IDENTIFYING THE GENETIC BASIS OF RARE BLEEDING AND PLATELET DISORDERS USING SYSTEMATIC PHENOTYPING AND GENOME SEQUENCING
(Abstract release date: 05/19/16)
EHA Library. Turro E. 06/11/16; 135274; S518
Dr. Ernest Turro
Contributions
Contributions
Abstract
Abstract: S518
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:30 - 16:45
Location: Room H4
Background
The majority of rare bleeding, thrombotic and platelet disorders (BPDs) do not have an identified genetic basis. Whilst whole genomic sequencing is now an affordable approach, small family sizes, variable penetrance and phenotypic variability are barriers to identifying the responsible genetic variants. We have used a systematic phenotyping approach combined with novel clustering analyses to identify implicated genes and candidate causal mutations called by next generation sequencing (NGS).
Aims
Detection of novel genetic causes of BPDs.
Methods
A total of 848/1247 index cases and 78/87 affected relatives have been sequenced/phenotyped. The Human Phenotype Ontology (HPO) has been expanded to better capture clinical and laboratory data. Genes known to harbour variants responsible for BPDs have been screened. New algorithms have been developed to identify patients with similar phenotypes and a potentially shared genetic basis of disease.
Results
In 115 cases a definitive or likely genetic explanation has been identified and in 13 a partial genetic explanation. Four genes harbouring variants responsible for platelet abnormalities including DIAPH1, SRC and TRPM7 have been identified. Variants responsible for atypical presentations of previously known syndromes, including MYH9-related disease and Hermansky-Pudalk syndrome, have also been identified. Finally, we have shown that large numbers of cases are explained by variants in recently reported genes, e.g. 27 by variants in ACTN1, eight by variants in the 5'UTR of ANKRD26 and two by variants in STIM1. In total a long list of 45 genes have been identified as harbouring variants responsible or possibly responsible for BPDs in our collection and many are under further investigation.
Conclusion
A systematic method of detailed phenotyping and NGS has formed the basis of screening and clustering analysis. We have identified genes harbouring variants responsible for BPDs and have confirmed previous findings. Syndromic phenotypes have been better defined and a large number of candidate variants remain to be explored. Having used WGS as the main method of DNA sequencing will now allow these methods to be extended to regulatory regions of the genome.
Session topic: Platelet disorders 1
Keyword(s): Bleeding, Genetic, Platelet
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:30 - 16:45
Location: Room H4
Background
The majority of rare bleeding, thrombotic and platelet disorders (BPDs) do not have an identified genetic basis. Whilst whole genomic sequencing is now an affordable approach, small family sizes, variable penetrance and phenotypic variability are barriers to identifying the responsible genetic variants. We have used a systematic phenotyping approach combined with novel clustering analyses to identify implicated genes and candidate causal mutations called by next generation sequencing (NGS).
Aims
Detection of novel genetic causes of BPDs.
Methods
A total of 848/1247 index cases and 78/87 affected relatives have been sequenced/phenotyped. The Human Phenotype Ontology (HPO) has been expanded to better capture clinical and laboratory data. Genes known to harbour variants responsible for BPDs have been screened. New algorithms have been developed to identify patients with similar phenotypes and a potentially shared genetic basis of disease.
Results
In 115 cases a definitive or likely genetic explanation has been identified and in 13 a partial genetic explanation. Four genes harbouring variants responsible for platelet abnormalities including DIAPH1, SRC and TRPM7 have been identified. Variants responsible for atypical presentations of previously known syndromes, including MYH9-related disease and Hermansky-Pudalk syndrome, have also been identified. Finally, we have shown that large numbers of cases are explained by variants in recently reported genes, e.g. 27 by variants in ACTN1, eight by variants in the 5'UTR of ANKRD26 and two by variants in STIM1. In total a long list of 45 genes have been identified as harbouring variants responsible or possibly responsible for BPDs in our collection and many are under further investigation.
Conclusion
A systematic method of detailed phenotyping and NGS has formed the basis of screening and clustering analysis. We have identified genes harbouring variants responsible for BPDs and have confirmed previous findings. Syndromic phenotypes have been better defined and a large number of candidate variants remain to be explored. Having used WGS as the main method of DNA sequencing will now allow these methods to be extended to regulatory regions of the genome.
