Importance of EQA/PT for the detection of genetic variants in comprehensive cancer genome testing
Scientific Reports,
Год журнала:
2025,
Номер
15(1)
Опубликована: Янв. 7, 2025
Comprehensive
genomic
profiling
(CGP)
is
increasingly
used
as
a
clinical
laboratory
test
and
being
applied
to
cancer
treatment;
however,
standardization
external
quality
assessments
(EQA)
have
not
been
fully
developed.
This
study
performed
cost-effective
EQA
proficiency
tests
(PT)
for
CGP
testing
among
multiple
institutions
those
belong
the
working
group
of
Japan
Association
Clinical
Laboratory
Science
(JACLS).
revealed
that
preanalytical
processes,
such
derived
nucleic
acids
(NA)
extraction
from
formalin
fixed
paraffine
embedded
(FFPE)
samples,
are
critical.
First,
with
extracted
DNA
cell
lines
showed
detection
rate
100%
(9
out
9)
in
KRAS
(c.38G
>
A;
p.G13D),
PIK3CA
(p.H1047R),
B-Raf
proto-oncogene,
serine/threonine
kinase
(BRAF)
(c.1799
T
p.V600E)
cases
10%
variant
allele
frequency
(VAF).
However,
BRAF
decreased
67%
(6
VAF
4.9%.
Second,
when
was
FFPE
pathogenic
variants
companion
diagnostic
indications
were
detected
all
10
participating
laboratories.
Each
had
<
20%
VAFs
on
average
(8.1–19.1%)
wide
variability
laboratories
observed
(relative
standard
deviation,
13–60%).
Nonetheless,
(c.1798_1799delinsAA;
p.V600K)
8.1%
VAF,
EGFR
(c.2235_2249del;
p.E746_A750del)
9.7%
(c.2254_2277del;
p.S752_I759del)
9.8%
70%
(7/10),
60%
(6/10)
frequency,
respectively.
Therefore,
pre-analytic
processing
critical
analysis.
Further,
incorrect
results
reported
case
independent
calling
BRAF;
c.1798_1799delinsAA
(p.V600K)
mistakenly
interpreted
c.1798G
A,
c.1799
A
other
strand.
In
conclusion,
EQA/PT
institutes
common
samples
importance
pre-analysis
helped
us
understand
significance
pipeline
pitfalls
usually
ignored
by
internal
control
single
institute.
Язык: Английский
Mitral Valve Prolapse Caused by TLL1 Gain-of-Function Mutation
Canadian Journal of Cardiology,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 1, 2025
Mitral
valve
prolapse
(MVP)
is
a
common
cardiac
valvular
anomaly
that
can
be
caused
by
mutations
in
genes
of
various
biological
pathways.
Individuals
three
generations
kindred
presented
with
apparently
dominant
heredity
isolated
MVP.
Clinical
evaluation
and
echocardiography
for
all
complying
family
members
(n=13).
Whole
exome
genome
sequencing
data
two
affected
individuals
were
analyzed,
delineating
shared
heterozygous
variants,
further
tested
segregation
within
the
(Sanger
sequencing).
Tolloid
Like
1
(TLL1)
enzymatic
activity
was
assayed
media
HEK293
cells
transfected
wild-type
versus
mutant
TLL1.
The
only
variant
segregating
as
expected
MVP
p.T253A,
catalytic
domain
Of
eight
heterozygotes,
six
had
trivial
mitral
regurgitation.
Activity
assay
extra-cellular
HEK293-transfected
showed
over
time
(12
hours),
mutated
TLL1
protein
X3.4
higher
than
wild
type.
Our
genetic
biochemical
studies
show
Gain-of-Function
mutation,
prolonging
half-life
active
extracellular
matrix
(ECM),
causes
autosomal
variable
expressivity.
encodes
an
metalloprotease
regulating
ECM
composition
maintenance.
