Genetics Flashcards
Whos involved in the NHS genomic medicine service
Mainstream clinicians (Paediatrics etc)
Consultant Clinical Geneticist
Genetic Counsellor
NHS Genomic Scientists (Bioinformatics)
What is the role of a clinical geneticist?
Involved in making diagnoses
eg. dysmorphology, neurological conditions, inherited cancer syndromes
To explain the diagnosis to the family
Discuss prognosis
Discuss options available eg. genetic testing, screening, prenatal diagnosis
Refer to appropriate specialists for management
When do we refer to clinical genetics?
Prenatal: malformations detected on prenatal scan
Paediatric: developmental delay, seizures, physical malformations
Cancer: early onset, extensive family history, multiple cancers
Adult medicine: cardiomyopathies, kidney disease (ADPKD), neurology
What do and can genomic tests look for?
Look for chromosome deletion or duplication (CGH)
Look for translocation (Karyotype)
Look for single gene change (panel, genome)
What is an increase and decrease in a number of chromosome sets called?
An increase in number of chromosome sets in a cell is called polyploidy (di-tri-tetra etc). A change in chromosme number that involves less than a whole chromosom set is aneuploidy. In its simplest form- the loss or gain of a singe chromosome,
e.g. 2n-1=monsomy, 2n+1 = trisomy.
Why is picking up aneuploidy important?
Aneuploidy is more common than you may think- studies shown 35-70% of early embryonic deaths and spontaneous abortions are caused by aneuploidy. Aout 1 in every 170 live births is aneuploid. 5-7% of early childhood deaths is related to aneuploidy.
What happens in comparative Genomic Hybridisation?
Can detect deletion or duplication of single exons
Main indication is intellectual disability/physical malformations
What is a gene
Function – encodes a (RNA) protein
Passengers – trinucleotide repeats, endogenous retroviruses
DNA methylation/acetylation
What parts of the gene can we read in clinic?
Exons and introns
What are the types of variant found in a gene?
Single Nucleotide Variant (SNV):
Missense (one amino acid for another)
Loss of function (STOP, Frameshift)
Splice site
Short Trinucleotide Repeat (STR)
How do we classify a genomic variant?
Class 1 (Benign): present in >5% of healthy controls
Class 2 (Likely Benign)
Class 3 (uncertain significance): conflicting evidence
Class 4 (Likely Pathogenic)
Class 5 (Pathogenic): absent from healthy controls, present in several people who have same medical condition, mutation impacts protein function in assay
What are the categories of genetic disorders?
Chromosome abnormalities
Single gene disorders
Autosomal dominant
Autosomal recessive
X-linked
Multifactorial and polygenic disorders
What are some genetic, multifactorial and environmental diseases
Gen: Down’s syndrome
Cystic Fibrosis
Huntington disease
Haemophilia
Multifactorial: Spina bifida
Cleft lip/palate
Diabetes
Schizophrenia
Environmental:
Poor diet
Infection
Accidents
Drugs
What is the most common cause of aneuploidy?
The most common cause of aneuploidy is non-disjunction (the failure of chromosomes to separate at anaphase).
Can occur in meiosis 1 or 2.
Non-disjunction in meiosis 1- all gametes are abnormal with either both members of chromosomal pair in gamete or none.
what do 5% of children with down syndrome have?
robertsonian translocation, most often between chromosomes 21 and 14. Centromeres from the 2 chrms fuse and short arms are lost. Someone who carries this translocation is phenotypically normal even though they are aneuploid- only have 45 chrms and 2 short arm missing ( as in picture above). At meiosis,these carriers produce 6 types of gametes, 3 of which are lethal.
The three viable combinations left are normal phenotype and normal but translocation carrier and translocation DS.
This risk is NOT maternal age related. Counselling is important as there is 1 in 3 chance of producing carrier.
What should we do if a baby has a chromosome translocation?
