Background: Intellectual Disability (ID) affects 2-3% of population worldwide (1). Whole exome sequencing (WES) has been considered a successful strategy for ID genetic studies, providing a growing list of both candidate and validated ID genes (2). The majority of the studies in literature used clinical samples. Very few studies using population-based samples has been conducted, a design that can provide more realistic ID prevalence estimates. Additionally, few studies have been performed in middle-income countries. In southern Brazil, in the 2004 Pelotas Birth Cohort study, whose participants have been followed eight times since birth (3), ID prevalence was 4.5%. A total of 12.6% were classified as idiopathic (4). These individuals were chosen for evaluation by WES. In this study we aim to clarify ID etiology, performing WES in individuals with idiopathic ID from the 2004 Pelotas Birth Cohort study to identify de novo variants (DNVs). Methods: WES was performed on 13 ID patients (8 boys) and their parents, in a trio design, when participants were 15 years of age. A score below 70 at WPPSI and WISC-III (5,6) intelligence scales at 4 and 7 years of age was considered inclusion criteria to select individuals to genetic study, including clinical, cytogenetics and molecular diagnosis of the cohort members. Individuals who persist without diagnosis were selected for exome analysis. Genomic DNA was obtained from participants' blood and saliva samples. WES was performed using the Twist Human Core Exome kit (Twist bioscience) on an Illumina sequencer (Illumina, Inc.). Alignment/mutation detection (based on GRCh37) was done by custom bioinformatics processes (germ algorithm v3.5). Pathogenicity of the variants was classified according to American College of Medical Genetics (ACMG) protocol (7). Results: Our analysis revealed no pathogenic or probably pathogenic variants that could explain the clinical findings observed in 13 participants. One proband (7,7% of the adolescents) presented a variant of uncertain significance (VUS) in heterozygosis. The variant NM_003688.3: c.2410G>A: p.(Gly804Ser) was identified in the exon 25 of the CAlcium/calmodulin dependent Serine Protein Kinase (CASK) gene (Xp11.4). This mutation (dbSNP: rs1064796884) results in a non-conservative amino acid substitution. Clinical findings included microcephaly, intellectual disability, anxiety and depression as documented in this cohort member. Microcephaly and mild intellectual disability were reported in family history also. Preliminary karyotype and CGH-array were normal. Discussion: This study is one of the few population-based cohort studies from low and middle income countries. Only one individual had a compatible response from classic clinical characteristics. The prevalence of positive genetic results observed is in agreement with those found in population-based studies(8). The CASK gene was already linked to FG Syndrome, 4 [FGS4, OMIM:300422] and Intellectual disability and microcephaly with pontine and cerebellar hypoplasia [OMIM:300749]. It is possible that the remaining individuals have mutations in regulatory regions and we were not able to assess(9). Data obtained from these patients may be reanalyzed in the future, and they may be eligible for whole genome sequencing(10).