PracticeUpdate: Haematology & Oncology

EUROPEAN HEMATOLOGY ASSOCIATION 2016 CONGRESS 16

Three novel genes harbour variants linked to bleeding and platelet disorder Using next-generation sequencing, three genes have been identified as harbouring variants responsible or possibly responsible for bleeding and platelet disorders. This progress made using systematic phenotype and genome sequencing was presented at the EHA 2016 congress. E rnest Turro, PhD, of the University of Cambridge, UK, explained that approximately 3 million people suffer from explained by variants in recently reported genes, for example, 27 by variants in ACTN1, eight by variants in the 5’UTR of ANKRD26, and two by variants in STIM1.

EHA 2016 9–12 JUNE 2016 • COPENHAGEN, DENMARK Our coverage of the European Hematology Association 2016 Congress includes the latest on novel gene variants linked to bleeding and platelet disorders, IDH-1/2 mutation in relapsed or refractory AML, SL-401 for blastic plasmacytoid dendritic cell neoplasm, and results of the CASTOR and INO-VATE trials.

a rare bleeding disorder or disease of platelets. The genetic causes of dozens of such disorders are known. The majority, however, do not have an identified genetic basis. “Though rare diseases are individually rare,” said Dr Turro, “together they affect many millions of people around the world. While whole genomic sequencing is now an affordable approach, small family sizes, variable penetrance and phenotypic variability are barriers to identifying the responsible genetic variants. Platelets, which play a role in heart attacks and stroke, are involved in one in three deaths in the general population. Therefore, a better understanding of rare platelet diseases may also benefit millions of people who experience these common life-threatening events. Dr Turro and colleagues have used a systematic phenotyping approach combined with novel clustering analyses to identify implicated genes and candidate causal variants called by next- generation sequencing. A total of 848/1247 index cases and 78/87 affected relatives have been sequenced/ phenotyped. The Human Phenotype Ontology has been expanded to better capture clinical and laboratory data. Genes known to harbour variants responsible for bleeding and platelet disorders have been screened and new algorithms developed to identify patients with similar phenotypes and a potentially shared genetic basis of disease. In 115 cases, a definitive or likely genetic explanation, and in 13 a partial genetic explanation, has been identified. Variants responsible for atypical presentations of previously known syndromes, including MYH9-related disease and Hermansky-Pudalk syndrome, have also been identified. Dr Turro and colleagues, supported by the UK’s National Institute for Health Research, have shown that large numbers of cases are

The three novel genes harbouring variants responsible for platelet abnormalities are DIAPH1, SRC, and TRPM7. Variants in DIAPH1 underlie a new genetic link between very large platelets and hearing loss. A variant in SRC, a well-known cancer gene, is responsible for fragile bones, bone marrow scarring and low platelet count. Finally, variants in TRPM7 underlie arrhythmias and low platelet count, which may be treatable with magnesium supplementation. Dozen of other genes have been identified as harbouring variants that may possibly be responsible for bleeding and platelet disorders and are under further investigation. Within months of publication, these and other research findings are already benefiting patients through a new cheap, fast and accurate diagnostic test (thrombogenomics.org.uk ) available to patients in the UK and other countries. Within months of publication, these and other research findings are already benefiting patients through a new cheap, fast and accurate test ( thrombogenomics.org.uk ) available to patients in the UK and other countries. “The ThromboGenomics test,” Dr Turro said, “enables rapid and cheap diagnosis for all known bleeding and platelet disorders. Obtaining a definitive molecular diagnosis not only brings peace of mind to patients, but it is also important for identifying affected relatives, predicting and managing the likely progression of disease and providing the best possible treatment.” Using whole genome sequencing as the main method of DNA sequencing will allow for extension of the research into regulatory regions of the genome. “It is essential,” Dr Turro said, “that researchers and clinicians from countries across the globe work together to ensure that sufficient numbers of patients are recruited to enable a good chance of uncovering the responsible genetic variants.”

It is essential that researchers and clinicians from countries across the globe work together to ensure that sufficient numbers of patients are recruited to enable a good chance of uncovering

the responsible genetic variants.

PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY