Hereditary haemorrhagic telangiectasia: mutation
detection, test sensitivity and novel mutations
N L Prigoda, S Savas, S A Abdalla, B Piovesan, D Rushlow, K Vandezande, E Zhang,
H Ozcelik, B L Gallie, M Letarte
............................................................... ............................................................... .
See end of article for
Dr Michelle Letarte, The
Hospital for Sick Children,
555 University Avenue,
Toronto, ON, M5G 1X8
Received 17 March 2006
Revised version received
24 April 2006
Accepted for publication
27 April 2006
Published Online First
11 May 2006
J Med Genet 2006;43:722–728. doi: 10.1136/jmg.2006.042606
Background: Hereditary haemorrhagic telangiectasia (HHT) is a genetic disorder present in 1 in 8000
people and associated with arteriovenous malformations. Genetic testing can identify individuals at risk of
developing the disease and is a useful diagnostic tool.
Objective: To present a strategy for mutation detection in families clinically diagnosed with HHT.
Methods: An optimised strategy for detecting mutations that predispose to HHT is presented. The strategy
includes quantitative multiplex polymerase chain reaction, sequence analysis, RNA analysis, validation of
missense mutations by amino acid conservation analysis for the ENG (endoglin) and ACVRL1 (ALK1)
genes, and analysis of an ACVRL1 protein structural model. If no causative ENG or ACVRL1 mutation is
found, proband samples are referred for sequence analysis of MADH4 (associated with a combined
syndrome of juvenile polyposis and HHT).
Results: Data obtained over the past eight years were summarised and 16 novel mutations described.
Mutations were identified in 155 of 194 families with a confirmed clinical diagnosis (80% sensitivity). Of
155 mutations identified, 94 were in ENG (61%), 58 in ACVRL1 (37%), and three in MADH4 (2%).
Conclusions: For most missense variants of ENG and ACVRL1 reported to date, study of amino acid
conservation showed good concordance between prediction of altered protein function and disease
occurrence. The 39 families (20%) yet to be resolved may carry ENG, ACVRL1, or MADH4 mutations too
complex or difficult to detect, or mutations in genes yet to be identified.
develop epistaxis before the age of 20.2However, age of
onset, incidence, and severity are highly variable3; individuals
may not be diagnosed until a life threatening complication
presents. Arteriovenous malformations can occur in the
pulmonary, cerebral, and hepatic circulation leading to
stroke, internal haemorrhage, and severe anaemia.2–5
Two genes are causally related to HHT. Mutations in
the 30 kb endoglin (ENG; OMIM 187300) gene, associated
with a high prevalence of pulmonary arteriovenous mal-
formations (PAVMs),6lead to HHT1.7Mutations in the 15 kb
activin receptor-like kinase-1 gene (ACVRL1; ALK-1, OMIM
600376) lead to HHT2,8which is characterised by a lower
frequency of pulmonary and cerebral arteriovenous malfor-
mations than HHT1, but which may have a higher incidence
of liver involvement.6 9As in other diseases with a high new
mutation rate,10most families with HHT have a unique
mutation, rendering molecular diagnosis labour intensive.
In all, 168 ENG and 138 ACVRL1 mutations of all types
have been reported.11–13Two additional genes have been
associated with HHT recently. Mutations in the MADH4
tumour suppressor gene have been associated with a
combined syndrome of juvenile polyposis and HHT (JPHT;
OMIM 175050).14An unidentified HHT3 gene linked to
chromosome 5 is also likely to account for a subset of HHT
We present a strategy for mutation detection in families
clinically diagnosed with HHT. We document 80% test
sensitivity in mutation identification. We report 16 novel
mutations and seven new polymorphisms. We evaluate the
use of evolutionary conservation analysis to predict the effect
of missense variants on protein function and disease
ereditary haemorrhagic telangiectasia (HHT) is an
autosomal dominant disorder manifested in 1/8000
Most affected individuals
Further details on the methods used are found in the online
Samples for 291 HHT families were referred from Canada and
several other countries. Informed consent was obtained from
each family according to institutional guidelines for clinical
testing and research studies. Research procedures were
approved by the ethics committee of the Research Institute
of the Hospital for Sick Children.
