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Human genetics research
Monogenic to multifactorial disease genetics: how do we improve efficiency?
When we study rare and inherited diseases, we find a wide spectrum of genetic and phenotypic heterogeneity and an equally wide selection of causative mutation types. No single platform is capable of finding all causative variants with the speed and cost efficiency needed in a typical research setting.
Here are examples of human genetic disease projects and technology solutions that can deliver meaningful data within a week from sample to data.
Whether you need to analyse one gene or thousands of genes, we enable you to select the right tool for the job, helping you to find answers more efficiently.
Educational content
ESHG 2020.2: catch-up on our corporate satellite talk
Advancing human genetics research to bring precision medicine into the clinic
Dr. Luca Quagliata, Senior Director of Medical Affairs, Thermo Fisher Scientific
Watch now
Custom Ion AmpliSeq Panel in combination with Ion Genexus System for rapid RASopathies testing: a pilot study
Dr. José Luis Costa, Affiliated Researcher of Genetic Dynamics of Cancer Cells, Ipatimup, Portugal
Watch now
Molecular profiling of autoimmune inflammatory disease for prediction of response to therapy and immunological evolution of disease
Prof. Carl Goodyear, Professor of Translational Immunology, Institute of Infection, Immunity & Inflammation, University of Glasgow, UK
Watch now
Polygenic risk scores analysis for Alzheimer’s disease; transforming early detection and clinical management
Dr. Richard Pither, CEO, Cytox Ltd., Oxford, UK
Watch now
What technologies should you consider for different problems in human genetics?
Single-gene inheritance pattern (Mendelian disease)
See how you can quickly identify causative alleles in inherited diseases through candidate gene analysis using next generation sequencing of custom-assembled gene panels.
Molecular analysis of inherited cardiomyopathy using next generation semiconductor sequencing technologies - Chaoxia Lu et al
Approach:
- Identify causative variants of different inherited cardiomyopathies using a single Ion AmpliSeq gene panel.
- Perform targeted next-generation sequencing (NGS) on candidate genes.
- Verify genetic variants by Sanger sequencing.
Results:
- Potential pathogenic variants found in 23.6% of study samples, including a homozygous variant in the SLC25A4 gene.
- Of the pathogenic variants found, 15 had been reported in the Human Gene Mutation Database or ClinVar database, while 11 were novel.
- Most variants were found in MYH7 (8/26) and MYBPC3 (6/26) gene. Titin (TTN) truncating mutations account for 13% of the dilated cardiomyopathy cases (3/23).
About the technology
| For multiplex analysis of multiple genes, multiple samples for low cost variant detection: | |||
 |  | ||
 | |||
| For single gene, single sample variant detection or NGS verification: | |||
 |  | ||
Multi-factorial (non-Mendelian) disease
Inherited diseases can also be caused by a combination of genetic loci which together result in potentially complex and variable phenotype, making disease identification more difficult. We show how a combination of chromosomal microarray analysis (CMA) and whole exome analysis (WES) can improve discovery rates over WES alone.
How can we identify non-Mendelian loci and quantify their contribution to disease?
Recent studies have shown that a combination of genomic array and sequential exome analysis, is an effective approach in the evaluation of subjects with unexplained intellectual disability, autism spectrum disorder and/or congenital anomalies. The expected clinical yield of these tests are for high resolution genomic array 15-20% and in combination with exome sequencing >50% (Vissers L et al. Nature Genetics, 2010, PMID: 21076407).
Example: Autism study
Molecular diagnostic yield of chromosomal microarray analysis and whole exome analysis using next-generation sequencing in children with autism spectrum disorder. Tammimies K et al. (2015) JAMA
Approach:
- Collect research samples from 258 unrelated children with Autistic Spectrum Disorder (ASD)
- Perform chromosomal microarray analysis (CMA)
- Perform whole exome sequencing (WES) on 100 probands, where DNA samples from both parents are available
Results:
- Of 258 probands, 24 identified pathogenic alleles from CMA and 8 of 95 from WES
- 96 de novo variants that could be contributive were also identified
About the technology
Non-familial congenital & germline disorders Reproductive health research Complex traits & pharmacogenomics
Trinucleotide repeat disorders
Incurable neurodegenerative diseases such as Huntington’s disease, spinocerebellar ataxias, fragile X syndrome, and SBMA are caused by unstable repetitive triplet elements within defined loci. Variability in repeat length is observed in normal alleles and can range from 15 to 40 nucleotides. Pathology results when repeat length exceeds a specific threshold, usually greater than 45. The disease phenotype may worsen from generation to generation due to de novo germline expansion of repeats.