Session topic: Platelet disorders 1
Keyword(s): Bleeding, Genetic, Platelet
Abstract: S518
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:30 - 16:45
Location: Room H4
Background
The majority of rare bleeding, thrombotic and platelet disorders (BPDs) do not have an identified genetic basis. Whilst whole genomic sequencing is now an affordable approach, small family sizes, variable penetrance and phenotypic variability are barriers to identifying the responsible genetic variants. We have used a systematic phenotyping approach combined with novel clustering analyses to identify implicated genes and candidate causal mutations called by next generation sequencing (NGS).
Aims
Detection of novel genetic causes of BPDs.
Methods
A total of 848/1247 index cases and 78/87 affected relatives have been sequenced/phenotyped. The Human Phenotype Ontology (HPO) has been expanded to better capture clinical and laboratory data. Genes known to harbour variants responsible for BPDs have been screened. New algorithms have been developed to identify patients with similar phenotypes and a potentially shared genetic basis of disease.
Results
In 115 cases a definitive or likely genetic explanation has been identified and in 13 a partial genetic explanation. Four genes harbouring variants responsible for platelet abnormalities including DIAPH1, SRC and TRPM7 have been identified. Variants responsible for atypical presentations of previously known syndromes, including MYH9-related disease and Hermansky-Pudalk syndrome, have also been identified. Finally, we have shown that large numbers of cases are explained by variants in recently reported genes, e.g. 27 by variants in ACTN1, eight by variants in the 5'UTR of ANKRD26 and two by variants in STIM1. In total a long list of 45 genes have been identified as harbouring variants responsible or possibly responsible for BPDs in our collection and many are under further investigation.
Conclusion
A systematic method of detailed phenotyping and NGS has formed the basis of screening and clustering analysis. We have identified genes harbouring variants responsible for BPDs and have confirmed previous findings. Syndromic phenotypes have been better defined and a large number of candidate variants remain to be explored. Having used WGS as the main method of DNA sequencing will now allow these methods to be extended to regulatory regions of the genome.
Session topic: Platelet disorders 1
Keyword(s): Bleeding, Genetic, Platelet
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:30 - 16:45
Location: Room H4
Background
The majority of rare bleeding, thrombotic and platelet disorders (BPDs) do not have an identified genetic basis. Whilst whole genomic sequencing is now an affordable approach, small family sizes, variable penetrance and phenotypic variability are barriers to identifying the responsible genetic variants. We have used a systematic phenotyping approach combined with novel clustering analyses to identify implicated genes and candidate causal mutations called by next generation sequencing (NGS).
Aims
Detection of novel genetic causes of BPDs.
Methods
A total of 848/1247 index cases and 78/87 affected relatives have been sequenced/phenotyped. The Human Phenotype Ontology (HPO) has been expanded to better capture clinical and laboratory data. Genes known to harbour variants responsible for BPDs have been screened. New algorithms have been developed to identify patients with similar phenotypes and a potentially shared genetic basis of disease.
Results
In 115 cases a definitive or likely genetic explanation has been identified and in 13 a partial genetic explanation. Four genes harbouring variants responsible for platelet abnormalities including DIAPH1, SRC and TRPM7 have been identified. Variants responsible for atypical presentations of previously known syndromes, including MYH9-related disease and Hermansky-Pudalk syndrome, have also been identified. Finally, we have shown that large numbers of cases are explained by variants in recently reported genes, e.g. 27 by variants in ACTN1, eight by variants in the 5'UTR of ANKRD26 and two by variants in STIM1. In total a long list of 45 genes have been identified as harbouring variants responsible or possibly responsible for BPDs in our collection and many are under further investigation.
Conclusion
A systematic method of detailed phenotyping and NGS has formed the basis of screening and clustering analysis. We have identified genes harbouring variants responsible for BPDs and have confirmed previous findings. Syndromic phenotypes have been better defined and a large number of candidate variants remain to be explored. Having used WGS as the main method of DNA sequencing will now allow these methods to be extended to regulatory regions of the genome.
Session topic: Platelet disorders 1
Keyword(s): Bleeding, Genetic, Platelet
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