Total genomic DNA was extracted from peripheral blood
lymphocytes with the Puregene (Gentra) kit, according to the
Quantitative multiplex polymerase chain reaction (QM-
PCR), with some modifications to previously reported
conditions,16 17was used to screen for changes in exon size
and copy number in all 15 exons of ENG and nine coding
exons of ACVRL1. The promoter and exons of ENG, and exons
2 to 10 of ACVRL, were sequenced. Sequencing was often
done in duplexes, where two exons were sequenced
simultaneously. QM-PCR fragments and sequencing chro-
matograms were analysed using GeneObjects software
(Visible Genetics Inc). Haplotype analysis (by polymorphic
markers d12S1677, d12S368, d12S1712, and d12S347) was
used to refine analysis for some families.
When no mutation was found, either in ENG or ACVRL1,
samples with appropriate consent were referred to the
Abbreviations: HHT, hereditary haemorrhagic telangiectasia; JPHT,
syndrome of juvenile polyposis and hereditary haemorrhagic
telangiectasia; PAVM, pulmonary arteriovenous malformation; SIFT,
‘‘sorting intolerant from tolerant’’ program
Marchuk laboratory at Duke University for MADH4 sequence
analysis. Each MADH4 mutation identified was confirmed in
our clinical laboratory.
RNA and protein methods
When required and possible, reverse transcriptase polymerase
chain reaction (RT-PCR) analysis was undertaken using a
fresh blood sample, gene specific primers, and the inclusion
of a puromycin step. Endoglin expression in peripheral blood
activated monocytes and umbilical vein endothelial cells was
analysed by35S-methionine labelling and immunoprecipita-
tion using monoclonal antibodies P3D1 and P4A4, as
Missense variations were analysed to identify disease causing
mutations. First, the literature was searched for reports with
sufficient evidence to conclude that the variation is causative.
Analysis was completed for all other exons of ENG and
ACVRL1 to ensure that no other mutation was present.
Evolutionary conservation analysis of ENG and ACVRL1
variants was carried out using the SIFT (‘‘sorting intolerant
from tolerant’’) tool.21–23To predict the effect of ACVRL1
missense variations on protein structure, several were
analysed by molecular modelling, as described previously.24
Summary of mutation analysis
Of 291 families referred for analysis, 24 were excluded
because the clinical information was insufficient to confirm a
diagnosis, and 73 were excluded because of inadequate DNA.
The remaining 194 families were analysed by a combination
of QM-PCR, duplex sequencing, long PCR, and RNA
sequencing. We identified mutations in 155 of 194 families
(table 1), resulting in 80% mutation detection sensitivity. Of
all mutations identified, 61% were in ENG (HHT1), 37% in
ACVRL1 (HHT2), and 2% in MADH4 (JPHT).
All types of mutations were identified in the ENG and
ACVRL1 genes. In our series, missense mutations were
associated more often with HHT2 (62%) than with HHT1
(27%), while splice site variants were associated more often
with HHT1 (13%) than with HHT2 (2%). Nonsense mutations
occurred with equal frequency (15%). Small deletions and
Seven ENG and four ACVRL1 mutations (7% overall) were
whole exon deletions or duplications identified by QM-PCR
and not by sequencing. This study is the first to report whole
exon deletions in the ACVRL1 gene (exons 3 to 8, exon 10,
exons 9 and 10). QM-PCR also detected intraexonic deletions
and insertions (36% of ENG mutations and 12% of ACVRL1
mutations), which were also detectable by sequencing. Many
of the mutations included here for sensitivity analysis have
been reported before16–20 24–26and are not discussed in the text.