How can we find disease-causing simple tandem repeat variants?
Example: Fragile X
More than 30 Mendelian disorders are linked to STR expansions. In Fragile X syndrome, tandem CGG repeats within the FMR1 gene are associated with onset and severity of frontotemporal dementia and amyotrophic lateral sclerosis.
Approach:
- The FMR1 CGG repeat region can range in size, and analysis of the gene requires resolution of long fragment lengths of 800bp or more
- Perform fragment sizing (fragment analysis) by capillary electrophoresis sequencing using the Applied Biosystems SeqStudio Genetic Analyzer and Asuragen AmplideX PCR/CE FMR1 and C9orf72 reagents
- Amplify the Asuragen AmplideX PCR/CE FMR1 and C9orf72 reagents from blood samples taken from Fragile X research subjects
- Run the AmplideX PCR/CE FMR1 and C9orf72 reagents under the following run parameters: SeqStudio module = LongFragAnalysis (modified), injection time = 2 sec, injection voltage = 6 kV, run time = 3,300 sec, and run voltage = 6 kV
- Run time takes around 30 minutes
Results:
- Consistent detection of expected n and n + 1 alleles demonstrates single-repeat assay resolution.
- Genotype and allele repeat lengths were 100% concordant with expected values.
About the technology
How do new mutations arise in families that don’t have a history of the disease?
How to find these causative mutations?
Example: Primary Ciliary Dyskinesia Case Study
A rare genetic disorder of ciliary function, affecting 1/20,000 live births, this disease has phenotypic heterogeneity and is difficult to diagnose. Early diagnosis is essential for effective disease management. Kano G et al. (2016) Mol Med Reports
Approach:
- Identify individuals affected by syndrome using ultrastructural analysis of cilia
- Perform Ion AmpliSeq exome sequencing to identify variants
- Verify by Sanger sequencing
Results:
Identified two DNAH5 (dynein heavy chain 5) mutations:
- Mother was heterozygous for one allele (DNAH5 c.9101delG)
- Father was heterozygous for a different allele (DNAH5 c.5983C>T)
- Affected child had one of each of the defective alleles inherited from parents
About the technology
Human genetics research studies provide the disease-predisposing alleles that feed into family planning screening tools. In today’s multiethnic society, some genetic disorders previously confined to specific ethnic groups may now occur at increasing frequency in broader populations. Conventional carrier screening that targets single disorders according to ancestry or family history, based on assumptions about prevalence, may not accurately reflect changing frequencies.
How best to identify hereditary conditions to prevent inheritance in the next generation?
Expanded carrier screening
New advancements and decreasing costs of genetic analysis technologies such as next-generation sequencing (NGS) are enabling carrier screening research across a broader range of disorders. This type of research enables discovery of carrier status regardless of ancestry or geographic region, with high accuracy, quick turnaround time, and low cost.
Approach:
- Increase carrier status detection rates for a broad range of inherited disorders. A 420-gene panel enables the analysis of 28,000 non-benign ClinVar variants for single-nucleotide variants (SNVs), insertions and deletions (indels), and copy number variants (CNVs) by NGS
- Consolidate stand-alone assays to improve lab efficiency—Difficult-to-detect targets are consolidated in a single NGS assay eliminating the use of multiple platforms and technologies
- Simplify adoption and implementation in your lab with an end-to-end solution— Intuitive and customisable data analysis software quickly translates data into results and report formats you need
- Have a choice of automated or manual sample preparation
About the technology
High Throughput Chromosomal Microarray
Chromosomal microarray is the standard recognised by world leading organisations like ACOG, ESHG, ACMG for the detection of chromosomal abnormalities such as deletions, duplications, and uniparental disomy (UPD). The combination of high-resolution DNA copy number data and the ability to screen a panel of SNVs on a single array makes the Applied Biosystems CytoScan HT-CMA assay the new standard for high-throughput cytogenetics analysis.
