Genetics in Cardiology Flashcards
What is Down Syndrome?
Genetic disorder caused by presence of all or part of a third copy of chromosome 21. Usually associated with physical growth delays, mild to moderate intellectual disability and characteristic facial features.
What are some phenotypic features of Down Syndrome?
- Epicanthic folds - Flat nasal bridge - Small palpebral fissures - Railroad track ears - Upturned nose - Thin upper lip - Sandal-wedge gap - Brushfield spots in Iris
- Cardiac Defects**
What are the common cardiac defects in Down syndrome?
Defects through embryological development ≈ cardiac defect ≈ mixing of arterial and venous blood
- ASD
- VSD
- AVSD
- PDA
What genes cause the cardiac problems in Down Syndrome?
DER21 gene shown via FISH to be increased in separation in abnormal chromosome 21 cf normal chromosome 21
What is the name of the chromosome region most commonly present in excess in a patient with congenital heart disease?
DS-CHD region≈ multiple genes ≈ upregulated in CHD ≈
DUP21NA
DUP21BA
DUP21BS
What is DiGeorge Syndrome?
Give some phenotypic features.
22q11.2 deletion ≈ 25-30 genes deleted ≈ DiGeorge Syndrome
- Congenital heart problems: interruption of aortic arch; TOF; Ventricular septal defect - Abnormal faces - Thymic aplasia - Cleft palate - Hypothyroidism
Why do deletions arise in DiGeorge’s Syndrome?
Repetitive DNA (SINE or LINE) ≈ improper alignment ≈ deletion or duplicated ≈ deletion ≈ syndrome
What occurs in DiGeorge Syndrome without deletion?
Chromosome 22q11.2 deletion syndrome can arise without deletion ≈ DiGeorge Syndrome ≈ same phenotype but no apparent deletion ≈ ∆TBX1 ≈1) base substitution = missense mutation; 2) Base deletion = frameshift mutation ≈ truncated protein ≈ nonsense mutation
If TBX-1 is a transcription factor, how does it work?
TF binds TF-binding site ≈ generates a kink in DNA ≈ euchromatin ≈ access for RNA polymerase ≈ transcription of gene ≈ mRNA ≈ translation≈ protein
What model has been proposed regarding dose and functionality of TBX1?
Dose-dependancy model of TBX1 ≈ dimerises ≈ transcription of gene however low or high dose ≈ suboptimal dimerisation ≈ no binding site found or binding site blocked ≈ lack of gene transcription
What is Long-QT Syndrome and how is it determined?
Condition in which QT interval prolonged due to aberrant repolarisation of the heart after a heartbeat ≈ exceeds 99th percentile values
What is the inheritance of LQTS?
Autosomal dominant
What is non-penetrance?
Genetic trait present in genotype ≠ phenotype ≈ epistasis or environmental effects
What is variable expressivity?
Genotype of genetic trait ≈ phenotype ≈ variable expression in non-binary phenotype ≈ proportion of carries of given genotype for a trait of interest
Why is non-penetrance ≠ variable expressivity?
Non-penetrance is an individual with a genotype that is not expressed whilst variable expressivity is the amount of non-binary phenotype trait expressed
What are the main mutational mechanisms LQTS can occur?
GOF ≈ ∆SCN5A ≈ Na+ and Ca++ in ≈ increased depolarisation ≈ LQTS
LOF ≈ ∆KCNQ1 or KCNH2 ≈ reduced K+ efflux current ≈ delays in repolarisation ≈ LQTS
What is locus heterogeneity?
Mutations at two or more different loci/genes ≈ production of identical phenotypes ≈ disease
What is locus monogeneity?
Mutations in the same locus/gene ≈ production of identical phenotype ≈ disease
In LQTS, is locus heterogeneity or monogeneity displayed and why?
In LQTS, locus heterogeneity is displayed as mutations in KCNQ1, KCNH2, SCN5A, CACNA1C ≈ mutations in different loci/genes ≈ phenotype ≈ LQTS
Why is it important to identify a mutation? With regards to mutations in specific regions in LQTS, what is the significance?
∆ ≈ severity ≈ risk of death/prognosis ≈ individualised care + personalised medicine
Significance: C-loop mutations have a higher LQTS death rate + require ß-blocker treatment cf non C-loop mutations are associated less with LQTS death rate and improved less by ß-blocker treatment
What is familial hypercholesterolaemia?
High concentration of serum LDL cholesterol > 7.5mM
What are some clinical signs of FH?
- Xanthelasma - Xanthomata - Atherosclerosis - Obesity - Corneal Arcus - Hypertension
What criteria are used to define FH?
Simon Broome Criteria 1) Cholesterol > 7.5mM or LDL > 4.9mM
Definite FH: + Tendon xanthoma in patient or 1st/2nd degree relative or DNA conformation
Possible FH: FH of MI in 1st degree relative <60 years or 2nd degree relative <50 years or FH of cholesterol > 7.5mM in 1st/2nd degree relative
What is the inheritance pattern of Familial Hypercholesterolemia?
Autosomal dominant
Which genes can cause FH?
- LDLr-/-
- ApoE -/-
- ApoB -/-
- PCSK9
What is the main form of treatment for FH?
- Statins
- PCSK9 mAb (Inclirisan or Alirocumab)
What are the two functional forms of PCSK9 mutation and their effects on LDL-C and subsequent disease?
1) GOF ≈ increase PCSK9 ≈ increased LDLr cleavage ≈ higher circulating LDL-C ≈ premature heart disease
2) LOF ≈ reduced PCSK9 ≈ reduced LDLr cleavage ≈ lower circulating LDL-C ≈ prevention of heart disease
What two drugs can be used to target PCSK9?
1) Inclisiran ≈ synthetic dsRNA with 3x GalNAc ≈ taken up by Liver ≈ dicer cleaves + incorporates into RISC ≈ssRNA in RISC degrades PCSK9 mRNA ≈ reduced PCSK9 protein translation ≈ reduced PCSK9 cleavage of LDLr ≈ reduced LDL uptake into liver
2) Alirocumab ≈ mAb ≈ binds and inhibits PCSK9 enzyme ≈ reduced functionality ≈ reduced LDLr cleavage ≈ higher uptake of LDL ≈ lower circulating levels
What is cascade testing?
ID of gene mutation ID in patient ≈ use ID mutation to ID affected biological relatives or if not found, use specialist gender and age-specific LDL cholesterol criteria to identify affected biological relatives
Outline the MOA of Alirocumab.
PCSK9 mAb ≈ reduced cleavage of LDLr ≈ elevated LDL uptake
Outline the MOA of Inclisiran.
synthetic dsRNA x3 GalNAc ≈ hepatic uptake ≈ loaded into RISC ≈ degrade PCSK9 mRNA ≈ reduced PCSK9 protein translation ≈ reduced PCSK9 cleavage of LDLr ≈ reduced LDL uptake into liver
What are the pros and cons of cascade testing?
+ Easier to know what to look for if genotype already ID
+ Easier to choose specific tests to assist finding genotype - specific tests or sensitive tests
+ Easier to interpret results with known FH link
- If gene not identified, can be difficult to interpret results
- If gene not identified can be difficult to look for genotype in individual/proband/other relatives - Can lead to negated investigation in family if proband is an atypical case or gene not ID
