A Cohort Study of Individuals with Neurodevelopmental Disorders and/or Congenital Anomalies Investigated by High- Resolution Chromosomal Microarrays in Southern Brazil: The Significance of Autism Spectrum Disorder

Abstract

Chromosomal microarray (CMA) is the reference in evaluation of copy number variations (CNVs) in individuals with neurodevelopmental disorders (NDDs), such as intellectual disability (ID) and/or autism spectrum disorder (ASD), which affect around 3–4% of the world’s population. Modern platforms for CMA, also include probes for single nucleotide polymorphisms (SNPs) that detect homozygous regions in the genome, such as long contiguous stretches of homozygosity (LCSH). These regions result from complete or segmental chromosomal homozygosis and may be indicative of uniparental disomy (UPD), inbreeding, population characteristics, as well as replicative DNA repair events. In this retrospective study, we analyzed CMA reading files requested by geneticists and neurologists for diagnostic purposes along with available clinical data. Our objectives were interpreting CNVs and assess the frequencies and implications of LCSH detected by Affymetrix CytoScan®HD (41%) or 750K (59%) platforms in 1,012 patients from the south of Brazil. The patients were mainly children with NDDs and/or congenital anomalies (CAs). A total of 206 CNVs were interpreted as pathogenic, including 132 deletions and 74 duplications, were found in 17% of the patients of the cohort and across all chromosomes. Further 12% presented rare variants of uncertain clinical significance, including LPCNVs, as the only clinically relevant CNV. Within the realm of NDDs, ASD carries a particular importance, owing to its escalating prevalence and its growing repercussions for individuals, families, and communities. ASD was one of the clinical phenotypes, when not the main reason for referral to testing, for about one-third of the cohort and these patients were further analyzed as a sub-cohort. Considering only the patients with ASD, the diagnostic rate was 10%, within the range reported in the literature (8–21%). It was higher (16%) when associated with dysmorphic features and lower (7%) for "isolated" ASD (without ID and without dysmorphic features). In 953 CMAs of the whole cohort, LCSH (≥ 3 Mbp) were analyzed not only in the context of their potential pathogenic significance but were also explored to identify common LCSH in the south Brazilians population. CMA revealed at least one LCSH in 91% of the patients. For about 11.5% of patients, the LCSH suggested consanguinity from the first to the fifth degree, with a greater probability of clinical impact, and in 2.8%, they revealed a putative UPD. LCSH found at a frequency of 5% or more were considered common LCSH in the general population, allowing us to delineate 10 regions as potentially representing ancestral haplotypes of neglectable clinical significance. The main referrals to the CMA were developmental delay (56%), DI (33%), ASD (33%) and syndromic features (56%). Some phenotypes in this population may be predictive of a higher probability of indicating a carrier of a pathogenic CNV. Here we present the largest report of CMA data in a cohort with NDDs and/or CAs from the South of Brazil. We characterize the rare CNVs found along with the main phenotypes presented by each patient and show the importance and usefulness of LCSH interpretation in CMA results that incorporate SNPs, as well as we illustrate the value of CMA to investigate CNV in ASD.

Comprehensive evaluation of the child with global developmental delays or intellectual disability

“…A large study of individuals with NDDs identified dysmorphic features in approximately 47% of cases. 23) Various syndromes with distinct dysmorphic features can also result in GDD/ID; thus, clinicians must be knowledgeable and acquainted with these conditions. Fragile X syndrome, among the most prevalent of these syndromes, is characterized by identifiable clinical features that are easily noted in affected males with the full mutation.…”

“…Additionally, gait apraxia, kyphoscoliosis, sleep disturbances, episodes of laughter and cream, and a reduced response to pain are other variable characteristics of this disorder. 2,12,23,24) Anomalies affecting the musculoskeletal system, eyes, heart, genitourinary tract, and connective tissues may also be discerned during routine systemic physical examinations, potentially those indicating a specific diagnosis or guiding laboratory investigations. Behavioral assessment provides the basis for describing any atypical pattern of a child's behavior, such as aggression, repetitive and selfinjurious behavior, decreased social engagement, and impulsivity.…”