Table 2 summarises novel mutations and polymorphisms
found in our cohort.
Novel ENG mutations
Study of 94 HHT1 families revealed 75 unique mutations;
nine previously unreported mutations are described briefly
and shown in table 2 with the clinical phenotype of the
proband. Supplementary figure 1 illustrates the position of
these mutations on the mRNA diagrams. (The supplementary
figures can be viewed on the journal website (http://
Mutation spectrum for 153 HHT families
Mutation type ENG (%) ACVRL1 (%) MADH4 (%)All (%)Methods*
Whole exon and multiexon deletions and duplications
*Methods used for mutation detection: S=sequencing; Q=quantitative multiplex polymerase chain reaction.
Novel mutations identified
FamilyGene Mutation typeExon Nucleotide change Amino acid change Phenotype*
(dup exon 2 to 4)
del exon 10
del exons 9 and 10
E, T, F
E, T, P
6 and 516
2 to 4
E, T, P, F
E, T, G, F
T, P, C
E, T, P, F
E, T, F
140 and 510
Whole exon deletion
3 to 8
9 and 10
E, T, F
G, P, F
E, T, G, F
T, H, F
*Proband phenotype: C=cerebral arteriovenous malformation; E=epistaxis; F=family history; G=gastrointestinal bleeds; H=hepatic arteriovenous
malformation; P=pulmonary arteriovenous malformation; T=telangiectases.
HHT mutation analysis strategy723
Three novel mutations affecting ENG splice sites were
identified. In family 163, the +5 G to A substitution changed
the Shapiro-Senapathy27splice score from 76.8 to 62.4,
predicting missplicing of exon 1. Family history for the
proband included a brother and father with PAVMs. In
family 520, the 27 C to G substitution in intron 6 activated a
cryptic AG acceptor site, shown by RNA analysis to cause an
insertion of CATTAG, leading to a premature stop. In family
524, deletion of 186 nucleotides at position 896 of exon 7
removed the 39 splice site and part of intron 7. This mutation
probably causes skipping of exon 7, leading to a frameshift.
The proband, whose father had a pulmonary haemorrhage of
unknown cause, presented with epistaxis as the only clinical
We identified four novel small ENG insertions leading to
frameshift mutations (table 2). In family 508, the proband
and mother were each diagnosed with PAVMs. In families 6
and 516, later shown to have a common ancestor, there were
three generations of affected individuals.
The proband of family 202 had both pulmonary and
cerebral arteriovenous malformations. QM-PCR analysis
showed 2.7 copies of exon 4, and 2.9 copies for each of
exons 3 and 2, revealing a duplication of ENG exons 2 to 4.
Figure 1A illustrates one of the QM-PCR reactions. RNA
amplification spanning exons 1 through 6 confirmed the
presence of a larger transcript (fig 1B). Sequencing of the
transcript confirmed the duplication of exons 2, 3, and 4,
leading to a larger protein with in-frame insertion of G23 to
Q174. This mutation was also analysed at the protein level
(fig 1C). Immunoprecipitation of endoglin from metaboli-
cally labelled activated peripheral blood lymphocytes showed
that the normal surface glycoprotein (E; 90 kDa monomer)
was reduced in the proband sample to an estimated 57 (10)%
(mean (SD)) of normal levels. A mutant 110 kDa monomer
(band M) was observed, representing a protein with an
additional 151 amino acids.
A novel ENG missense mutation was found in family 521:
the c.923CRA substitution in exon 7 resulted in a p.A308D
conversion. A308 is not highly conserved across species, and
this substitution was considered ‘‘tolerated’’ by SIFT. N307 is
predicted to be an N-glycosylation site. It is possible that the
A308D change could affect the glycosylation of N307 because
the negatively charged side chain of aspartic acid could have
unfavourable interactions with the negatively charged
oligosaccharides. However, the NetNGlyc program (Gupta
R, Jung E, Brunak S, in preparation) showed little effect of
the A308D substitution (data not shown). Nevertheless, two
unaffected family members did not carry this substitution,
while three affected members did. The probability that the
observed pattern occurs by random chance alone is less than
4%. Furthermore, this variant was not observed in 200
normal alleles sequenced for exon 7, supporting A308D as a
disease causing mutation.