Approach:
- Consolidate testing with a dual CNV and SNV design
- Increase sample throughput with a multiplex format fully automated assay protocol
- Fast and easy high-resolution genome-wide copy number analysis with the free Chromosome Analysis Suite software
- Ensure reliability and reproducibility with a fully automated assay protocol
About the technology
Unravel the exome odyssey
Overcome the challenges of the exome odyssey with reliable single-exon deletion and duplication detection using the Applied Biosystems CytoScan XON Suite, for cost-effective and streamlined analysis of exon-level CNVs. Designed to cover the whole genome, with increased coverage in 7,000 clinically relevant genes, the CytoScan XON Suite provides CNV data that works as a strong complement to mutation analysis performed by next-generation sequencing (NGS).
Approach:
- Comprehensively detect single-exon deletions and duplications in a cost-effective manner
- Complement NGS mutation analysis with reliable exon-level deletion and duplication detection
- Confirm CNV findings from alternative technologies
- Simplify and streamline sequence variant analysis
About the technology
Genotyping continues to be an important molecular tool for predictive genomics in the research and clinical setting. In recent years the research focus has shifted to development of risk stratification and pharmacogenomic strategies within populations, aiming to improve health outcomes and healthcare economics. Below you can learn from leaders in the field about the best practice and technologies to apply to your genetic association study whether it is large or small.
A national-scale personalised medicine project genotyping 500,000 Finnish individuals
Discover how the FinnGen Research Project is studying chronic disease at a population scale. Prof. Aarno Palotie of FIMM in Finland, and Massachusetts General Hospital and the Broad Institute in the US talked to us about this groundbreaking study.
Score one for large-scale genotyping as polygenic risk scoring advances
Predicting an individual’s risk of disease based on their genotype is one of the most appealing outcomes of genomic medicine but what is the potential of polygenic risk scores?
What does it take to bring genetic risk stratification to African populations?
Find out with this blog featuring the MADCaP Network whose investigators are building research capacity and data resources to apply risk scoring to prostate cancer in African populations.
What’s the most effective way to cover genomic variation in your population?
Learn how UK Biobank solved this challenge by reading this interview with Mark McCarthy, Robert Turner Professor of Diabetes at the University of Oxford and Consultant Endocrinologist at the Oxford University Hospitals Trust, Oxford, UK.
What is the best way to integrate genotyping into precision medicine studies?
In this webinar, Dr. Mark Bouzyk, Cofounder and Chief Scientific Officer of AKESOgen, USA, talks about his experience working on pharmacogenomics studies and the Million Veterans Program.
How will pharmacogenomics look in the future and what are the obstacles to getting there?
In this interview, Ulrich Broeckel, MD from Right Patient, Right Drug Diagnostics, USA discusses the value of and research into pre-emptive pharmacogenomics.
About the technology
Single-gene inheritance pattern (Mendelian disease)
See how you can quickly identify causative alleles in inherited diseases through candidate gene analysis using next generation sequencing of custom-assembled gene panels.
Molecular analysis of inherited cardiomyopathy using next generation semiconductor sequencing technologies - Chaoxia Lu et al
Approach:
- Identify causative variants of different inherited cardiomyopathies using a single Ion AmpliSeq gene panel.
- Perform targeted next-generation sequencing (NGS) on candidate genes.
- Verify genetic variants by Sanger sequencing.
Results:
- Potential pathogenic variants found in 23.6% of study samples, including a homozygous variant in the SLC25A4 gene.
- Of the pathogenic variants found, 15 had been reported in the Human Gene Mutation Database or ClinVar database, while 11 were novel.
- Most variants were found in MYH7 (8/26) and MYBPC3 (6/26) gene. Titin (TTN) truncating mutations account for 13% of the dilated cardiomyopathy cases (3/23).
About the technology
| For multiplex analysis of multiple genes, multiple samples for low cost variant detection: | |||
| | ||
| |||
| For single gene, single sample variant detection or NGS verification: | |||
| | ||
Multi-factorial (non-Mendelian) disease
Inherited diseases can also be caused by a combination of genetic loci which together result in potentially complex and variable phenotype, making disease identification more difficult. We show how a combination of chromosomal microarray analysis (CMA) and whole exome analysis (WES) can improve discovery rates over WES alone.
