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Clin Genet ; 92(3): 259-266, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28105640

RESUMO

Amyotrophic lateral sclerosis (ALS) is a clinically and genetically heterogeneous fatal neurodegenerative disease. Around 10% of ALS cases are hereditary. ALS gene discoveries have provided most of our understanding of disease pathogenesis. We aimed to describe the genetic landscape of ALS in Australia by assessing 1013 Australian ALS patients for known ALS mutations by direct sequencing, whole exome sequencing or repeat primed polymerase chain reaction. Age of disease onset and disease duration were used for genotype-phenotype correlations. We report 60.8% of Australian ALS families in this cohort harbour a known ALS mutation. Hexanucleotide repeat expansions in C9orf72 accounted for 40.6% of families and 2.9% of sporadic patients. We also report ALS families with mutations in SOD1 (13.7%), FUS (2.4%), TARDBP (1.9%), UBQLN2 (.9%), OPTN (.5%), TBK1 (.5%) and CCNF (.5%). We present genotype-phenotype correlations between these genes as well as between gene mutations. Notably, C9orf72 hexanucleotide repeat expansion positive patients experienced significantly later disease onset than ALS mutation patients. Among SOD1 families, p.I114T positive patients had significantly later onset and longer survival. Our report highlights a unique spectrum of ALS gene frequencies among patients from the Australian population, and further, provides correlations between specific ALS mutations with disease onset and/or duration.


Assuntos
Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/genética , Estudos de Associação Genética , Genótipo , Fenótipo , Idade de Início , Alelos , Esclerose Lateral Amiotrófica/epidemiologia , Austrália , Proteína C9orf72/genética , Éxons , Feminino , Frequência do Gene , Estudos de Associação Genética/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Penetrância , Análise de Sequência de DNA , Superóxido Dismutase-1/genética , Sequenciamento do Exoma
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