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Master's Dissertation
DOI
https://doi.org/10.11606/D.41.2021.tde-20052021-094305
Document
Author
Full name
Leonardo Galleni Leão da Silva
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2021
Supervisor
Committee
Vainzof, Mariz (President)
Bertola, Débora Romeo
Giannetti, Juliana Gurgel
Moreno, Cristiane de Araújo Martins
Title in Portuguese
Caracterização molecular de pacientes brasileiros com Miopatia de Central Core, através de ferramentas de Sequenciamento de Nova Geração
Keywords in Portuguese
1. Miopatia de Central Core
2. Sequenciamento de Nova Geração
3. Receptor de rianodina
Abstract in Portuguese
A miopatia de Central Core (CCD) é uma doença neuromuscular hereditária, caracterizada pela presença de "cores" nas fibras musculares. Clinicamente, os o início dos sintomas nos pacientes é perinatal, com hipotonia, atrofia muscular, hiporreflexia e atraso no desenvolvimento motor. A CCD é causada predominantemente por mutações no gene RYR1.Este gene codifica o receptor de ryanodina, que é um canal de liberação de cálcio intracelular do retículo sarcoplasmático para ocitosol, em resposta a despolarização da membrana plasmática. Mutações nesse gene estão também associadas a suscetibilidade a Hipertermia Maligna (MHS). O objetivo deste trabalho consistiu em realizar estudo molecular para identificação de mutações primárias em pacientes com quadro clínico e histológico CCD, para diagnostico e aconselhamento genético da família. Foram avaliadas 21 famílias com pacientes CCD, e identificamos variantes no gene RYR1 em 20 famílias. Foi possível confirmar a patogenicidade molecular em 16 delas.A maioria destas variantes (23/24) são de sentido trocado, e únicas nas famílias. Duas mutações foram recorrentes em duas famílias. Identificamos 6 famílias (5nãoconsanguíneas)com variantes bialelicas resultando em 28% dos casos com possível herança AR. Identificamos 9 variantes não descritas na literatura, sendo cinco delas de significado patogênico.Identificamos uma família com duas mutações no exon 102, segregando em cis, sugerindo um efeito aditivo de duas mutações em um mesmo alelo. Este trabalho ressalta a importância da utilização da tecnologia de Sequenciamento de Nova Geração para o diagnóstico de doenças genéticas, e seu impacto na melhoria do aconselhamento genético adequado de famílias que possuem doenças genéticas raras e que ainda necessitam de estudos para serem melhor compreendidas
Title in English
Molecular characterization of brazilian patients with Central Core Disease using Next Generation Sequencing tools
Keywords in English
1. Central Core Disease
2. Next Generation Sequencing
3. Ryanodine receptor
Abstract in English
Central Core myopathy is an inherited neuromuscular disease, characterized by the presence of Cores in muscle biopsy. The Clinical manifestation of symptoms is perinatal. Patients present hypotonia, muscle atrophy, hyporeflexia, and delayed motor development. CCD is predominantly cause by mutations in the RYR1 gene. This gene encodes the ryanodine receptor 1, which is an intracellular calcium release channel from the sarcoplasmic reticulum to the cytosol, in response to depolarization of the plasma membrane. Mutations in this gene are also associated with Malignant Hyperthermia susceptibility (MHS). The objective of this work was to carry out a molecular study to identify primary mutations in patients with clinical and histological characteristics of CCD, for diagnosis and genetic counseling of the family. We evaluated 21 families with CCD patients and identified RYR1 gene variants in 20 families. It was possible to confirm molecular pathogenicity in 16 of them. Most of these variants (23/24) are missenses and unique in families. Two variants were recurrent in two different families. We identified six families with biallelic mutations, five non-consanguineous, resulting in 28% of cases with possible AR inheritance. We identified nine variants not described in the literature, which five of them were classified as pathogenic. We identified a family with two mutations in exon 102, segregating in cis, suggesting an additive effect of two mutations in the same allele. This work highlights the importance of using New Generation Sequencing technologies for the diagnosis of genetic diseases and their impact on improving adequate genetic counseling for families that have rare genetic diseases, and that still need studies complementary to elucidate them
 
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Leonardo_Galleni.pdf (5.30 Mbytes)
Publishing Date
2021-05-23
 
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