PracticeUpdate: Haematology & Oncology

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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.
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.
Ernest Turro, PhD, of the University
of Cambridge, UK, explained that
approximately 3 million people suffer from
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
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.
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 ) 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 ( ) 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.
EUROPEAN HEMATOLOGY ASSOCIATION 2016 CONGRESS 16
PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY