The genotype-phenotype landscape of familial amyotrophic lateral sclerosis in Australia

E. P. McCann, K. L. Williams, J. A. Fifita, I. S. Tarr, J. A. O'Connor, D. B. Rowe, G. A. Nicholson, I. P. Blair

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

LanguageEnglish
Pages259-266
Number of pages8
JournalClinical Genetics
Volume92
Issue number3
Early online date20 Jan 2017
DOIs
Publication statusPublished - Sep 2017

Fingerprint

Amyotrophic Lateral Sclerosis
Genotype
Phenotype
Mutation
Genetic Association Studies
Amyotrophic lateral sclerosis 1
Exome
Age of Onset
Gene Frequency
Neurodegenerative Diseases
Genes
Polymerase Chain Reaction

Keywords

  • amyotrophic lateral sclerosis
  • correlation
  • genotype
  • mutation
  • phenotype

Cite this

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title = "The genotype-phenotype landscape of familial amyotrophic lateral sclerosis in Australia",
abstract = "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.",
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The genotype-phenotype landscape of familial amyotrophic lateral sclerosis in Australia. / McCann, E. P.; Williams, K. L.; Fifita, J. A.; Tarr, I. S.; O'Connor, J. A.; Rowe, D. B.; Nicholson, G. A.; Blair, I. P.

In: Clinical Genetics, Vol. 92, No. 3, 09.2017, p. 259-266.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The genotype-phenotype landscape of familial amyotrophic lateral sclerosis in Australia

AU - McCann, E. P.

AU - Williams, K. L.

AU - Fifita, J. A.

AU - Tarr, I. S.

AU - O'Connor, J. A.

AU - Rowe, D. B.

AU - Nicholson, G. A.

AU - Blair, I. P.

N1 - This article is protected by copyright. All rights reserved.

PY - 2017/9

Y1 - 2017/9

N2 - 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.

AB - 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.

KW - amyotrophic lateral sclerosis

KW - correlation

KW - genotype

KW - mutation

KW - phenotype

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UR - http://purl.org/au-research/grants/nhmrc/1107644

UR - http://ulrichsweb.serialssolutions.com/title/1507691574235/18322

U2 - 10.1111/cge.12973

DO - 10.1111/cge.12973

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SP - 259

EP - 266

JO - Clinical Genetics

T2 - Clinical Genetics

JF - Clinical Genetics

SN - 0009-9163

IS - 3

ER -