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Scientific Publications on Next Generation Sequencing Applications in Human Genetics Including Hereditary Disorder Screening and Forensic

This page introduces a selection of scientific publications on different aspects of next generation sequencing (NGS) application in human genetics. This includes topics such as; screening for hereditary disorders, prenatal diagnostics, precision medicine, as well as forensic. Publications related to infectious diseases in human diagnostics and medicine are listed in the corresponding category. Publications in cancer genetics, screening, and medicine are listed in a separate category. 

Scientific Publications on Next Generation Sequencing Applications in Human Genetics

Advancing epilepsy genetics in the genomic era

Epilepsy is a group of disorders that is characterized by seizures. The major cause of epilepsy are believed to be genetic factors (Hildebrand et al. 2013).
The authors describe the genetic basis of epilepsy starting with the well know genetic factors the nicotinic acetylcholine receptor and the ion channels. The influence of copy number variations (CNV) on epilepsy is discussed.
It is described how genome-wide association studies (GWAS) and massively parallel sequencing realized by NGS helped to identify new genes and variants that are associated with epilepsy. A number of lately discovered genes are introduced and its function and relation to epilepsy are discussed. As all classes of epilepsy are genetically heterogeneous the heterogeneity is explained on individual genes and groups of genes.
For a number of epilepsy cases the genetic factors are still unknown, the author stated that non coding regions might also affect the occurrence of epilepsy.
The clinical implications of NGS application like targeted gene panels and exome sequencing in epilepsy diagnosis and research are discussed.
Myers and Mefford 2015

Biomarker discovery: quantification of microRNAs and other small non-coding RNAs using next generation sequencing

This publication provides some general guidelines for the quantification, data processing, and analysis of small non-coding RNAs (sncRNAs) from clinical samples using NGS. An introduction to different RNA types as potential biomarkers is presented, followed by a comparison of three commercially-available library preparation methods. In this study, the influence of the number of total reads per sample on the number of miRNAs detected was evaluated. Furthermore, tissue specific expression of miRNA was investigated in four human sample matrices (whole blood, brain, heart, and liver).
Lopez et al 2015

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Complex genetics of pulmonary diseases: lessons from genome-wide association studies and next-generation sequencing

This review describes how genome-wide association studies (GWASs) from the NHGRI GWAS catalogue were studied in order to identify genetic variants (such as SNPs) associated with pulmonary diseases. Furthermore, pulmonary diseases such as asthma, COPD, and sarcoidosis are discussed extensively along with a summary of the existing literature on these disorders. The association of the microbiome with pulmonary diseases is briefly discussed.
The authors infer that the identification of gender-specific and admixed population-specific pulmonary disease polymorphisms have not been sufficiently investigated to date.
Pouladi et al 2015

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Computational approaches for the analysis of ncRNA through deep sequencing techniques

Following a brief, general introduction to non coding RNAs, this mini review discusses a range of software tools available for ncRNA NGS data analysis, including small ncRNA analysis, circular RNA detection, and long ncRNA analysis.
Veneziano et al 2015

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Diagnosis of late-onset Pompe disease and other muscle disorders by next-generation sequencing

Late-onset Pompe disease (LOPD) is a rare lysosomal storage disorder leading to glycogen accumulation and muscle weakness. This publication describes the testing of a novel NGS gene panel targeting the GAA gene and 77 genes related to the diagnosis of other muscle disorders.
The panels is developed in order to improve the LOPO diagnostics and allow better differential diagnosis of other muscle disorders with similar pattern such as muscular dystrophies with limb-girdle weakness pattern, rigid spine syndromes, scapuloperoneal syndromes, congenital myasthenic syndromes, congenital myopathies (nemaline, myofibrillar), congenital muscular dystrophies, metabolic myopathies (fatty acid oxidation disorders, glycogen storage disorders), and peroxisomal disorders.
Results showed high sensitivity and specificity of all targeted genes. The clinical utilization was tested with samples of 34 patients with suspected muscle disorders whereof diagnosis of 11 patients was possible with applying the NGS panel based diagnostics.
It is proposed to use NGS targeted gene panel as a first tier testing for muscle disorders diagnosis.