Test the parents
What are the clinical effects of cytogenetic abnormalities
Congenital abnormalities
Delayed development – usually severe
Dysmorphic features
Small stature, microcephaly, failure to thrive
In adults – infertility, stillbirths, miscarriages
What can Turner syndrome cause? (45, X)
Prenatal: increased nuchal translucency
Neonatal: Lymphoedema
Cardiac: Aortic coarctation
Fertility: dysplastic ovaries (risk of malignancy)
Features of Klinefelter 46, XXY
Delayed puberty
Can be tall and slim due to delayed puberty
Azoospermia
Often incidental diagnosis when investigating male infertility
What is 22q11 deletion syndrome
1: 2500
1.5Mb-2.5Mb deletion at 22q
90% have learning problems
Cardiac malformations
Hypoparathyroidism
Features of autosomal Dominant Inheritance
Mutation transmitted from male to male
Both males and females are affected unless sex limited.
Only one copy of a gene pair is altered.
Recurrence risk up to 50% (1 in 2).
Possibility of new mutations.
Gonadal mosaicism may occur
What is variable penetrance
% of individuals carrying a genetic variant who manifest a disease
What is age related penetrance?
% of individuals who develop a given genetic disease at different ages
What is variable expressivity
different phenotypes expressed by different people with the same genetic disease
What is myotonic dystrophy type 1?
CTG expansion in DMPK gene (>34 repeats)
Muscle weakness
Cataracts, Diabetes
Larger expansion = more severe phenotype
Expansion can increased in size from parent to child
What is gonadal mosaicism?
is a condition in which the precursor cells toovaandspermatazoaare a mixture of two or more genetically different cell lines.
A study by Schiff et a in 2010 looked at semen samplesfrom 100 men found low-level germline mosaicism (~2%) in one third of infertile men, with increased incidence withadvancing paternal age.
Slide 39 of genetics lecture
Cancer genetics
Cancer is very common- affects 1 in 2 people in their lifetime
Most cancers are a result of somatic mutations, which is why many cancers are localised to a particular organ or tissue of the body.
In the context of cancer, the term ‘somatic mutations’ refers to those changes that have accumulated in the cancer genome, either as drivers of oncogenesis or as passenger mutations, but are not present constitutionally in the individual.
Constitutional (germline) variants in cancer predisposition genes are present in affected individuals in all the body’s nucleic cells, as well as the cancer genome, and may therefore be inherited. These underlie inherited cancer predisposition syndromes, such asLynch syndromeandhereditary breast and ovarian cancer syndrome.
Breast cancer features
BRCA1andBRCA2are key mediators of DNA repair by homologous recombination
Pathogenic variants associated with high lifetime risk of:
Breast cancer: 65–79% forBRCA1, 61–77% forBRCA2
Ovarian cancer: 36–53% forBRCA1, 11–25% forBRCA2
Individuals with germline BRCA variants have access to screening, risk reducing surgery and prenatal counselling
What are the biggest causes of breast cancer?
1 in 7 women will develop breast cancer in their lifetime
Most not due to a germline variant/cancer predisposition syndrome- approx. 23% due to modifiable risk factors eg obesity, alcohol, lack of exercise and contraceptives/HRT
5-10% considered due to monogenic hereditary cancer predisposition syndromes, 20% ‘familial’ in absence of obvious underlying genetic risk factors (oligo/polygenic)
Inherited breast cancers more likely to occur at a younger age/ in multiple family members
What are some high penetrance breast cancer predisposition genes?
PALB2;
STK11(Peutz-Jeghers syndrome);
PTEN(PTEN hamartoma tumour syndrome/Cowden syndrome);
TP53(TP53 tumour predisposition syndromes/Li-Fraumeni syndrome); and
CDH1(hereditary diffuse gastric cancer syndrome).
What syndrome can cause Bowel Cancer?
