Lynch syndrome associated with two MLH1 promoter variants and allelic imbalance of MLH1 expression.
Hum Mutat
; 36(6): 622-30, 2015 Jun.
Article
en En
| MEDLINE
| ID: mdl-25762362
ABSTRACT
Lynch syndrome is a hereditary cancer syndrome caused by a constitutional mutation in one of the mismatch repair genes. The implementation of predictive testing and targeted preventative surveillance is hindered by the frequent finding of sequence variants of uncertain significance in these genes. We aimed to determine the pathogenicity of previously reported variants (c.-28A>G and c.-7C>T) within the MLH1 5'untranslated region (UTR) in two individuals from unrelated suspected Lynch syndrome families. We investigated whether these variants were associated with other pathogenic alterations using targeted high-throughput sequencing of the MLH1 locus. We also determined their relationship to gene expression and epigenetic alterations at the promoter. Sequencing revealed that the c.-28A>G and c.-7C>T variants were the only potentially pathogenic alterations within the MLH1 gene. In both individuals, the levels of transcription from the variant allele were reduced to 50% compared with the wild-type allele. Partial loss of expression occurred in the absence of constitutional epigenetic alterations within the MLH1 promoter. We propose that these variants may be pathogenic due to constitutional partial loss of MLH1 expression, and that this may be associated with intermediate penetrance of a Lynch syndrome phenotype. Our findings provide further evidence of the potential importance of noncoding variants in the MLH1 5'UTR in the pathogenesis of Lynch syndrome.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Variación Genética
/
Proteínas Nucleares
/
Neoplasias Colorrectales Hereditarias sin Poliposis
/
Expresión Génica
/
Regiones Promotoras Genéticas
/
Desequilibrio Alélico
/
Proteínas Adaptadoras Transductoras de Señales
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Female
/
Humans
/
Male
Idioma:
En
Revista:
Hum Mutat
Asunto de la revista:
GENETICA MEDICA
Año:
2015
Tipo del documento:
Article
País de afiliación:
Australia