Utilize este identificador para referenciar este registo: http://hdl.handle.net/10400.1/3043
Título: Genetic analysis of a consanguineous family with inherited Perrault syndrome
Autor: Jorge, Susana Patrícia Guerreiro
Orientador: Abramowicz, Marc
Pirson, Isabelle
Silva, Gabriela
Palavras-chave: Sindrome de Perrault
Degeneração dos ovários
Perda auditiva sensorineural
Distúrbio recessivo
Perrault syndrome
Premature ovarian failure
Sensorineural hearing loss
Recessive disorder
Data de Defesa: 2011
Resumo: Perrault syndrome is a rare autosomal recessive disorder and its hallmarks are bilateral sensorineural hearing loss in both female and male, ovarian dysgenesis in females and in some patients neurological abnormalities, revealing a clinical heterogeneity. Two genes have already been associated with the syndrome in two families, however they do not explain the disease in all affected individuals. Four affected patients, three females and one male from the same large consanguineous family with unaffected parents, were diagnosed with Perrault syndrome, suggesting a default inherited by descent from a common ancestor. The aim of the study was to identify the gene that is responsible for the disease by determining the causal mutation. In a first step, using genome-wide SNP genotyping, we delineated a single large genomic segment that was homozygous in all patients, at chr19:608,234-6,766,463. This segment is hence expected to encompass the causal mutation. Then, using bioinformatic tools the genes present there were prioritized and the AMH, KISS1R, TCF3 and DAZAP1 were chosen as possible candidates for the defect. These genes were sequenced in the four patients by direct dideoxy incorporation (Sanger) in search of a pathogenic mutation. No mutation was found. As the gene harboring the genetic cause of the syndrome remained unidentified, the full exome of one proband was sequenced by massively parallel sequencing and an homozygous variant in the ZNF77 gene was identified, which was present in all affected patient of the family. However we found copies of this mutation in control subjects from the same ethnic group, with an estimated allelic frequency that would result in 1 affected individual in 300. Considering the possibility of compound heterozygosity in spite of parental consanguinity, we re-examined the full exome, but failed to identify a gene with robust evidence for bi-allelic inactivation. We conclude that the candidate gene analyses and full exome sequencing very likely failed to identify the causal gene, either because of insufficient sequencing depth, or because the mutation was non coding, or because the mutated exon was not captured by the exome sequencing approach.
Descrição: Dissertação de mest., Biotecnologia, Faculdade de Ciências e Tecnologia, Univ. do Algarve, 2011
Peer review: yes
URI: http://hdl.handle.net/10400.1/3043
Designação: Mestrado em Biotecnologia
Aparece nas colecções:UA01-Teses

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