Heterozygous
Loss-of-Function
have
been
previously
shown
to
cause
atrial
septal
defects.
findings
enable
novel
insights
into
molecular
pathways
physiology
disease,
role
human
development,
differing
phenotypes
same
gene.
Язык: Английский
Unraveling MECP2 structural variants in previously elusive Rett syndrome cases through IGV interpretation
npj Genomic Medicine,
Год журнала:
2025,
Номер
10(1)
Опубликована: Март 13, 2025
Rett
syndrome
(RTT)
is
a
severe
neurodevelopmental
disorder,
with
MECP2
mutations
accounting
for
90–95%
of
classic
and
50–70%
atypical
cases.
However,
many
clinically
diagnosed
RTT
patients
remain
without
molecular
diagnoses.
While
point
large
rearrangements
in
are
well
studied,
the
role
small-intermediate
structural
variants
(SVs)
remains
mostly
elusive.
Using
standard
short-read
whole
genome
sequencing,
we
identified
novel
de
novo
SVs
three
out
previously
unresolved
cases:
complex
SV
two
deletions
(
~
5Kbp
~60Kbp)
~105Kbp
inversion;
~200Kbp
translocation;
~3Kbp
deletion.
These
findings
suggest
that
such
elusive
might
be
common
cause
"MECP2-negative"
RTT.
Incorporating
detection
into
routine
genetic
testing
through
bioinformatic
analysis
sequencing
or
manual
review
using
IGV
could
improve
diagnostic
rates
expand
our
understanding
similar
disorders.
Язык: Английский
Novel BRAT1 Deep Intronic Variant Affects Splicing Regulatory Elements Causing Cerebellar Hypoplasia Syndrome: Genotypic and Phenotypic Expansion
Clinical Genetics,
Год журнала:
2024,
Номер
unknown
Опубликована: Ноя. 25, 2024
ABSTRACT
Biallelic
mutations
in
BRAT1
result
lethal
neonatal
rigidity
and
multifocal
seizure
syndrome
a
milder
neurodevelopmental
disorder
of
cerebellar
atrophy
with
or
without
seizures
(NEDCAS,
MIM
618056).
Combining
linkage
analysis
whole‐genome
sequencing
(WGS),
we
identified
novel
deep
intronic
variant,
NC_000007.14
(NM_152743.4):c.128‐1585
T
>
G,
3
siblings
consanguineous
Bedouin
family
exhibiting
NEDCAS.
In
silico
analyses
followed
by
molecular
studies
demonstrated
this
variant's
impact
on
splice
regulatory
elements,
forming
cryptic
exon,
resulting
deleterious
frameshift
aberrant
transcript.
Previously
reported
pathogenic
splice‐site
were
adjacent
to
exons,
affecting
canonical
consensus
sites,
identifiable
whole‐exome
sequencing.
The
disease‐causing
variant
is
thus
unique
underscores
the
potential
elements
disease
pathogenesis,
demonstrating
utility
WGS
identifying
noncoding
variants
unresolved
cases.
affected
individuals
(deep
into
their
twenties)
are
among
longest‐surviving
patients
described
date—delineating
NEDCAS
phenotype
at
these
ages.
Although
sharing
homozygosity
same
they
show
varying
penetrance
nystagmus
extreme
variability
extent
ataxia
age
onset
developmental
delay.
Notably,
summarize
all
documented
date
phenotypic
associations.
Язык: Английский
Developmental dysplasia of the hip caused by homozygousTRIM33pathogenic variant affecting downstream BMP pathway
Journal of Medical Genetics,
Год журнала:
2024,
Номер
61(10), С. 959 - 965
Опубликована: Июль 25, 2024
Developmental
dysplasia
of
the
hip
(DDH),
formerly
termed
congenital
dislocation
hip,
is
most
common
disease
musculoskeletal
system
in
newborns.
While
familial
predilection
to
DDH
has
been
well
documented,
molecular
genetics/pathways
this
disorder
are
poorly
understood.
