Monogenic Disorders Associated with ASD in a Large Portuguese Sample

Poster Presentation
Friday, May 11, 2018: 5:30 PM-7:00 PM
Hall Grote Zaal (de Doelen ICC Rotterdam)
F. Duque1,2,3, J. Rosmaninho-Salgado4, C. Café1, S. Mouga1,5, D. Sousa1, A. Oliveira1,2, S. Ferreira6, P. Maciel7, I. Carreira6, A. M. Vicente8 and G. Oliveira1,2,3,9, (1)Centro Hospitalar e Universitário de Coimbra - CHUC, Coimbra, Portugal, (2)University Clinic of Pediatrics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal, (3)Faculty of Medicine, Institute for Biomedical Imaging and Life Sciences (IBILI) and Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal, (4)Serviço de Genética Médica do Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal, (5)IBILI - Institute for Biomedical Imaging and Life Sciences, Faculty of Medicine, University of Coimbra, Coimbra, Portugal, (6)Laboratório de Citogenética e Genómica, Faculty of Medicine, University of Coimbra, Coimbra, Portugal, (7)Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal, (8)Instituto Nacional Saude Doutor Ricardo Jorge, Lisbon, PORTUGAL, (9)Centro de Investigação e Formação Clínica – Hospital Pediátrico – Centro Hospitalar e Universitário de Coimbra (HP-CHUC), , Portugal, Portugal

Autism spectrum disorder (ASD) is a challenging neurodevelopmental disorder, with a multifactorial origin and a complex inheritance. The great majority of ASD cases are “idiopathic” (without a known etiology). At present, the etiology of autism can only be explained in about 15-20% of the cases. The extreme heterogeneity of ASD further complicates our understanding of its biology and pathophysiology. Some individuals with ASD have an identifiable genetic etiology, for example, known rare single-gene disorders. Syndromic autism refers to genetically well-defined disorders in which ASD is observed at higher than expected frequencies. The most common of these syndromes associated with ASD is fragile X (FMR1), accounting for 2-5% of cases of ASD. Other monogenic disorders associated with ASD include tuberous sclerosis (TSC1, TSC2), neurofibromatosis (NF1), Angelman syndrome (UBE3A), Rett syndrome (MECP2) and PTEN mutations in patients with macrocephaly and autism, among others.


To report a subset of individuals with single-gene disorder associated with ASD in a large Portuguese sample.

Methods: Participants included 1608 children and adolescents, ranging in age from 2 to 18 years old (mean ± SD; 13.4 ± 6.2 years old) and a Male/Female ratio – 4.6/1. Subjects were seen as part of an outpatient clinic in a tertiary Pediatric Hospital between 1995 and 2016. To be included, all participants had to have ASD diagnosis, according to, at least positive score in two for ADI-R, ADOS and fulfilment of DSM-5 criteria. Associated medical or genetic condition that presumably is the cause of autism was considered after a detailed medical history, a carefully physical and neurologic examination and, if still there was no diagnosis, a thoroughly laboratory evaluation, which included routine testing procedures for fragile X mutations (FRAXA and FRAXE) and molecular cytogenetic abnormalities studied by comparative genome hybridization array and sequencing techniques. We also conducted a metabolic investigation. Moreover, these ASD children underwent intellectual and functional adaptive evaluations with Griffiths Mental Development Scale and/or Wechsler Intelligence Scale and Vineland Adaptive Behavior Scale (VABS), respectively.


Our findings revealed 40 Fragile X syndrome (FMR1) (2.48%) and a rare FRAXE mutation, seven Rett syndrome, six Tuberous sclerosis, four PTEN mutations, three KCNQ3-mutation, two individuals of each syndrome – Angelman, CHARGE and Pitt-Hopkins like syndrome 2 (NRXN1). With one case of each, we report a Cornelia de Lange and a Rubinstein-Taybi syndrome with ASD. Comprehensive genotype-phenotype description will be presented. Also, we highlight some interesting and published results: putative missense mutations were identified in the NLGN4 gene in two separate, unrelated, autistic patients, G99S and K378R are described.


Most of the known genetic causes of ASD are also causes of ID, implying that these two identities share common genetic basis. Comprehensive cognitive and behavior phenotyping revealed moderate to severe developmental delay/intellectual disability among syndromic ASD, in our study. Our findings are concordant with contemporaneous investigation, with extreme heterogeneity of ASD further complicates our understanding of its biology and pathophysiology.

See more of: Genetics
See more of: Genetics