[Twenty years of on-site clinical genetics consultations for people with ASD]. / Vingt ans de consultations de génétique clinique sur site dans les hôpitaux de jour pour les personnes atteintes de troubles du spectre autistique de la région parisienne.

Despite advances in neurogenetics of autism spectrum disorders (ASD), many patients fail to be systematically investigated, owing to preconceived ideas, limited access to genetics facilities and inadequacy of consultations to children with behavioural problems. To improve access to services, we reversed the paradigm and delivered on-site genetics consultations to ASD children of Greater Paris day care hospitals and specialized institutions. Since 1998, an ambulatory medical genetics team has been in operation, offering on-site consultations and services to patients and relatives in their usual environment. Because the mobile medical genetics unit operates under the umbrella of a university hospital, service laboratories were shared, including molecular cytogenetics and next generation sequencing (NGS). For the past 20 years, 502 patients from 26 institutions benefited from on-site consultations and genetics services in their usual environment. Less than 1 % of parents declined the offer. Previously undiagnosed genetics conditions were recognized in 71 ASD children, including pathogenic CNV variants (34/388 : 8.8 ; de novo : 19, inherited : 4), Fragile X (4/312 : 1.3 %) and deleterious variants in disease causing genes (33/141 ; 23.4 % : de novo : 23 ; inherited : 10, including 5 X-linked and 5 compound heterozygote mutations). Brain MRI were possible in 347 patients and 42 % were considered abnormal (146/347). All diagnosed patients presented atypical/syndromic ASD with moderate to severe intellectual disability. Thanks to such flexible organisation, a considerable number of missed consultations were tracked and families first benefited from medical genetics services. Owing to constraints imposed by behavioural problems in ASD, we suggest considering on-site genetics services to implement standard of care and counteract the loss of chance to patients and relatives.

TITLE: Vingt ans de consultations de génétique clinique sur site dans les hôpitaux de jour pour les personnes atteintes de troubles du spectre autistique de la région parisienne. ABSTRACT: Malgré les avancées de la recherche, un grand nombre de patients atteints de troubles du spectre autistique (TSA) n'ont pas accès aux explorations aujourd'hui disponibles, du fait d'idées reçues, de l'insuffisance des structures à même de les explorer et de l'inadaptation des consultations hospitalières à leurs troubles du comportement. Pour améliorer l'accès aux soins et au progrès des connaissances, nous avons inversé le paradigme et offrons depuis 20 ans des consultations de génétique clinique sur site dans les hôpitaux de jour et les institutions spécialisées de la région parisienne. Depuis 1998, une équipe mobile de génétique médicale propose aux patients et à leurs familles des consultations dans leur environnement habituel. L'unité mobile opère sous l'égide de l'hôpital universitaire Necker Enfants-Malades, qui leur donne accès aux services de biochimie, de cytogénétique moléculaire et de séquençage de nouvelle génération (NGS). En vingt ans, 502 patients appartenant à 26 institutions ont bénéficié de consultations sur site et d'un accès aux plateformes de génétique moléculaire. Moins de 1 % des parents ont décliné la proposition. Des affections génétiques ont été identifiées chez 71 patients présentant un TSA : anomalies cytogénétiques causales (34/388 : 8,8 % ; de novo : 19, héritées : 4), X Fragile (4/312 : 1,3 %) et mutations monogéniques reconnues responsables de TSA (33/141 ; 23,4 % : de novo : 23 ; héritées : 10, dont 5 liées à l'X et 5 récessives autosomiques). L'IRM cérébrale a été possible chez 347 patients et considérée comme anormale chez 42 % d'entre eux (146/347). Tous les patients diagnostiqués présentaient un TSA atypique ou syndromique, avec déficience intellectuelle modérée à sévère. Grâce à ce mode d'intervention, un grand nombre de consultations manquantes ont été rattrapées et les familles ont pu bénéficier d'une consultation de génétique. Eu égard aux contraintes imposées par les troubles du comportement dans les TSA, les consultations sur site constituent, pour les patients et leurs apparentés, un moyen d'améliorer l'accès aux soins et de réduire le risque de méconnaissance d'une pathologie organique à présentation psychiatrique.

Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder.

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.

Corpus callosum metrics predict severity of visuospatial and neuromotor dysfunctions in ARID1B mutations with Coffin-Siris syndrome.

ARID1B mutations in Coffin-Siris syndrome are a cause of intellectual disability (0.5-1%), with various degrees of autism and agenesis of the corpus callosum (10%). Little is known regarding the cognitive and motor consequences of ARID1B mutations in humans and no link has been made between corpus callosum anomalies and visuospatial and neuromotor dysfunctions. We have investigated the visuospatial and neuromotor phenotype in eight patients with ARID1B mutations. A paramedian sagittal section of the brain MRI was selected, and corpus callosum was measured in anteroposterior length, genu and trunk width. Spearman's rank order coefficients were used to explore correlations between visuospatial and social cognitive variables and dimensions of the corpus callosum. A significant correlation between genu width size and visual cognition was observed. Retrocerebellar cysts were associated with corpus callosum anomalies. Here, we show that corpus callosum anomalies caused in ARID1B mutations may be predictive of the visuospatial and motor phenotype in Coffin-Siris syndrome.