WE42257-headerB

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.

Talks, posters, and recent presentations on human genetics

Catch the latest

What technologies should you consider for different problems in human genetics?

CE qPCR NGS Targeted Sequencing Microarray NGS Exome Sequencing

Single-gene inheritance pattern (Mendelian disease)

Inherited diseases can be caused by mutations in single genes. Typically, researchers need to find out why some family members are affected whilst others are not, and to establish the inheritance pattern – ie whether it is autosomal dominant, autosomal recessive, or X-linked. This helps to identify causative loci for future screening and intervention purposes. Whilst Genome-Wide Association Studies (GWAS) in large family studies have been useful to find causative genetic loci affected with these types of diseases, such classical strategies are not well suited for identifying loci in smaller families who have insufficient genetic information.

How can we find causative variants when family history is limiting?

WE42257_pod1

Example: Hereditary Hearing Loss

Novel PTPRQ mutations identified in three congenital hearing loss patients with various types of hearing loss.  Sakuma et al. (2015) Ann Otol Rhinol Laryngol

Download the publication

Approach:

  • Identify families with HHL of unknown origin. Two hundred and twenty subjects with sensorineural hearing loss from unrelated and non-consanguineous families were studied
  • Perform targeted next-generation sequencing (NGS) on candidate genes using Ion AmpliSeq panel on Ion Torrent sequencing platform to identify potential variants in target genes
  • Verify identified loci using Sanger sequencing

Results:

  • Four novel causative PTPRQ mutations were identified 
  • Family 1—affected proband shown to have homozygous mutations inherited from each parent
  • Family 2—transheterozygous affected individual possessed 2 different mutations, in same gene

Request more information

About the technology

Request more information


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). 

Download the poster: Jonson et al 2016 ›

WE42257_pod2

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

Download the publication

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

Request more information

About the technology

Request more information

Non-familial congenital & germline disorders Reproductive health research Complex traits & pharmacogenomics

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

Download the publication

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

Request more information

About the technology

Request more information


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 newly arising pathogenic repeat expansions be identified?

WE42257_pod3

Example: Spinocerebellar Ataxias

Analysis of SCA8, SCA10, SCA12, SCA17 and SCA19 in patients with unknown spinocerebellar ataxia: a Thai multicentre study. Chobutum L et al. (2015) BMC Neurology

Download the publication

Approach:

  • Isolate DNA from affected or potentially affected individual
  • Collected DNA samples of patients with progressive cerebellar degeneration, in which genetic tests for SCA1, SCA2, MJD, SCA6, SCA7 and DRPLA (CAG repeat diseases) were negative
  • Analyse repeat length of candidate genes SCA8, SCA10, SCA12, SCA17 and SCA19 using fluorescent PCR and fragment analysis by capillary electrophoresis on the 3730xl DNA Analyzer
  • Verify exon and repeat sequence using Sanger sequencing by capillary electropherosis

Results:

The study identified 8 affected individuals with small pathogenic de novo triplet expansion in TBP SCA17.  Sanger sequencing by capillary electropherosis verified the CAG repeat in these affected individuals.

Request more information

About the technology

Request more information

Familial inheritance disorders Reproductive health research Complex traits & pharmacogenomics

Human genetics research studies provide the disease-predisposing alleles that then feed into family planning screening tools. If two parents are both carriers of a recessive, disease-linked gene, then there is a 25% chance that their children will inherit the disease in question. Understanding the risk factors in different populations is the first stage in developing preventative medicine.

How best to identify hereditary conditions to prevent inheritance in the next generation?

WE42257_pod4

Carrier screening

Carrier screening determines whether a healthy person possesses a copy of a disease-linked gene. The ideal carrier screening tool needs to incorporate all possible deleterious mutations that are found across ethnicities so that just a single test can be applied in every subject studied.  This approach would cut down work, costs and multiple rounds of trial and error. 

Download the application note

Approach:

  • Select the most common variants from international populations in 600 disease-linked genes
  • Design and verification process must enable high confidence and reproducibility in broad screening research
  • Make it customisable so that researchers can study the widest range of populations possible and add new alleles as they are discovered
  • Have a choice of automated or manual sample preparation

Request more information


About the technology

Request more information


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).

Download the application note

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

Request more information


About the technology

Request more information

Non-familial congenital & germline disorders Familial inheritance disorders Complex traits & pharmacogenomics

Genotyping continues to be an important molecular tool for precision medicine in the research and clinical setting. Study strategy has evolved rapidly in recent years, led by large population biobanks and precision medicine initiatives. Below, you can access the experience of leaders in the field on how they have solved the common genotyping challenges in complex trait genomics and pharmacogenomics.

mark-mccarthy-125

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.


