Genetics
Research
Highlights
OCTOBER 2016
FH-CPSS project results are published
N Engl
J Med 2016;375:1628-37.
FEBRUARY 2015
FH-CPSS project passes the 10,000 samples mark
The Child-Parent Screening Study is being run by Professor David Wald at The
Wolfson Institute of Preventive Medicine. It is a new
approach to screen for Familial Hypercholesterolaemia (FH) that is
based on measuring cholesterol in children aged 1-2 years when they
attend for routine childhood immunisation.
Cholesterol levels and genetic tests are being carried out in
10,000 children, with the genetic analysis being carried out in the
regional genetics lab at GOSH. Over 10,000 samples have now
been tested.
This research study will determine the accuracy of screening by
this method and the feasibility of a national screening
programme.
DECEMBER 2014
Overall objective:
11 centres across England have been designated as Genomics
Medicine Centres (GMC) and will work closely with Genomics England
(GEL) and NHS England (NHSE) to deliver the required 100,000
samples for whole genome sequencing.
The samples will be categorised as:
1) Rare Disease: Patients and their parents are required for
Trio analysis
2) Cancer: For each patient, tumour and blood samples are
required for the project
The Role of GOSH:
GOSH is the lead centre for the North Thames Genomics Medicine
Centre (NTGMC) that includes the following centres:
- Great Ormond Street (NTGMC Lead) - Rare disease only
- North West London Hospitals (KGC) - Rare disease &
Cancer
- Neurogenetics Laboratory (ION) - Rare disease only
- Moorfields Eye Hospital (MEH) - Rare disease only
- The Royal Free Hospital (RFH) - Rare disease only
- UCL Advanced Diagnostics (UCL-AD) - Cancer only
- Barts and the London (Barts) - Rare disease & Cancer
The NTGMC has been contracted to provide 14,808 DNA samples for
whole genome sequencing over the three year project.
As the designated lead, all samples from across North Thames
will be sent to GEL via our lab in Barclay house. The
regional genetics lab will receive samples from our local delivery
partners.
NOVEMBER 2014
Prenatal Assessment of Genomes & Exomes - PAGE Study
We are participating in the PAGE study which aims to improve the
prenatal diagnosis of fetal structural abnormalities by evaluating
the role of exome and genome sequencing and developing
cost-effective assays using these new technologies.
Women undergoing invasive diagnostic testing in participating
units will be asked for informed consent for any excess chorionic
villi or amniocytes to be used for the PAGE study.
In addition both parents will be asked to donate a blood sample
as we will be sequencing trios.
The aim is to recruit 1000 trios (mother, father and fetus) for
exome sequencing, around 40 of which will be selected for whole
genome sequencing as well. Any woman undergoing invasive diagnostic
testing with an NT>4mm or one or more
sonographic abnormality is eligible for recruitment.
Exome sequencing will be done at the Sanger Institute. Any
pathogenic results will be validated in the two coordinating
regional centres. Results will be reviewed by a review panel
including representative from clinical, molecular and cytogenetics
from participating laboratories. Pathogenic results with
implications for families will be fed back to families through
their local regional genetics services. Results will not be
available in the course of the research, but any that have clinical
relevance to future pregnancies will be reported after the
pregnancy is completed.
MARCH 2014
Experts back prenatal Down's syndrome blood
test
Leading scientists have given their backing to introducing a 99%
accurate blood test to detect Down's syndrome in unborn babies on
the NHS. In a new development, a scientific impact
paper published by the Royal College of Obstetricians
and Gynaecologists (RCOG) supports giving the test to all women who
want it in early pregnancy.
Non-invasive prenatal testing (NIPT) can predict whether a baby
has Down's and also screens for the rare genetic conditions
Edward's syndrome and Patau syndrome. NIPT is currently only
available in private hospitals but is being considered for use on
the NHS by the UK National Screening Committee, which will make a
formal recommendation once the results of a trial at Great
Ormond Street Hospital for Children in London become
known. The trial is being undertaken as part of the RAPID
(Reliable Accurate
Prenatal Non-Invasive
Diagnosis) research programme led by Professor Lyn
Chitty.
FEBRUARY 2013
Use of low-density lipoprotein cholesterol gene score
to distinguish patients with polygenic and monogenic familial
hypercholesterolaemia: a case-control study
Research published in The Lancet
provides new evidence that a substantial proportion of individuals
with a clinical diagnosis of Familial Hypercholesterolaemia (FH)
inherit a combination of small-effect changes in several genes
(polygenic) rather than a large-effect mutation in a single gene
(monogenic). These findings have implications for the majority of
national guidelines on family screening for FH that advocate
testing relatives of all individuals with a clinical diagnosis of
FH, including those of the UK National Institute for Health and
Care Excellence (NICE).
"Cascade [family] testing of the roughly 40% of patients with a
clinical diagnosis of FH and an identifiable causative mutation
would eliminate staff and screening costs associated with screening
relatives of the remaining 60% of patients without an identifiable
mutation. This is very likely to be more cost-effective, but
proving this will require a more detailed analysis", says British
Heart Foundation Professor Steve Humphries from University College
London, who led the research.
FH is one of the most common inherited disorders affecting over
12 million people worldwide (1 in 500 of the general population).
It causes very high levels of low-density lipoprotein cholesterol
(LDL-C) or "bad cholesterol" in the blood, and if untreated,
results in a five to eight times greater risk of early coronary
heart disease (CHD). Identification of patients with FH needs to be
improved because at least 75% of cases remain undetected,
untreated, or improperly treated, despite good evidence that early
detection and treatment with statins can significantly improve life
expectancy.
DNA-based cascade screening to identify other family members
with FH, who would benefit from treatment, has been
recommended by NICE on the presumption of a monogenic inheritance
of the disorder, where first-degree relatives would have a 50:50
chance of having the condition. However, 60% of people with
clinically suspected FH have no identifiable mutation in any of the
three genes (LDLR,APOB, orPCSK9) known to cause FH.
"The current study was designed to investigate whether
individuals who inherit many, small-effect, LDL-C raising sequence
differences in a wide range of genes might have received a clinical
diagnosis of FH, which would influence the efficacy of any cascade
screening programme since the odds of finding relatives with
grossly elevated LDL-C in such cases would be less than the
expected 50%", explains Humphries.
Recent genetic studies have identified many common genetic
variants associated with a small increment in LDL-C levels.
Genotyping for 12 of these single nucleotide polymorphisms (SNPs)
was done on blood samples from 321 mutation-negative UK patients
with FH, as well as 319 UK patients with FH with a known mutation,
and 3020 healthy individuals (controls) from the UK Whitehall II
study.
Each participant was assigned a weighted LDL-C-raising gene
score based on the number of risk-associated gene copies inherited.
The results were validated by repeating the analysis in a sample of
over 700 patients with FH from Belgium.
The findings showed that clinically suspected, but mutation
negative FH, was associated with inheritance of a greater than
average number of small-effect LDL-C-raising sequence
differences.
According to Humphries, "We propose that the clinical diagnosis
of FH should be restricted to those in whom a mutation can be
identified, whereas those with no detected mutation should be given
the clinical diagnosis of polygenic hypercholesterolaemia. Both
groups of patients will need statin therapy, but the cost
effectiveness of FH cascade testing will differ depending on
whether or not there is a polygenic or a single mutation
cause."