Lynch syndrome
single pathogenic variant in one of the four genes encoding the ‘major’ MMR proteins (MLH1, PMS2, MSH2 and MSH6)
A further ‘hit’ (variant or deletion) is then required in the second allele of the same gene to confer malignant potential to a cell
Patients with Lynch syndrome have a genetic predisposition to colorectal cancer (50%-80%) at a younger than expected age, as well as other cancer types.
Variants causing Lynch syndrome very rarely occur de novo; the majority are inherited
What is Lynch syndrome associated with?
such that patients will frequently have a family history of colorectal cancer or of other associated cancers such as endometrial, stomach, ovarian and urinary tract cancer.
2 yearly colonoscopies from 25-75y
Gynaecological risk- endometrial and ovarian cancer- surveillance from 35y
How does Familial denomatous Polyposis cause bowel cancer?
Mutations in the APC gene
Second ‘hit’ results in hundreds of colorectal adenomas
Almost 100% risk of cancer developing by 5th decade
Colonoscopy from 12-14y
Prophylactic colectomy 15-20y
What are the genetics behind renal cancer?
3–5% of renal cancer cases have an underlying inherited genetic cause
Testing offered to patients with renal cancer <40y or additional features suggestive of syndromic cause
Eg Von Hippel-Lindau (VHL) syndrome
RCC, retinal angioma, spinal/cerebellar haemangioblastomas, phaeochromocytoma, renal/pancreatic cysts, pancreatic neuroendocrine tumours
Features of autosomal Recessive inheritance?
Both parents heterozygous (carriers)
1 in 4 recurrence risk for siblings
2 in 3 carrier risk for unaffected siblings
Usually low risk for children of affected person or half sibs. Risk depends on population carrier frequency.
risk in consanguineous families
Genetic features of CF
CFTR gene on chromosome 7
Hundreds of missense mutations, vary by ethnic group
Prenatal: hyper echoic bowel
Neonatal: meconium ileus
Postnatal: bronchiectasis, exocrine pancreas
Features of X-Linked inheritance
Genes carried on the X chromosome.
More males than females affected.
Females are carriers. 50% sons affected. 50% daughters are carriers.
All daughters of affected males are carriers.
None of the offspring of affected males have the disorder.
Possibility of new mutations.
Gonadal mosaicism may occur.
Influenced by X inactivation (lyonisation)
What is Duchenne muscular dystrophy?
Dystrophin
Out-of-frame deletion: Duchenne muscular dystrophy
In-frame deletion: Becker muscular dystrophy
Skeletal myopathy
Cardiomyopathy
Precision medicine for certain dystrophin variants
Neural tube defect/ spina bifida is an example of what type of inheritance?
Multifactorial
Features of mitochondrial disorders
Exclusively maternally inherited deriving from those present in the cytoplasm of the ovum.
Contain own circular 16.5Kb chromosome
Heteroplasmy can occur which causes mixed population of normal and abnormal mitochondria
All offspring of affected carrier female are at risk of being affected
All daughters of affected carrier female are at risk of transmitting condition
Affected males cannot pass condition to any of their children
What is Leber’s hereditary optic neuropathy (LHON)?
Gradual, painless visual loss
Males 5 times more likely to be affected
Complex 1 gene variants (mitochondrial genome)
Only transmitted by females (who may or may not have visual loss)
What is Genomic imprinting?
For most genes both copies are expressed
Some genes are maternally or paternally expressed- this is called INPRINTING
Prader-Willi and Anglemans syndrome are both caused by either cytogenetic deletions of the same region of chromosome 15q or by uniparental disomy of chromosome 15 (where both copies of 15 come from the same parent)
What happens in Prader-Willi syndrome
Neonatal hypotonia and poor feeding
Moderate Mental Retardation
Hyperphagia and obesity
Small genitalia
Caused by a deletion in the paternally inherited chromosome 15 or maternal uniparental disomy
What is Angelmans syndrome
“Happy puppet” unprovoked laughing/clapping
Microcephally
Mental retardation
Seizures
Ataxia
Broad based gait
Caused by a deletion in the Maternally inherited chromosome 15 or paternal uniparental disomy