Lévesque et al. 2016

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Diverse CRISPRs Evolving in Human Microbiomes

In this study, 751 data sets from the human microbiome project were assessed in order to identify novel CRISPRs in bacterial genomes. The author describes a targeted assembling strategy used to improve CRISPR identification, a strategy which was tested in three different samples and compared with whole metagenome analysis-based CRISPR identification. Furthermore, the distribution of CRISPRs across human tissues and between individuals was investigated and evaluated for selected samples. Substantial sequence differences were discovered in the CRISPR spacer regions among subjects. Additionally, this paper describes how CRISPR spacer sequences can be used to trace back the viral exposure of a microbial community.
Rho 2012

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Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities

In this study a targeted sequencing approach was used to study 253 samples of Chinese children unexplained Epilepsy and Intellectual/Developmental Disabilities. Several reported and new mutants were identified in this study including premature/delayed termination codon mutations, insertion/deletion mutations and splicing site mutations. Some mutations (KCNAB1 and KCNQ2) are related to potassium channel genes and suggest that ion channels play a vital role in the pathogenesis of epilepsy and ID/DD.
Finally, different facts that might influence the detection rate of the targeted specific NGS approach used in this study are discussed in this publication.
Zhang et al. 2015

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Genome-wide association studies: applications and insights gained in Ophthalmology

Genome-wide association studies (GWAS) are applied in order to obtain information about mutations including SNPs that can be associated to certain hereditary diseases. High Throughput technologies such as next generation sequencing (NGS) are the basis for GWAS.
This review summarized different GWAS that are performed in order to obtain more information on genetic factors that are associated with the occurrence or the elevated risk for certain hereditary diseases.
GWAS for different diseases and disorders including: age-related macular degeneration (AMD), glaucoma, diseases of the cornea (including Fuchs corneal endothelial dystrophy (FCED), keratoconus (KC)), diabetic retinopathy (DR), rhegmatogenous retinal detachment (RD), refractive error, optic disc parameters, central corneal thickness (CCT), Corneal curvature (CC), and intraocular pressure (IOP) are discussed.
The limitations and an outlook for the application of GWAS is provided.
In summary, this review provides on good overview on genetic factors that are associated with different hereditary diseases in ophthalmology.
Chandra et al. 2014

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Improving molecular diagnosis of Chinese patients with Charcot-Marie-Tooth by targeted next-generation sequencing and functional analysis

25. March 2016, Oncotarget published the study of Li-Xi et al.
"Improving molecular diagnosis of Chinese patients with Charcot-Marie-Tooth by targeted next-generation sequencing and functional analysis"

Charcot-Marie-Tooth (CMT) disease is one of the most common hereditary peripheral neuropathy. This study describes the utilization of targeted gene sequencing in combination with duplication/ deletion analysis for genetic screening of Chinese families with CMT disease.

From 22 tested Chinese patients eight displayed PMP22 duplication after multiplex ligation-dependent probe amplification (MLPA) analysis. Targeted NGS analysis was performed with a panel of 44 CMT relevant genes. After NGS analysis and verification by Sanger sequencing 10 potential pathogenic variants were detected including three novel variants. In four patients no potential pathogenic variants were found. The new discovered variants are discussed in context with the phenotypes of the patients.

In summary, targeted NGS gene sequencing was utilized in combination with MLPA for PMP22 duplication identification, since targeted gene sequencing is less effective for duplication identification. Whole genome sequencing (WGS) and whole exome sequencing (WES) seems to be more attractive for identification of potential pathogenic variants. These methods can also detect variants that are not included in the known CMT causative genes tested in this targeted NGS approach. Drawbacks of WGS and WES are the high output of unspecific data leading to higher sequencing costs and more complex data analysis.