Язык: Английский
Importance of EQA/PT for the detection of genetic variants in comprehensive cancer genome testing
Research Square (Research Square),
Год журнала:
2024,
Номер
unknown
Опубликована: Дек. 16, 2024
Abstract
Comprehensive
genomic
profiling
(CGP)
is
increasingly
used
as
a
clinical
laboratory
test
and
being
applied
to
cancer
treatment;
however,
standardization
external
quality
assessments
(EQA)
have
not
been
fully
developed.
This
study
performed
cost-effective
EQA
proficiency
tests
(PT)
for
CGP
testing
among
multiple
institutions
those
belong
the
working
group
of
Japan
Association
Clinical
Laboratory
Science
(JACLS).
revealed
that
preanalytical
processes,
such
derived
nucleic
acids
(NA)
extraction
from
formalin
fixed
paraffine
embedded
(FFPE)
samples,
are
critical.
First,
with
extracted
DNA
cell
lines
showed
detection
rate
100%
(9
out
9)
in
KRAS
(c.38G
>
A;
p.G12D),
PIK3CA
(p.H1047R),
B-Raf
proto-oncogene,
serine/threonine
kinase
(
BRAF)
(c.1799T
p.V600E)
cases
10%
variant
allele
frequency
(VAF).
However,
BRAF
decreased
67%
(6
VAF
4.9%.
Second,
when
was
FFPE
pathogenic
variants
or
companion
diagnostics
were
detected
all
10
participating
laboratories.
Each
had
<
20%
VAFs
on
average
(8.1–19.1%)
wide
variability
laboratories
observed
(relative
standard
deviation,
13–60%).
Nonetheless,
(c.1798_1799delinsAA;
p.V600K)
8.1%
VAF,
EGFR
(c.2235_2249del;
p.E746_A750del)
9.7%
(c.2254_2277del;
p.S752_I759del)
9.8%
70%
(7/10),
60%
(6/10)
probability,
respectively.
Therefore,
pre-analytic
processing
critical
analysis.
Further,
incorrect
results
reported
case
independent
calling
BRAF;
c.1798_1799delinsAA
(p.V600K)
interpreted
c.1798G
A,
c.1799T
A
other
allele.
In
conclusion,
EQA/PT
institutes
common
samples
importance
pre-analysis
helped
us
understand
significance
pipeline
pitfalls
usually
ignored
by
internal
control
single
institute.
Язык: Английский
GeniePool 2.0: advancing variant analysis through CHM13-T2T, AlphaMissense, gnomAD V4 integration, and variant co-occurrence queries
Database,
Год журнала:
2024,
Номер
2024
Опубликована: Янв. 1, 2024
Originally
developed
to
meet
the
challenges
of
genomic
data
deluge,
GeniePool
emerged
as
a
pioneering
platform,
enabling
efficient
storage,
accessibility,
and
analysis
vast
datasets,
enabled
due
its
lake
architecture.
Building
on
this
foundation,
2.0
advances
through
integration
cutting-edge
variant
databases,
such
CHM13-T2T,
AlphaMissense,
gnomAD
V4,
coupled
with
capability
for
co-occurrence
queries.
This
evolution
offers
an
unprecedented
level
granularity
scope
in
analyses,
from
enhancing
our
understanding
pathogenicity
phenotypic
associations
facilitating
research
collaborations.
The
introduction
CHM13-T2T
provides
more
accurate
reference
human
genetic
variation,
AlphaMissense
enriches
platform
protein-level
impact
predictions
missense
mutations,
V4
comprehensive
view
diversity.
Additionally,
innovative
feature
is
pivotal
exploring
combined
effects
variations,
advancing
comprehension
compound
heterozygosity,
epistasis,
polygenic
risk
factors
disease
pathogenesis.
scalable
which
aims
enhance
contribute
research,
potentially
supporting
new
discoveries
clinical
innovations.
Database
URL:
https://GeniePool.link.
Язык: Английский