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Master's Dissertation
DOI
https://doi.org/10.11606/D.5.2022.tde-09062022-124921
Document
Author
Full name
Bárbara Leitão Braga
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2022
Supervisor
Committee
Mendonça, Berenice Bilharinho de (President)
Gomes, Nathalia Lisboa Rosa Almeida
Jorge, Alexander Augusto de Lima
Xavier, Ana Claudia Latrônico
Title in Portuguese
Comparação do perfil genético de pacientes nascidos pequenos para a idade gestacional com e sem genitália atípica
Keywords in Portuguese
Ambiguidade genital
Diferenças do desenvolvimento sexual
Hipospadia
Recém-nascido pequeno para a idade gestacional
Sequenciamento de nucleotídeos em larga escala
Síndrome de Silver-Russell
Técnicas de diagnóstico molecular
Abstract in Portuguese
A hipospadia é um distúrbio congênito comum da formação genital masculina. Crianças nascidas pequenas para a idade gestacional (PIG) apresentam alta frequência de hipospadia de etiologia indeterminada. Nenhum estudo anterior investigou a etiologia molecular da hipospadia em meninos nascidos PIG usando sequenciamento paralelo em larga escala. Nosso objetivo é relatar os achados genéticos de uma coorte de pacientes nascidos PIG com hipospadia mediana ou proximal através de sequenciamento paralelo em larga escala e analisar o perfil molecular de pacientes PIG sem hipospadia. Dentro de uma coorte de indivíduos DDS 46,XY, foram selecionados 79 com este fenótipo, incluindo treze indivíduos com características sindrômicas. Os pacientes sindrômicos com três ou mais características clínicas principais da síndrome de Silver-Russell (SRS) foram estudados primeiramente por MLPA. As demais amostras de DNA foram estudadas por sequenciamento paralelo em larga escala. Entre os pacientes sindrômicos, a perda de metilação do DNA na região de controle de imprinting H19/IGF2 foi identificada em oito indivíduos com suspeita clínica de SRS e a dissomia uniparental do cromossomo 7 foi identificada em um paciente. Duas novas variantes patogênicas em heterozigose composta foram identificadas no gene CUL7 estabelecendo o diagnóstico de síndrome 3M em um paciente, e uma nova variante homozigótica no TRIM37 foi identificada em outro menino com fenótipo de nanismo de Mulibrey. Entre os indivíduos não sindrômicos, oito variantes heterozigotas raras foram identificadas em sete genes relacionados ao DDS. No entanto, nenhuma das variantes encontradas explica o fenótipo dos pacientes. Em conclusão, não foi encontrado defeito genético que esclareça a etiologia da hipospadia na maioria das crianças PIG não sindrômicas, corroborando a hipótese de que causas multifatoriais, novos genes e/ou defeitos epigenéticos não identificados podem influenciar nessa condição
Title in English
Analysis of the genetic profile of patients born small for gestational age with and without atypical genitalia
Keywords in English
Genital ambiguity
Highthroughput nucleotide sequencing
Hypospadias
Infant small for gestational age
Molecular diagnostic techniques
Silver-Russell syndrome, Disorders of sex development
Abstract in English
Hypospadias is a common congenital disorder of male genital formation. Children born small for gestational age (SGA) present a high frequency of hypospadias of undetermined etiology. No previous study investigated the molecular etiology of hypospadias in boys born SGA using massively parallel sequencing. Our objective is to report the genetic findings of a cohort of patients born SGA with medium or proximal hypospadias and the analyses of the molecular profile of patients born SGA without hypospadias. We identified 79 SGA individuals from a large cohort of 46,XY DSD patients, including 13 individuals with syndromic features. DNA samples from subjects were studied by either whole exome sequencing or target gene panel approach. The syndromic patients having three or more main clinical features of Silver-Russell syndrome (SRS) were first studied by MLPA. Among the syndromic patients, loss of DNA methylation at the imprinting control region H19/IGF2 was identified in 8 individuals with SRS clinical diagnosis and uniparental disomy (UPD) of chromosome 7 in one patient. Two novel pathogenic variants in compound heterozygous state were identified in the CUL7 gene establishing the diagnosis of 3M syndrome in one patient, and a novel homozygous variant in TRIM37 was identified in another boy with Mulibrey nanism phenotype. Among the nonsyndromic subjects, eight rare heterozygous variants were identified in seven DSD-related genes. However, none of the variants found can explain the phenotype by themselves. In conclusion, a genetic defect that clarifies the etiology of hypospadias was not found in most of the non-syndromic SGA children, supporting the hypothesis that multifactorial causes, new genes, and/or unidentified epigenetic defects may have an influence in this condition
 
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Publishing Date
2022-06-14
 
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