate to severe intellectual disability. The diagnostic yield of fragile X syndrome and array CGH testing combined with next-generation sequencing was significantly higher than fragile X syndrome and array CGH alone (p value 0.009). No inborn errors of metabolism were detected with the metabolic screening. Conclusion Based on the diagnostic rate observed in this cohort, we suggest that a stepwise procedure be considered, first screening pathogenic CNVs and a limited number of disease genes in a much larger number of patients, especially those with syndromic ASD and intellectual disability.http://link.springer.com/article/10.1186/s13229-019-0284-2Autism spectrum disorderGene panelNext-generation sequencingMicroarrayCopy number variantSequence variant |
| spellingShingle | Arnold Munnich Caroline Demily Lisa Frugère Charlyne Duwime Valérie Malan Giulia Barcia Céline Vidal Emeline Throo Claude Besmond Laurence Hubert Gilles Roland-Manuel Jean-Pierre Malen Mélanie Ferreri Sylvain Hanein Jean-Christophe Thalabard Nathalie Boddaert Moïse Assouline Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder Molecular Autism Autism spectrum disorder Gene panel Next-generation sequencing Microarray Copy number variant Sequence variant |
| title | Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder |
| title_full | Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder |
| title_fullStr | Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder |
| title_full_unstemmed | Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder |
| title_short | Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder |
| title_sort | impact of on site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder |
| topic | Autism spectrum disorder Gene panel Next-generation sequencing Microarray Copy number variant Sequence variant |
| url | http://link.springer.com/article/10.1186/s13229-019-0284-2 |
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