A genetic study of autism in Costa Rica: multiple variables affecting IQ scores observed in a preliminary sample of autistic cases

BACKGROUND: Autism is a heritable developmental disorder of communication and socialization that has not been well studied in Hispanic populations. Therefore, we are collecting and evaluating all possible cases of autism from a population isolate in the Central Valley of Costa Rica (CVCR) for a clinical and genetic study. METHODS: We are assessing all subjects and parents, as appropriate, using the newly translated Spanish versions of the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS) as well as tests of intelligence and adaptive behavior. Detailed obstetric and family medical/psychiatric histories are taken. All cases are tested for Fragile X and will be extensively evaluated for cytogenetic abnormalities. RESULTS: To date we have obtained clinical evaluations on over 76 cases of possible autism referred to our study and report data for the initial 35 complete cases. The mean age of the probands is 6.7 years, and 31 of the 35 cases are male. Twenty-one of the cases have IQs <50 and only 6 cases have IQs ≥ 70. Over half of the mothers had complications during pregnancy and/or delivery. No cases have tested positively for Fragile X or PKU. Chromosomal G-banding is not yet complete for all cases. CONCLUSION: Diagnostic data gathered on cases of autism in the CVCR using Spanish versions of the ADI-R and ADOS look similar to that generated by studies of English-speaking cases. However, only 17% of our cases have IQs within the normal range, compared to the figure of 25% seen in most studies. This result reflects an ascertainment bias in that only severe cases of autism come to treatment in the CVCR because there are no government-sponsored support programs or early intervention programs providing an incentive to diagnose autism. The severity of mental retardation seen in most of our cases may also be exaggerated by the lack of early intervention programs and the use of IQ tests without Costa Rican norms. Still, we must formally train healthcare providers and teachers to recognize and refer autistic cases with normal or near normal IQs that are not seen in treatment

A large-scale survey of the novel 15q24 microdeletion syndrome in autism spectrum disorders identifies an atypical deletion that narrows the critical region

<p>Abstract</p> <p>Background</p> <p>The 15q24 microdeletion syndrome has been recently described as a recurrent, submicroscopic genomic imbalance found in individuals with intellectual disability, typical facial appearance, hypotonia, and digital and genital abnormalities. Gene dosage abnormalities, including copy number variations (CNVs), have been identified in a significant fraction of individuals with autism spectrum disorders (ASDs). In this study we surveyed two ASD cohorts for 15q24 abnormalities to assess the frequency of genomic imbalances in this interval.</p> <p>Methods</p> <p>We screened 173 unrelated subjects with ASD from the Central Valley of Costa Rica and 1336 subjects with ASD from 785 independent families registered with the Autism Genetic Resource Exchange (AGRE) for CNVs across 15q24 using oligonucleotide arrays. Rearrangements were confirmed by array comparative genomic hybridization and quantitative PCR.</p> <p>Results</p> <p>Among the patients from Costa Rica, an atypical <it>de novo </it>deletion of 3.06 Mb in 15q23-q24.1 was detected in a boy with autism sharing many features with the other 13 subjects with the 15q24 microdeletion syndrome described to date. He exhibited intellectual disability, constant smiling, characteristic facial features (high anterior hairline, broad medial eyebrows, epicanthal folds, hypertelorism, full lower lip and protuberant, posteriorly rotated ears), single palmar crease, toe syndactyly and congenital nystagmus. The deletion breakpoints are atypical and lie outside previously characterized low copy repeats (69,838-72,897 Mb). Genotyping data revealed that the deletion had occurred in the paternal chromosome. Among the AGRE families, no large 15q24 deletions were observed.</p> <p>Conclusions</p> <p>From the current and previous studies, deletions in the 15q24 region represent rare causes of ASDs with an estimated frequency of 0.1 to 0.2% in individuals ascertained for ASDs, although the proportion might be higher in sporadic cases. These rates compare with a frequency of about 0.3% in patients ascertained for unexplained intellectual disability and congenital anomalies. This atypical deletion reduces the minimal interval for the syndrome from 1.75 Mb to 766 kb, implicating a reduced number of genes (15 versus 38). Sequencing of genes in the 15q24 interval in large ASD and intellectual disability samples may identify mutations of etiologic importance in the development of these disorders.</p

The NRG1 exon 11 missense variant is not associated with autism in the Central Valley of Costa Rica

<p>Abstract</p> <p>Background</p> <p>We are conducting a genetic study of autism in the isolated population of the Central Valley of Costa Rica (CVCR). A novel Neuregulin 1 (NRG1) missense variant (exon 11 G>T) was recently associated with psychosis and schizophrenia (SCZ) in the same population isolate.</p> <p>Methods</p> <p>We genotyped the NRG1 exon 11 missense variant in 146 cases with autism, or autism spectrum disorder, with CVCR ancestry, and both parents when available (N = 267 parents) from 143 independent families. Additional microsatellites were genotyped to examine haplotypes bearing the exon 11 variant.</p> <p>Results</p> <p>The NRG1 exon 11 G>T variant was found in 4/146 cases including one de novo occurrence. The frequency of the variant in case chromosomes was 0.014 and 0.045 in the parental non-transmitted chromosomes. At least 6 haplotypes extending 0.229 Mb were associated with the T allele. Three independent individuals, with no personal or family history of psychiatric disorder, shared at least a 1 megabase haplotype 5' to the T allele.</p> <p>Conclusion</p> <p>The NRG1 exon 11 missense variant is not associated with autism in the CVCR.</p

Alelos intermedios y expandidos en el gen FMR1 en una población con autismo de Costa Rica

Objective: We aimed to determine the distribution of intermediate and expanded FMR1 alleles in Costa Rican individuals diagnosed with autism. Materials and methods: A total of 212 autism spectrum disorder (ASD) cases of Costa Rican individuals and 943 male newborn controls were screened by means of polymerase chain reaction to determine the frequency of intermediate, premutation, and full mutation FMR1 alleles. Full mutation suspected cases were confirmed by Southern blot analyses. Frequencies of FMR1 alleles in the case group were compared with frequencies observed in a population-based sample of male newborn controls. Results: A significant excess of intermediate allele carriers was found in ASD individuals as compared to controls (χ2 test, p < 0.001). Four, out of 188 males in the case group, were identified as full mutation carriers. Conclusions: Our results suggest a possible involvement of the gray zone or intermediate alleles in ASD.Objetivo: Determinar la distribución de los alelos FMR1 intermedios y expandidos en individuos costarricenses diagnosticados con autismo. Materiales y métodos: Para determinar la frecuencia de la mutación intermedia, la premutación y la mutación completa en el gen FMR1, se tamizaron 212 casos con autismo y 943 recién nacidos de sexo masculino como controles. Los casos con sospecha de ser portadores de la mutación completa se confirmaron mediante análisis de transferencia de Southern. Las frecuencias de los alelos del gen FMR1 en el grupo de casos se compararon con las frecuencias observadas en una muestra basada en la población de controles de recién nacidos varones. Resultados: Se encontró un exceso significativo de portadores de alelos intermedios en los individuos con autismo en comparación con los controles (χ2, p < 0.001). Cuatro varones del grupo de casos fueron identificados como portadores de la mutación completa. Conclusiones: Nuestros resultados sugieren una posible participación de los alelos intermedios en el autismo.Consejo Nacional de Investigaciones Científicas y Tecnológicas/[]/CONICIT/Costa RicaUniversidad de Costa Rica/[742-A3-303]/UCR/Costa RicaUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA