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Next generation sequencing technologies for rare Mendelian disorders: striking potential and ongoing challenges
Molecular and Cellular Probes 29 (2015) 259
Contents lists available at ScienceDirect
Molecular and Cellular Probes journal homepage: www.elsevier.com/locate/ymcpr
Next generation sequencing technologies for rare Mendelian disorders: striking potential and ongoing challenges
Diseases are considered as rare (“orphan”) disorders if they occur with a frequency of <1:2000 in the general population. However, they are only rare if regarded individually: altogether >7000 such diseases are known to date (giving a cumulative prevalence of 6e8% [1]) which not only pose individual problems and suffering for the affected families but also collectively represent a considerable burden for modern health care systems [2]. The majority of rare disorders is caused by monogenic inheritance, but since there are mostly only few affected families for a given disease, the identification of the disease-causing gene(s) has not been achieved in many cases until recently. With the development of novel sequencing techniques (socalled next generation sequencing, NGS), there has been a tremendous progress in the detection of the genetic basis for rare diseases over the past 2e3 years [3]. While the standard procedure of Sanger sequencing of one or a few known genes is both time- and costconsuming and insufficient for highly heterogeneous disorders, chip-based sequencing technologies now allow to generate the sequence of a group of genes (targeted panel diagnostics), the whole exome or even the whole genome of a patient in a considerable amount of time at bearable costs. This Special Issue illustrates these exciting developments in human genetics through a number of excellent reviews, original articles and case reports. Comparable to many other Mendelian diseases, Vona et al. comprehensibly summarize the history of gene identification for non-syndromic hearing loss, a highly heterogeneous condition, from low-throughput linkage analysis >20 years ago towards high-throughput NGS strategies nowadays. Similarly, MorrisRosendahl and Kaindl give an overview over the data gained by NGS for the neurodevelopmental disorder of autosomal recessive primary microcephaly. Even for more complex mechanisms as seen in congenital imprinting disorders, the novel highthroughput molecular techniques have already brought substantial additional knowledge over the past few years, as reviewed in Soellner et al. in the current issue. In the “Original Articles” section, three manuscripts illustrate NGS-based findings for infantile cholestatic disorders (Herbst et al.), ciliopathies such as Joubert, Meckel and Bardet-Biedl syndromes (Knopp et al.) and cardiomyopathies (Waldmüller et al.). Last but not least, four case reports give additional examples how the novel molecular techniques helped to identify disease-causing variant(s) leading to the diagnosis of Troyer syndrome (Tawamie et al.) or leukoencephalopathy with
This article belongs to the Special Issue: Monogenic orphan diseases in man. http://dx.doi.org/10.1016/j.mcp.2015.08.001 0890-8508/© 2015 Published by Elsevier Ltd.
brainstem and spinal cord involvement (Koehler et al.) or identified novel mutations for severe encephalopathy (Granzow et al.) and a connective tissue disorder with overlap to Marfan and LoeysDietz syndromes (Kuechler et al.). However, we also have to be aware of the problems and downfalls of the novel NGS techniques. First of all, for exome- or even genome-wide approaches the geneticist has to rely on software tools which help to sort the huge amount of data for the relevant mutation(s). As illustrated in the paper by Granzow et al., different filtering of the same data may give quite diverging results, so that interpretation of the data must still be regarded cautiously. Further, there is on-going debate about ethical issues concerning the huge amount of genetic data that is produced for a single patient with NGS-based techniques [4]. For example, it is still rather unclear, whether or not additional genetic findings that are not related to the disease in question, such as risk variants for cancerous or multifactorial diseases, should be transmitted to the patient/family and if so, in what setting. Therefore, next generation sequencing has brought remarkable progress for the delineation of rare genetic diseases, but data analysis still has to be improved and ethical issues thoroughly discussed before these techniques can be applied on a routine basis.
References [1] European Organisation for Rare Diseases. Rare diseases: understanding this public health priority. http://www.eurordis.org/IMG/pdf/princeps_documentEN.pdf. [2] A. Angelis, D. Tordrup, P. Kanavos, Socio-economic burden of rare diseases: a systematic review of cost of illness evidence, Health Policy 8510 (2014) 350e359. [3] K. Danielsson, L.J. Mun, A. Lordemann, J. Mao, C.H. Lin, Next-generation sequencing applied to rare diseases genomics, Expert Rev. Mol. Diagn. 14 (2014) 469e487. [4] S. Davey, Next generation sequencing: considering the ethics, Int. J. Immunogenet. 41 (2014) 457e462.
