Principles of Genomics: Application (GAT2)

why is genomic important now?

• human genome project took 13 years, 6 coutnries and $3 billion → remains world’s largest collaborative project

• revolution in medicine → whole genome sequencing now takes less than a day and costs less than £1000

• other ground breaking projects: UK 100,000 genome project, UK biobank WGS for 500,000 participants, UK generation study WGS for 100,000 newborn babies

describe the 100,000 genome project of 2018

• Genomics England’s first initiative → internationally groundbreaking project

• genomes from 85,000 patients with cancer and rare diseases were sequenced → 100,000 genomes as some participants had 2 copies of their genomes sequenced (1 from healthy cells and 1 from cancer cells)

• sequence and study role of genes and genomes in health and disease

what was the impact of the 100k genomes project?

rare disease

• = disease that affects less than 1 in 5000

• 7% of people affected by rare disease in their lifetime

• reduces diagnostic odyssey → trial and error process of finding the correct diagnosis for a patient with a rare genetic disease

• comparison of WGS of patients with same condition to reveal patterns

• development and use of targeted treatments

cancer

• identify mutations associated with cancer

• germline mutations were identified by comparing genomes of people with cancer vs without

• somatic mutations identified by comparing genomes from cancer cells vs non cancer cells

• development and use of preventative and targeted treatments

what was created after the 100k genomes project? describe it

NHS Genomic Medicine Service

• published a report which set out all the potential benefits they could see with using genomics within healthcare

• e.g. quicker diagnosis or rare conditions, personalised treatment, better understanding of conditions

describe the infrastructure of the NHS genomic medicine service

• NHSE Genomics unit → national oversight, coordination and funding

• 7 NHS GMS Alliances → multidisciplinary clinical leadership to embed genomic medicine

• 7 NHS Genomic Laboratory Hubs (GHLs) → deliver genomic testing outlines in the national genomic test directory

• 17 NHS Clinical Genomics Services → deliver comprehensive clinical genomic and counselling to direct diagnosis and management

• Genomics England → supports national provision of whole genome service including bioinformatics

what is the national genomic test directory?

published list of all the genomic tests that are delivered via the NHS Genomic medicine service

• list is divided into cancer and rare diseases

• fast track application process can be used for new tests to be reviewed by scientific and clinical experts to be added to the directory

what is the 2022 NHS Genomic strategy?

sets out 5 year action plan:

• embed genomics across NHS

• deliver genomic testing and enable precision medicine

• enabling genomics to be at the forefront of the data and digital revolution

what does the NHS 10 year health plan mean for genomics?

• expand existing NHS genomic medicine service to create a new genomics population health service → used in healthy individuals as well to predict the risk of disease in the future

• every cancer patient will receive comprehensive genomic analysis and molecular profiling

• reduce diagnostic odyssey

• expand genetic testing for inherited causes of major diseases

• pharmacogenomics integrated into routine clinical rpactice

• develop a Unified Genomic Record linked to single patient record and NHS app

what are the different cases in which genomic testing can be used to help diagnose and predict disease?

• cystic fibrosis

• familial hypercholesterolaemia

• breast cancer

describe familial hypercholesterolaemia

• genetic condition that causes high cholesterol from birth :. not lifestyle related

• autosomal dominant inheritance pattern

• patients can be identified using routine cholesterol checks, family history and the Simone Broome Criteria = diagnostic criteria

• possible or definite cases should be offered genetic testing

• tendon xanthomas = physical signs of high cholesterol where you get accumulation of cholesterol around tendons

according to the simone boone criteria, what suggests a definite FH diagnosis?

• under 16: cholesterol concentration greater than 6.7 mmol/l

• adults: cholesterol concentration greater than 7.5 mmol/l

• with either tendon xanthomas in patient/1st/2nd degree relative OR DNA-based evidence of an LDL receptor mutation

according to the simone boone criteria, what suggests a possible FH diagnosis?

• under 16: cholesterol concentration greater than 6.7 mmol/l

• adults: cholesterol concentration greater than 7.5 mmol/l

• at least 1 of the following:

  • family history of MI in 2nd degree relative at younger than 50

  • family history of MI in 1st degree relative at younger than 60

  • family history of raised cholesterol greater than 7.5 mmol/l in adult 1st or second degree relative

  • family history of raised cholesterol greater than 6.7 mmol/l in child or sibling aged under 16

what are treatment options for FH?

• high potency statins

• if required, treatment can be intensified using ezetimibe (PCSK9i), a bile acid sequestrant and/or fibrates

• diet, exercise, smoking, alcohol reduction advice

• lipid modifying therapy for children witj FH should be considered by age 10

• risks of future pregnancies whilst taking lipid-modifying drugs should be discussed at least annually → choice of effective contraception → small increased risk of cardiovascular events with use of combined oral contraceptives :. consider other forms of contraception

describe breast cancer

• BRCA1 and BRCA2 are tumour suppressor genes with a central role in DNA repair

• pathogenic variants in BRCA genes does not cause cancer on its own, but reduces person’s ability to repair DNA damage → DNA damage occurs as part of normal cell division can accumulate and cause cancer

• germline BRCA variants are inherited in an autosomal dominant inheritance pattern t pattern

• variants can increase risk of breast (men and women), ovarian (women), prostate (men) and pancreatic (men and women) cancers

• both men and women can pass germline variants to their children

which ancestry is more at risk of having a pathogenic BRCA variant?

ashkenazi jews and sephardi jews

what are the treatment options for patients with BRCA gene variants?

• annual breast cancer screening from age 25-30

• risk-reducing masectomy

• chemoprophylaxis: tamoxifen, anastrazole and raloxifene

describe cystic fibrosis

• autosomal recessive genetic disorder resulting from variants in the CTFR gene (over 2000 different CTFR variants identified that can cause CF)

• CTFR is a trans membrane protein that transports anions (especially chloride) in and out of cells

• treatment = CTFR modulators which are variant specific

what are the symptoms of CF?

• wheezing, coughing, SOB, airway damage

• malabsorption and poor weight gain

• jaundice and liver disease

• diarrhoea and constipation

• meconium ileus in newborns

• diabetes

• infertility in males

what type of genetic testing is done with cystic fibrosis?

• R65 test → test for variant that increases risk of hearing loss when given aminoglycoside antibiotics in CF patients → assocaited with MT-RNR1 mitochondrial gene variation → done at point of CF diagnosis as this does not waste time if a patient acquired an infection

• R185 → offered to family of CF patients, prospective egg/sperm donors to assess whether they are carriers of the variants which can cause CF

• newborn sweat test → tests for excess chloride in sweat samples as chloride cannot be reabsorbed into sweat ducts due to defective CTFR protein

describe genetic testing

results are relevant to both patient and their family members

• cascade testing: systematic process of offering genetic testing to at-risk relatives after a specific pathogenic variant is identified in an affected family member

• supports family planning

what is the heelprick test?

newborn test which tests for 10 genetic conditions

• AKA newborn bloodspot test