Novel ACVRL1 mutations
Within the ACVRL1 gene we have identified a total of 43
unique mutations in 58 resolved families. Six of these
mutations are novel and are listed in table 2. Detailed
descriptions of some of the mutations are listed below.
In family 534, a splice site mutation (C to G at the 23
position of intron 3), decreased the Shapiro-Senapathy27
splice score from 84 to 72. RT-PCR showed two mutant
transcripts: c.314_315ins208 included all of intron 3, and
c.314_336del23, caused by a cryptic AG site in exon 4
resulting in deletion of 23 nucleotides (data not shown).
9b4 C426 11 Exon
222222 Copy No
1.9 2.72 2.9 1.8
chain reaction (RT-PCR). A duplication of ENG exons 2, 3, and 4 was found in family 202. (A) QM-PCR results for control and proband samples: peaks
correspond to the exons indicated in italics. Peak height for control samples were set to two copies; in the proband sample, copy numbers were
calculated for each exon by GeneObjectsTMfragment analysis tool and are shown below the tracing. (B) RT-PCR products amplified using a forward
primer outside exon 1 and a reverse primer within exon 6 were run on an agarose gel. The control sample shows a strong band corresponding to the
normal transcript (785 bp) and a fainter lower band (approximately 650 bp) corresponding to an alternately spliced product found in all normal
samples tested to date. The proband sample does not contain this smaller band but a larger one (1238 bp), corresponding to the transcript with the
duplication. (C) Endoglin protein was immunoprecipitated in duplicate, from metabolically labelled peripheral blood activated monocytes of proband
and control. Reduced levels of the normal bands and an additional 110 kDa band that corresponds to a protein with additional amino acids coded by
the in frame duplication. bp, base pair; C, control sample; E, normal surface endoglin protein, 90 kDa; L, 100 bp ladder; M, mutant protein; 110 kDa;
P, proband sample; p, intracellular precursor, 80 kDa.
ENG mutation identified by quantitative multiplex polymerase chain reaction (QM-PCR) and confirmed by reverse transcriptase polymerase
724Prigoda, Savas, Abdalla, et al
QM-PCR identified the first whole exon deletions to be
reported for the ACVRL1 gene. Families 140 and 510 (no
known relation) had an identical deletion of exons 3 to 8.
Figure 2A shows the QM-PCR of all ACVRL1 coding exons,
with a single copy of exons 3 to 8 in the proband. The
breakpoints were identified using long PCR with primers
spanning the deletion, followed by sequencing, which
confirmed an identical direct connection between introns 2
and 8 in the probands of each family (g.5365_9652del4288,
fig 2B). Haplotype analysis (fig 2C) suggests that these two
families share a common ancestor.
The proband of family 535 had a deletion of ACVRL1 exon
10 and a confirmed diagnosis of HHT. Five family members
showed correlation between presence of the deletion and
clinical manifestations. The proband of family 544 experi-
enced frequent nosebleeds and had several affected relatives.
coding exons in a single reaction, revealed one copy of exons 3 to 8 in the proband of family 510 relative to the control. (B) Long PCR followed by
sequencing shows intron 2 joined to intron 8, in samples from the probands of families 510 and 140, indicating an identical deletion. The sequence
shows only the deletion product, which is preferentially amplified. (C) Pedigree and haplotypes of family 510 and (D) family 140 show that the allele
189/208 linked to the ACVRL1 mutation is present in both families. C, control sample; P510, proband family 510; P140, proband family 140.