How can we identify non-Mendelian loci and quantify their contribution to disease?
Recent studies have shown that a combination of genomic array and sequential exome analysis, is an effective approach in the evaluation of subjects with unexplained intellectual disability, autism spectrum disorder and/or congenital anomalies. The expected clinical yield of these tests are for high resolution genomic array 15-20% and in combination with exome sequencing >50% (Vissers L et al. Nature Genetics, 2010, PMID: 21076407).
Example: Autism study
Molecular diagnostic yield of chromosomal microarray analysis and whole exome analysis using next-generation sequencing in children with autism spectrum disorder. Tammimies K et al. (2015) JAMA
Approach:
- Collect research samples from 258 unrelated children with Autistic Spectrum Disorder (ASD)
- Perform chromosomal microarray analysis (CMA)
- Perform whole exome sequencing (WES) on 100 probands, where DNA samples from both parents are available
Results:
- Of 258 probands, 24 identified pathogenic alleles from CMA and 8 of 95 from WES
- 96 de novo variants that could be contributive were also identified
About the technology
Non-familial congenital & germline disorders Reproductive health research Complex traits & pharmacogenomics
Trinucleotide repeat disorders
Incurable neurodegenerative diseases such as Huntington’s disease, spinocerebellar ataxias, fragile X syndrome, and SBMA are caused by unstable repetitive triplet elements within defined loci. Variability in repeat length is observed in normal alleles and can range from 15 to 40 nucleotides. Pathology results when repeat length exceeds a specific threshold, usually greater than 45. The disease phenotype may worsen from generation to generation due to de novo germline expansion of repeats.
How can we find disease-causing simple tandem repeat variants?
Example: Fragile X
More than 30 Mendelian disorders are linked to STR expansions. In Fragile X syndrome, tandem CGG repeats within the FMR1 gene are associated with onset and severity of frontotemporal dementia and amyotrophic lateral sclerosis.
Approach:
- The FMR1 CGG repeat region can range in size, and analysis of the gene requires resolution of long fragment lengths of 800bp or more
- Perform fragment sizing (fragment analysis) by capillary electrophoresis sequencing using the Applied Biosystems SeqStudio Genetic Analyzer and Asuragen AmplideX PCR/CE FMR1 and C9orf72 reagents
- Amplify the Asuragen AmplideX PCR/CE FMR1 and C9orf72 reagents from blood samples taken from Fragile X research subjects
- Run the AmplideX PCR/CE FMR1 and C9orf72 reagents under the following run parameters: SeqStudio module = LongFragAnalysis (modified), injection time = 2 sec, injection voltage = 6 kV, run time = 3,300 sec, and run voltage = 6 kV
- Run time takes around 30 minutes
Results:
- Consistent detection of expected n and n + 1 alleles demonstrates single-repeat assay resolution.
- Genotype and allele repeat lengths were 100% concordant with expected values.
About the technology
How do new mutations arise in families that don’t have a history of the disease?
How to find these causative mutations?
Example: Primary Ciliary Dyskinesia Case Study
A rare genetic disorder of ciliary function, affecting 1/20,000 live births, this disease has phenotypic heterogeneity and is difficult to diagnose. Early diagnosis is essential for effective disease management. Kano G et al. (2016) Mol Med Reports
Approach:
- Identify individuals affected by syndrome using ultrastructural analysis of cilia
- Perform Ion AmpliSeq exome sequencing to identify variants
- Verify by Sanger sequencing
Results:
Identified two DNAH5 (dynein heavy chain 5) mutations:
- Mother was heterozygous for one allele (DNAH5 c.9101delG)
- Father was heterozygous for a different allele (DNAH5 c.5983C>T)
- Affected child had one of each of the defective alleles inherited from parents
About the technology
Human genetics research studies provide the disease-predisposing alleles that feed into family planning screening tools. In today’s multiethnic society, some genetic disorders previously confined to specific ethnic groups may now occur at increasing frequency in broader populations. Conventional carrier screening that targets single disorders according to ancestry or family history, based on assumptions about prevalence, may not accurately reflect changing frequencies.
How best to identify hereditary conditions to prevent inheritance in the next generation?
