Case 16: genetics 2 Flashcards
1
Q
Application of NIPT
A
- Aneuploidy testing based on DNA molecule counting (abnormal number of chromosomes)
- Technique: single molecule DNA counting
- Analyse and sequence all foetal DNA. Analyse ratio of DNA to chromosomes to assess disease status
- Then confirm positive result with CVS/amniocentesis
- Can look at alleles and see ratio of those that contain a mutation to those that don’t to assess for recessive conditions (Homozygous or Heterozygous)
2
Q
NIPD/T limitations
A
- Maternal factors: Some women have very low foetal DNA fractions (due to women’s weight or foetal age). Lab techniques may not pick it up. Underlying chromosomal abnormality or tumour may affect results
- Pregnancy factors: Twin pregnancies (especially for NIPT), Resolving second gestational sac, Placental mosaicism (the foetal blood is mostly from the placenta)
3
Q
Testing for cord blood
A
only done if implications for management. Otherwise wait till they consent at 18
4
Q
Overview of indications for NIPD/T
A
- NIPD: determining foetal sex, testing for a specific mutation in a single gene disorder
- Aneuploidy testing
5
Q
Presentations of gene abnormality resul example:
- CFTR c.1521_1523delCTT p.F508del
Heterozygous
A
- CFTR gene- causative gene in Cystic Fibrosis
- Specific change in DNA coding sequence- CTT deleted between position 1521 & 1523
- Effect of DNA change on the protein produced (p.F508del) Phenylalanine missing at position 508 of the amino acid sequence
- Heterozygous: Present on one allele (one copy of the CFTR gene)
6
Q
Autosomal inheritance
A
- The mutation is present on both copies of the gene in order for the disease to develop
- Has to be on chromosomes 1-22 (the autosomes)
7
Q
Definitions: Heterozygous, Compound Heterozygous and Homozygous
A
- Heterozygous: Variant present on one allele, the other is normal. In autosomal recessive condition this means they are a carrier
- Compound Heterozygous: Both alleles contain a different variant, two different mutations present. No functioning copy of the gene so is affected by the recessive condition
- Homozygous: both alleles contain the same variant. Means the individual is affected by the recessive condition
8
Q
Cystic fibrosis pathophysiology
A
- CFTR gene codes for the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein, a cell membrane chloride transporter
- The gene is on chromosome 7
- Most common mutation: Delta F508
- Insufficient functioning CFTR protein for normal chloride transport, resulting in the production of thick sticky mucus production
- Multi-system disorder (lungs, intestines, pancreatic ducts, sweat glands, and reproductive organs).
9
Q
Cystic fibrosis inheritance
A
- Autosomal recessive inheritance
- Two functioning copies of the CFTR gene: Non carrier, not affected
- Mutation present on one copy of the CFTR gene: carrier not affected
- Mutation present on both copies of the CFTR: affected by CF
- Carrier frequency of CF: 1 in 25
10
Q
Risk of a child being affected by CF if one parent is a known carrier
A
- 1 in 100
- known carrier: probability of being a carrier is 1
- partner: probability of being a carrier is 1 in 25 (population risk)
- 1 in 4 chance of both passing on the mutation
- therefore overall risk of pregnancy being affected is 1 x 1/25 x 1/4 = 1/100
11
Q
Genetic testing: CF
A
- Partners of carriers are offered testing for the 50 most common CFTR mutation (account for 90% of mutations in Northern Europe)
- If no mutation is identifies it reduces risk of being a carrier from 1 in 25 to 1 in 250 (still some chance)
- Different mutations in different ethnic groups
12
Q
CF: Diagnosis
A
- Through newborn blood spot screening programme: measure trypsinogen (IRT) in blood samples. Refereed for further testing
- Sweat chloride test: gold standard, diagnosed if >60 (30-60 require further investigations)
- Genetic tests: not all mutations are detectable
- If clinical features are highly suggestable and investigations are negative then can still be diagnosed. If investigations positive but no symptoms then still diagnose
- After diagnoses refer to a cystic fibrosis centre
13
Q
CF: Monitoring
A
- Regular sputum cultures
- Pulmonary function tests (PFT): Spirometry and lung volume measurements
- CXR and CT: evaluate lung disease severity, identify complications like bronchiectasis
- Oral glucose tolerance test: screen for cystic fibrosis related complications
- DEXA
14
Q
CF presentation: age
A
- Infant: Meconium ileus
- Older child: chronic cough, recurrent wheezing, chronic respiratory infections, Malabsorption, failure to thrive
- Adult: cystic fibrosis related diabetes, infertility (absence of vas deferens (CBAVD), irregular menstrual cycle)
15
Q
CF: respiratory
A
- Persistent cough:Productive or non-productive, often exacerbated by mucus accumulation and infections.
- Wheezing and dyspnea:Resulting from airway obstruction and bronchospasm.
- Recurrent respiratory infections: pathogens such asStaphylococcus aureus,Haemophilus influenzae, andPseudomonas aeruginosa.
- Nasal polyps and chronic sinusitis
16
Q
CF: GI
A
- Meconium ileus:Neonates with CF may present with intestinal obstruction due to thickened meconium.
- Pancreatic insufficiency:Steatorrhea, weight loss, and malabsorption of fat-soluble vitamins due to pancreatic duct obstruction.
- Distal intestinal obstruction syndrome (DIOS):Partial or complete intestinal obstruction due to inspissated faecal material.
- Biliary cirrhosis:Impaired bile flow leading to liver damage, portal hypertension, and potential liver failure.
- Gastroesophageal reflux disease (GERD)
