Análise cromossômica por microarranjos em probandos com indicação clínica de Síndrome de Down sem alterações cariotípicas.

Abstract

Genetically determined conditions affect millions of families worldwide. More than 40% of cases of severe Intellectual Disability (ID) are caused by monogenic diseases or chromosomal abnormalities. In Brazil, a country with 185 million people, some disability is expected to affect about 25 million (14%) people, and of these, approximately 17 million (68%) would have ID. Downs Syndrome (DS) was recognized and first described by John Langdon Down in 1866. DS is the most common autosomal genetic abnormality, contributing with approximately 18% of all cases of DI. The average prevalence rate is 1:650 live births, which increases with advancing maternal age. DS aetiology is related to the excess of genetic material from an extra chromosome 21. DS could also results from chromosomal translocation resulting in trisomy 21 and post-zygotic mosaicism. The phenotype associated with DS varies in signs and intensity. However, ID is a highly conserved feature on those who are affected by the trisomy 21 and has a major impact on public health and individual quality of life. Despite the phenotypic pathognomonic characteristics of DS, there is still a challenge in the clinical diagnosis. The current study reported the laboratory investigation of 6 probands with complex phenotypes, which had features in common with the SD. However, while the physical examination generated the clinical hypothesis, the cytogenetic laboratory tests were not useful for diagnostic resolution. In this context, Chromosomal Microarray Analysis (CMA) was used to support the laboratory diagnosis of cases with clinical indication of SD whose karyotypes showed up without apparent numerical or structural chromosome changes. In our study, laboratory diagnosis using CMA was not possible for 83.3% (5-6) of the cases. For those, higher-resolution methods such as exon sequencing or new generation sequencing must be used to assist elucidating the underlying genomic alteration behind the observed the rare variant phenotypes. As discussed by Howell et al (2013), despite major advances in diagnosis using neuroimaging, molecular, and metabolic strategies a significant proportion of children with global developmental delay, with or without dysmorphic signs will remain without a conclusive diagnosis of the underlying cause clinically recognized phenotype. In our study, although there were no genomic changes suggestive of DS, the analyzed cases showed a gain and losses of genomic material identified by the CMA that have potential to explain the phenotype of probands and guide decision-making on the part of families and the health care providers. The results presented and discussed in this dissertation showed a detection rate of ~17%. However, no patient had DS, as suggested by the clinical hypothesis, as there was no involvement of the critical region of Down Syndrome on chromosome 21 in any case. The laboratory diagnosis rate for the DS was 78.5% in line with expectations and trends in the diagnosis of this syndrome worldwide. The CMA allowed establishing the genotype-phenotype correlation for one case, for which it was observed a proximal deletion of SHANK3 gene whose haploinsufficiency is responsible for Phelan- McDermid Syndrome. In this study we identified four genes that could be contribute to the phenotypes of probands, namely: AGL12, MAGEA8, IL1RAPL1, and CNTNAP2, located in 22p13, Xq28, Xp21 and 7q35, respectively. This set of genes should be highlighted in structural and functional genomic studies to pinpoint candidate genes correlated to rare phenotypes.