Expanded carrier screening
New advancements and decreasing costs of genetic analysis technologies such as next-generation sequencing (NGS) are enabling carrier screening research across a broader range of disorders. This type of research enables discovery of carrier status regardless of ancestry or geographic region, with high accuracy, quick turnaround time, and low cost.
Approach:
- Increase carrier status detection rates for a broad range of inherited disorders. A 420-gene panel enables the analysis of 28,000 non-benign ClinVar variants for single-nucleotide variants (SNVs), insertions and deletions (indels), and copy number variants (CNVs) by NGS
- Consolidate stand-alone assays to improve lab efficiency—Difficult-to-detect targets are consolidated in a single NGS assay eliminating the use of multiple platforms and technologies
- Simplify adoption and implementation in your lab with an end-to-end solution— Intuitive and customisable data analysis software quickly translates data into results and report formats you need
- Have a choice of automated or manual sample preparation
About the technology
High Throughput Chromosomal Microarray
Chromosomal microarray is the standard recognised by world leading organisations like ACOG, ESHG, ACMG for the detection of chromosomal abnormalities such as deletions, duplications, and uniparental disomy (UPD). The combination of high-resolution DNA copy number data and the ability to screen a panel of SNVs on a single array makes the Applied Biosystems CytoScan HT-CMA assay the new standard for high-throughput cytogenetics analysis.
Approach:
- Consolidate testing with a dual CNV and SNV design
- Increase sample throughput with a multiplex format fully automated assay protocol
- Fast and easy high-resolution genome-wide copy number analysis with the free Chromosome Analysis Suite software
- Ensure reliability and reproducibility with a fully automated assay protocol
About the technology
Unravel the exome odyssey
Overcome the challenges of the exome odyssey with reliable single-exon deletion and duplication detection using the Applied Biosystems CytoScan XON Suite, for cost-effective and streamlined analysis of exon-level CNVs. Designed to cover the whole genome, with increased coverage in 7,000 clinically relevant genes, the CytoScan XON Suite provides CNV data that works as a strong complement to mutation analysis performed by next-generation sequencing (NGS).
Approach:
- Comprehensively detect single-exon deletions and duplications in a cost-effective manner
- Complement NGS mutation analysis with reliable exon-level deletion and duplication detection
- Confirm CNV findings from alternative technologies
- Simplify and streamline sequence variant analysis
About the technology
Genotyping continues to be an important molecular tool for predictive genomics in the research and clinical setting. In recent years the research focus has shifted to development of risk stratification and pharmacogenomic strategies within populations, aiming to improve health outcomes and healthcare economics. Below you can learn from leaders in the field about the best practice and technologies to apply to your genetic association study whether it is large or small.
A national-scale personalised medicine project genotyping 500,000 Finnish individuals
Discover how the FinnGen Research Project is studying chronic disease at a population scale. Prof. Aarno Palotie of FIMM in Finland, and Massachusetts General Hospital and the Broad Institute in the US talked to us about this groundbreaking study.
Score one for large-scale genotyping as polygenic risk scoring advances
Predicting an individual’s risk of disease based on their genotype is one of the most appealing outcomes of genomic medicine but what is the potential of polygenic risk scores?
What does it take to bring genetic risk stratification to African populations?
Find out with this blog featuring the MADCaP Network whose investigators are building research capacity and data resources to apply risk scoring to prostate cancer in African populations.
What’s the most effective way to cover genomic variation in your population?
Learn how UK Biobank solved this challenge by reading this interview with Mark McCarthy, Robert Turner Professor of Diabetes at the University of Oxford and Consultant Endocrinologist at the Oxford University Hospitals Trust, Oxford, UK.
What is the best way to integrate genotyping into precision medicine studies?
In this webinar, Dr. Mark Bouzyk, Cofounder and Chief Scientific Officer of AKESOgen, USA, talks about his experience working on pharmacogenomics studies and the Million Veterans Program.
How will pharmacogenomics look in the future and what are the obstacles to getting there?
In this interview, Ulrich Broeckel, MD from Right Patient, Right Drug Diagnostics, USA discusses the value of and research into pre-emptive pharmacogenomics.
About the technology
For Research Use Only. Not for use in diagnostic procedures.