Tese
Avaliação de mutações germinativas em famílias portadoras da Síndrome da Apneia Obstrutiva do Sono (SAOS) através de exoma
Fecha
2022-06-30Autor
Pedro Guimarães de Azevedo
Institución
Resumen
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.