The publication is free available on Oncotarget

Improving the management of Inherited Retinal Dystrophies by targeted sequencing of a population-specific gene panel

1. April 2016, Scientific reports published the study of Bravo-Gil et al. "Improving the management of Inherited Retinal Dystrophies by targeted sequencing of a population-specific gene panel."

This study applied targeted next generation sequencing in order to investigate the genetic background in Spanish families with different types of Inherited Retinal Dystrophies (IRD).
For targeted gene sequencing a panel was developed that covers 64 genes related to retinal dystrophies reported in Spanish families. The panel was validated on two previously genetic characterized samples.
Thirty two families were tested with this panel, in 22 families "pathogenic" mutations were detected, whereof 21 lead to a conclusive diagnostics. The detected variants included CNVs, missense, nonsense, frame shift, splicing, and intron mutations. Fourteen novel variants could be detected that were not found in different public databases (e.g. dbSNP, 1000 Genomes).
The utilization of this new gene panels enabled the detection of two variants that were not detected by whole exome sequencing (WES). Due to the low coverage rate achieved by the WES study these variants were filtered out during the bioinformatic analysis.
In conclusion, it is stated that gene panels targeting genes or regions affecting a particular population can be especially beneficial for molecular diagnostics.

The publication is free available at NCBI

Review of Commercially Available Epilepsy Genetic Panels

This review accessed different commercially available epilepsy genetic panels in seven laboratories. NGS panels are widely used in order to identify the genetic causes of epilepsy and have revolutionized diagnostics.
The authors describe seven different tested panels, the number of genes included in the panels varies significant from 65 to 465 genes. Most test panels also target genes that are not described to be associated with primary epilepsy.
Different issues related to genetic panel testing for epilepsy are described. It is stated that having too many genes in the test panel is not always beneficial.
In summary, for genetic counselors it is important to explain the range of genetic disorders that can be detected with the different epilepsy test panels. Patients need to be aware about what testing they receive and its implications.
Chambers et al. 2015


Targeted multi-gene panel testing for the diagnosis of Bardet Biedl syndrome: Identification of nine novel mutations across BBS1, BBS2, BBS4, BBS7, BBS9, BBS10 genes

This paper describes a study were NGS was used in order to investigate the genetic background of BBS. A genetic panel targeting 17 BBS related genes were used for mutation analysis. In this study previous known and new variants were discovered in the BBS related genes.
The genotypically and phenotypically observations of this study and its correlation for particular genes such as BBS2, BBS3, BBS4, BBS7, and BBS10 are discussed.
In summary, the utilization of the NGS panel representing 17 known BBS genes enabled a molecular BBS diagnosis of about 87% of the investigated patients.
Solmaz et al. 2015


Scientific Publications on Next Generation Sequencing Applications in Forensic

Application of next-generation sequencing technology in forensic science

This publication gives a concise overview of NGS technologies and their possible applications in forensics. The applications reviewed include STR analysis, mitochondrial genome analysis, Y chromosome analysis, forensic microbiological analysis, ancestry study and phenotypic interferences, animal and plant DNA analysis, epigenetic analysis, and micro RNA analysis.
Yang et al. 2014

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Metagenomic analyses of bacteria on human hairs: a qualitative assessment for applications in forensic science

Human hair is a problematic substrate for DNA extraction as it often contains insufficient DNA for short tandem repeat profiles. In this study, metagenome analysis of hair by NGS was evaluated to determine its applicability to forensics. The analysis includes microorganism data, such as bacteria associated with hair. In this study, the microbiota of pubic and scalp hair was investigated.
Tridico et al 2014

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The future of forensic DNA analysis

The author introduces previous and current forensic methods and provides an outlook of forensic analysis in the future. Various methods and technologies are introduced, and their potential future applications are discussed. The speed to result, cost, data accuracy and quantity, databases, and corresponding analysis tools are some key factors that may influence the development of forensic analysis in the future.
Butler 2015



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