Sabine Hoffjan Ruhr-University Bochum, Department of Human Genetics, Bochum, Germany E-mail address: [email protected]. Available online 6 August 2015
Contents lists available at ScienceDirect
Molecular and Cellular Probes journal homepage: www.elsevier.com/locate/ymcpr
Next generation sequencing technologies for rare Mendelian disorders: striking potential and ongoing challenges
Diseases are considered as rare (“orphan”) disorders if they occur with a frequency of <1:2000 in the general population. However, they are only rare if regarded individually: altogether >7000 such diseases are known to date (giving a cumulative prevalence of 6e8% [1]) which not only pose individual problems and suffering for the affected families but also collectively represent a considerable burden for modern health care systems [2]. The majority of rare disorders is caused by monogenic inheritance, but since there are mostly only few affected families for a given disease, the identification of the disease-causing gene(s) has not been achieved in many cases until recently. With the development of novel sequencing techniques (socalled next generation sequencing, NGS), there has been a tremendous progress in the detection of the genetic basis for rare diseases over the past 2e3 years [3]. While the standard procedure of Sanger sequencing of one or a few known genes is both time- and costconsuming and insufficient for highly heterogeneous disorders, chip-based sequencing technologies now allow to generate the sequence of a group of genes (targeted panel diagnostics), the whole exome or even the whole genome of a patient in a considerable amount of time at bearable costs. This Special Issue illustrates these exciting developments in human genetics through a number of excellent reviews, original articles and case reports. Comparable to many other Mendelian diseases, Vona et al. comprehensibly summarize the history of gene identification for non-syndromic hearing loss, a highly heterogeneous condition, from low-throughput linkage analysis >20 years ago towards high-throughput NGS strategies nowadays. Similarly, MorrisRosendahl and Kaindl give an overview over the data gained by NGS for the neurodevelopmental disorder of autosomal recessive primary microcephaly. Even for more complex mechanisms as seen in congenital imprinting disorders, the novel highthroughput molecular techniques have already brought substantial additional knowledge over the past few years, as reviewed in Soellner et al. in the current issue. In the “Original Articles” section, three manuscripts illustrate NGS-based findings for infantile cholestatic disorders (Herbst et al.), ciliopathies such as Joubert, Meckel and Bardet-Biedl syndromes (Knopp et al.) and cardiomyopathies (Waldmüller et al.). Last but not least, four case reports give additional examples how the novel molecular techniques helped to identify disease-causing variant(s) leading to the diagnosis of Troyer syndrome (Tawamie et al.) or leukoencephalopathy with
This article belongs to the Special Issue: Monogenic orphan diseases in man. http://dx.doi.org/10.1016/j.mcp.2015.08.001 0890-8508/© 2015 Published by Elsevier Ltd.
brainstem and spinal cord involvement (Koehler et al.) or identified novel mutations for severe encephalopathy (Granzow et al.) and a connective tissue disorder with overlap to Marfan and LoeysDietz syndromes (Kuechler et al.). However, we also have to be aware of the problems and downfalls of the novel NGS techniques. First of all, for exome- or even genome-wide approaches the geneticist has to rely on software tools which help to sort the huge amount of data for the relevant mutation(s). As illustrated in the paper by Granzow et al., different filtering of the same data may give quite diverging results, so that interpretation of the data must still be regarded cautiously. Further, there is on-going debate about ethical issues concerning the huge amount of genetic data that is produced for a single patient with NGS-based techniques [4]. For example, it is still rather unclear, whether or not additional genetic findings that are not related to the disease in question, such as risk variants for cancerous or multifactorial diseases, should be transmitted to the patient/family and if so, in what setting. Therefore, next generation sequencing has brought remarkable progress for the delineation of rare genetic diseases, but data analysis still has to be improved and ethical issues thoroughly discussed before these techniques can be applied on a routine basis.
References [1] European Organisation for Rare Diseases. Rare diseases: understanding this public health priority. http://www.eurordis.org/IMG/pdf/princeps_documentEN.pdf. [2] A. Angelis, D. Tordrup, P. Kanavos, Socio-economic burden of rare diseases: a systematic review of cost of illness evidence, Health Policy 8510 (2014) 350e359. [3] K. Danielsson, L.J. Mun, A. Lordemann, J. Mao, C.H. Lin, Next-generation sequencing applied to rare diseases genomics, Expert Rev. Mol. Diagn. 14 (2014) 469e487. [4] S. Davey, Next generation sequencing: considering the ethics, Int. J. Immunogenet. 41 (2014) 457e462.
Sabine Hoffjan Ruhr-University Bochum, Department of Human Genetics, Bochum, Germany E-mail address: [email protected]. Available online 6 August 2015