Analysis of a novel ACVRL1 multiexon deletion. (A) Quantitative multiplex polymerase chain reaction (QM-PCR) analysis of all ACVRL1
Novel polymorphisms in ENG and ACVRL1
Frequency expressed in terms of individuals tested.
nd, not determined.
HHT mutation analysis strategy725
A deletion of exons 9 and 10 was found. The deletions in both
families were confirmed by QM-PCR using several distinct
alternate primer sets flanking exons 9 and 10. Additionally,
both samples showed a single copy of D12S1677, a short
tandem repeat located in intron 9. Both deletions extend 39 of
the ACVRL1 gene and their breakpoints were not identified.
A missense mutation, c.293ARG, was present in the
proband of family 542, who had telangiectases and severe
liver arteriovenous malformations necessitating a liver
transplant. NetNGlyc analysis predicted that the N98S
substitution would completely remove a potential N-glyco-
sylation site at N98 and create a new one at residue N96.
None of over 300 normal alleles sequenced for exon 3 showed
In family 514, an A352D substitution changed a highly
conserved non-polar hydrophobic residue to a negatively
charged hydrophilic one. Testing this mutant on a model of
the ALK1 (ACVRL1) protein, based on the three dimensional
structure of ALK5,24suggests that in this variant D352 will
form new hydrogen bonds with V353 and A327, with possible
steric clashes with I326. As both I326 and A327 are part of
the catalytic segment, the substitution is likely to interfere
with substrate binding.
Novel polymorphisms in ENG and ACVRL1 genes
We found two additional ENG polymorphic variants, present
in up to 2% of the population, and five new ACVRL1
polymorphic variants (table 3). The single base pair substitu-
tions in the coding sequence of ACVRL1 exons 6 and 10 were
silent and had a frequency of about 1%. Three intronic
polymorphisms, two in intron 5 and one in intron 3, were far
from exon boundaries in regions not usually sequenced. The
21-oligonucleotide deletion in intron 5 was found in five of
10 HHT families, and in five of 10 non-HHT control families.
Characterisation of missense variants
We used an evolutionary conservation tool to analyse all
missense variants (both mutations and polymorphisms pre-
viously reported and those first described in the current study)
in order to validate their potential as disease causing
mutations. In all, 110 variants (41 ENG, 69 ACVRL1) were
investigated using the SIFT tool.22A partial alignment of
proteins similar to human endoglin is shown in supplemen-
tary fig2 (seethejournal website: http://www.jmedgenet.com/
supplemental) to illustrate the evolutionary conservation and
the position of some variants. Table 4 gives a summary of the
results. Reliable SIFT predictions (either affecting or tolerated)
wereavailable for 101variants (92%), while predictions forthe
remaining nine variants were non-informative. Of 102
mutations reported, 82 (20 ENG and 62 ACVRL1) were
predicted to affect the protein function, and 12 to be tolerated.
For example, in ENG, SIFT correctly predicts L194P to be a
causative mutation because L194 is conserved among all
known species of endoglin and betaglycan (TGFBR3) proteins.
R197Q was predicted to be benign because Q197 was observed
in ENG rat and mouse orthologues. Among eight known
polymorphisms with informative SIFT analysis, four were
predicted to be benign and three to affect protein function
There was no informative SIFT prediction available for
three substitutions of the initiator methionine of endoglin
and for T5M and L8P of the leader peptide because there were
no corresponding sequences available for SIFT analysis.