More interviews, videos and webinars


About the technology

Familial inheritance disorders Non-familial congenital & germline disorders Reproductive health research

Single-gene inheritance pattern (Mendelian disease)

Inherited diseases can be caused by mutations in single genes. Typically, researchers need to find out why some family members are affected whilst others are not, and to establish the inheritance pattern – ie whether it is autosomal dominant, autosomal recessive, or X-linked. This helps to identify causative loci for future screening and intervention purposes. Whilst Genome-Wide Association Studies (GWAS) in large family studies have been useful to find causative genetic loci affected with these types of diseases, such classical strategies are not well suited for identifying loci in smaller families who have insufficient genetic information.

How can we find causative variants when family history is limiting?

WE42257_pod1

Example: Hereditary Hearing Loss

Novel PTPRQ mutations identified in three congenital hearing loss patients with various types of hearing loss.  Sakuma et al. (2015) Ann Otol Rhinol Laryngol

Download the publication

Approach:

  • Identify families with HHL of unknown origin. Two hundred and twenty subjects with sensorineural hearing loss from unrelated and non-consanguineous families were studied
  • Perform targeted next-generation sequencing (NGS) on candidate genes using Ion AmpliSeq panel on Ion Torrent sequencing platform to identify potential variants in target genes
  • Verify identified loci using Sanger sequencing

Results:

  • Four novel causative PTPRQ mutations were identified 
  • Family 1—affected proband shown to have homozygous mutations inherited from each parent
  • Family 2—transheterozygous affected individual possessed 2 different mutations, in same gene

Request more information

About the technology

Request more information


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). 

Download the poster: Jonson et al 2016 ›

WE42257_pod2

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

Download the publication

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

Request more information

About the technology

Request more information

Non-familial congenital & germline disorders Reproductive health research Complex traits & pharmacogenomics

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

Download the publication

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

Request more information

About the technology

Request more information


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 newly arising pathogenic repeat expansions be identified?

WE42257_pod3

Example: Spinocerebellar Ataxias

Analysis of SCA8, SCA10, SCA12, SCA17 and SCA19 in patients with unknown spinocerebellar ataxia: a Thai multicentre study. Chobutum L et al. (2015) BMC Neurology

Download the publication

Approach:

  • Isolate DNA from affected or potentially affected individual
  • Collected DNA samples of patients with progressive cerebellar degeneration, in which genetic tests for SCA1, SCA2, MJD, SCA6, SCA7 and DRPLA (CAG repeat diseases) were negative
  • Analyse repeat length of candidate genes SCA8, SCA10, SCA12, SCA17 and SCA19 using fluorescent PCR and fragment analysis by capillary electrophoresis on the 3730xl DNA Analyzer
  • Verify exon and repeat sequence using Sanger sequencing by capillary electropherosis

Results:

The study identified 8 affected individuals with small pathogenic de novo triplet expansion in TBP SCA17.  Sanger sequencing by capillary electropherosis verified the CAG repeat in these affected individuals.

Request more information

About the technology

Request more information

Familial inheritance disorders Reproductive health research Complex traits & pharmacogenomics

Human genetics research studies provide the disease-predisposing alleles that then feed into family planning screening tools. If two parents are both carriers of a recessive, disease-linked gene, then there is a 25% chance that their children will inherit the disease in question. Understanding the risk factors in different populations is the first stage in developing preventative medicine.

How best to identify hereditary conditions to prevent inheritance in the next generation?

WE42257_pod4

Carrier screening

Carrier screening determines whether a healthy person possesses a copy of a disease-linked gene. The ideal carrier screening tool needs to incorporate all possible deleterious mutations that are found across ethnicities so that just a single test can be applied in every subject studied.  This approach would cut down work, costs and multiple rounds of trial and error. 

Download the application note

Approach:

  • Select the most common variants from international populations in 600 disease-linked genes
  • Design and verification process must enable high confidence and reproducibility in broad screening research
  • Make it customisable so that researchers can study the widest range of populations possible and add new alleles as they are discovered
  • Have a choice of automated or manual sample preparation

Request more information


About the technology

Request more information


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).

Download the application note

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

Request more information


About the technology

Request more information

Non-familial congenital & germline disorders Familial inheritance disorders Complex traits & pharmacogenomics

Genotyping continues to be an important molecular tool for precision medicine in the research and clinical setting. Study strategy has evolved rapidly in recent years, led by large population biobanks and precision medicine initiatives. Below, you can access the experience of leaders in the field on how they have solved the common genotyping challenges in complex trait genomics and pharmacogenomics.

mark-mccarthy-125

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.


More interviews, videos and webinars


About the technology

Familial inheritance disorders Non-familial congenital & germline disorders Reproductive health research

For Research Use Only. Not for use in diagnostic procedures.