Avaliação de mutações germinativas em famílias portadoras da Síndrome da Apneia Obstrutiva do Sono (SAOS) através de exoma

Abstract

Obstructive sleep apnea syndrome (OSAS) is characterized by complete or partial obstruction of the upper airways, resulting in periods of sleep associated apnea. OSAS increases morbidity and mortality risk from cardiovascular and cerebrovascular diseases. While heritability of OSAS is estimated at ~40%, the precise underlying genes remain elusive. The aim of present study is define the genetic basis of seemingly monogenic OSAS in two Brazilian families. Brazilian families with OSAS that follows as seemingly autosomal dominant inheritance pattern were recruited. Whole exome sequencing of germline DNA and the generated data were analyzed using Mendel,MD software. Variants selected were analyzed using Varstation® with subsequent analyses that included validation by Sanger sequencing, pathogenic score assessment by ACMG criteria, cosegregation analyses (when possible) allele frequency, tissue expression patterns, pathway analyses, effect on protein folding modeling using SwissModel and RaptorX. Two families (six affected OSAS cases and three unaffected controls) were analyzed. A comprehensive multistep analyses yielded variants in COX20 (rs946982087) (family A), PTPDC1 (rs61743388) and TMOD4 (rs141507115) (family B) that seemed to be strong candidate genes for being OSAS associated genes in these families. In conclusion, sequence variants in COX20, PTPDC1 and TMOD4 seemingly are associated with OSAS phenotype in these families. Further studies in more, ethnically diverse families and nonfamilial OSAS cases are needed to better define the role of these variants as contributors to OSAS phenotype.