However, mutations in the initiation codon lead to null
alleles, and are causally related to disease. Variants L107R
and V125D were predicted to affect the protein function and
variants G331S and C382W to be tolerated; however, their
MSC scores were greater than 3.25 and considered to be non-
informative SIFT predictions. RT-PCR analysis showed,
however, that the mutation associated with G331S (an
alteration of the final nucleotide of exon 7) caused exon 7
We describe a strategy that combines QM-PCR, bidirectional
sequencing, RT-PCR, and missense analysis to identify
mutations for 155 of 194 families with a confirmed clinical
diagnosis of HHT. We previously showed that genetic testing,
if applied in a systematic and optimised programme, renders
care more effective and less expensive than clinical manage-
ment alone.28Test sensitivity for the cost–benefit study was
estimated at 75% before our strategy was clinically imple-
mented. An actual test sensitivity of 80% suggests that cost
savings from systematic genetic testing for HHT families may
be even greater than previously indicated.
QM-PCR is invaluable in detecting whole exon or multi-
exon deletions and duplications that cannot be identified by
sequencing and represent 7% of ENG mutations and 7% of
ACVRL1 mutations found in our series. To our knowledge,
this is the first report of whole exon or multiexon deletions in
any HHT2 families. QM-PCR analysis is also a more efficient
means of identifying intraexonic deletions and insertions
SIFT results for ENG and ACVRL1 missense variants
ENGM 20 L32R, V49F, G52V, G52D, C53R, W149C, A160D, P165L, L194P, L221P, W261R,
I263T, V311G, C363Y, K374S, F403S, S407N, C412S, G413V, S615L
W196R, G214S, D264N, L306P, A308D, V504M
M1V, M1T, M1R, L8P, L107R, V125D, G331S, C382W
P131L, D366H (0.5%)
G191D (6.4%), R197Q (0.9%), P352L, I575T
G48R, C51Y, R67W, C77W, N96D, G211D, E215K, G223R, K229R, L273P, I276T,
S284F, L285F, S305P, A306P, G309S, H314Y, R329H, D330N, D330Y, S333I, L337P,
N341K, C344Y, C344F, A347P, G350R, A352P, A352D, R374W, R374Q, Y375H,
M376V, M376R, P378H, P378L, E379K, V380G, R386H, D397N, D397G, I398N,
W399S, A400D, G402S, W406C, E407D, R411W, R411Q, R411P, P424T, P424S,
P424L, F425V, F425L, P433S, M438T, V441M, P452L, R479L, R484W, K487T
G48E, W50C, R67Q, N98S, A128D, D179A
?Novel mutations are in bold. Numbers in parentheses indicated frequency of previously reported polymorphic variants in our study.
726Prigoda, Savas, Abdalla, et al
than sequencing, because several exons are screened simul-
taneously. Of the mutations identified, 43% of ENG muta-
tions and 19% of ACVRL1 mutations could be detected by
QM-PCR. It is often difficult to distinguish missense
mutations from relatively rare polymorphic variants that
have not been identified in the general population. We
evaluated the use of SIFT analysis to predict variations that
affect protein function based on evolutionary conservation.
We confirmed that 82 of 102 mutations are predicted to affect
protein function. In the case of ACVRL1, there is a very good
correlation between putative disease causing mutations and
prediction based on evolutionary conservation; SIFT pre-
dicted that 62 of 68 missense variants affect the protein
function, while the other six are tolerated. In the case of ENG,
20 of 34 missense variants were predicted to affect protein
function, while six were tolerated. There were far fewer
proteins in the ENG alignment than in ACVRL1. Nine non-
informative predictions were observed for ENG; five of these
were for variants in the leader peptide, for which very few
sequences were available for comparison. For variant G331S,
RNA analysis revealed a splice site mutation, which overrides
the SIFT prediction. This leaves only three non-informative
SIFT predictions for ENG. SIFT predictions are subject to non-
trivial false positive and false negative rates and must be used
Our strategy failed to find mutations for 39 clinically
confirmed probands. Some of these patients are likely to have
mutations in the putative HHT3 gene, not yet identified but
located on chromosome 5.15A few families might have
undetected MADH4 mutations, as this gene was only
analysed for a subset of clinically confirmed HHT families
for whom no ENG or ACVRL1 mutation was found. New
evidence suggests that HHT patients should all be tested for
MADH4 mutations if no ENG or ACVRL1 mutation is found,
because individuals who carry MADH4 mutations may not
present with the classic signs of JPHT (gastrointestinal tract
involvement or juvenile polyposis) but as HHT patients.29
We also cannot rule out the possibility that distant
mutations, not readily detected by our strategy and perhaps
in unidentified regulatory regions, may affect any of the
above genes. To confirm the locus involved in disease, linkage
analysis requires several consenting individuals from infor-
mative families. Such data are not often available. Sequence
analysis of the ACVRL1 promoter and exon 1 may increase the
detection sensitivity. To date, we have sequenced the ENG
promoter for 32 samples without finding any mutations.
It is possible that our cohort includes patients who do not
have HHT. Clinical diagnosis of HHT is complicated by large
variation in visceral manifestations, even among individuals
with the same mutation, and by age dependent manifesta-
tions of visible signs. This ambiguity encourages specialists to
refer patients for genetic testing who have a suspected
diagnosis of HHT, some of whom may not have a genetic
predisposition. The number of individuals in the cohort who
truly carry a mutation that leads to HHT cannot be
determined with certainty; this complicates the calculation
of test sensitivity. In our series, no mutation was found for 63
families after complete analysis. For 24 families, clinical
diagnosis was deemed to be uncertain, either by the referring
physician or because the patient had fewer than three
Curac ¸ao criteria.30
A study of HHT patients in the Netherlands reported
sensitivity of 90% after sequence analysis alone.31The
difference in sensitivity may result from several factors other
than the molecular diagnostic strategy. In the Dutch study, a
relatively homogeneous cohort of patients was studied for as
long as 30 years by the same team of physicians, using
standardised diagnostic criteria. Our cohort of patients was
very heterogeneous in terms of location and physicians
involved, and we could only eliminate those who did not
meet the Curac ¸ao criteria. In addition, founder mutations
appeared at a greater rate in the Dutch study than in ours.
Despite these complications, molecular testing for HHT
families has several real benefits. Once a familial mutation is
identified, relatives at risk can be tested conclusively by one
efficient and relatively inexpensive test. Individuals with a
mutation are identified for intensive clinical surveillance,
while those without a mutation may safely be removed from
ELECTRONIC DATABASE INFORMATION
Electronic URL addresses for the databases and algorithms
used in this article are as follows:
HHT Mutation database: http://126.96.36.199/cgi-bin/
This research was supported by grants from Heart and Stroke
Foundation of Ontario (NA3434), March of Dimes (HHT-FY-02-226),
and Canadian Institute of Health Research (POP-62030). SS is
supported in part by a CIHR Strategic Training Program Grant – The
Samuel Lunenfeld Research Institute Training Program: Applying
Genomics to Human Health fellowship.
The supplementary tables are present on the journal
N L Prigoda, B Piovesan, D Rushlow, K Vandezande, E Zhang,
B L Gallie, HHT Solutions, Toronto Western Hospital, Toronto, Canada
S Savas, H Ozcelik, Fred A Litwin Centre for Cancer Genetics, Samuel
Lunenfeld Research Institute and Department of Pathology and
Laboratory Medicine, Mount Sinai Hospital; Department of Laboratory
Medicine and Pathobiology, University of Toronto, Toronto, Canada
S A Abdalla, Department of Laboratory Medicine and Pathobiology, St
Michael’s Hospital, Toronto, Canada
M Letarte, Cancer Research Program, The Hospital for Sick Children,
Heart and Stroke Richard Lewar Center of Excellence and Departments
of Immunology and Medical Biophysics, University of Toronto, Toronto,
Conflicts of interest: none declared
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Call for abstracts
International Forum on Quality & Safety in Health Care
18–20 April 2007, Palau De Congressos, Barcelona
Deadline: 25 September 2006
728Prigoda, Savas, Abdalla, et al