Core monogenic disorders Flashcards
CF incidence & carrier frequency (UK)
Incidence = 1 in 2600
Carrier freq = 1 in 25
CF clinical features
Chronic cough
Failure to thrive
Pancreatic insufficiency
Alkalosis and hypotonic dehydration
Neonatal intestinal obstruction
Clubbing of fingers
Recurrent infections
Electrolytes in sweat
Absence of vas deferens
Sputum with Staph or Pseudomonas
CFTR protein structure & function
Expressed in plasma membranes of secretory epithelial cells in pancreatic, respiratory, GI and reproductive systems
Conducts flow to chloride irons across cell membrane
Regulatory domain is phosphorylated to open channel. 2x transmembrane domains bind chloride ions, making the channel negatively charged and creating an ionic gradient allowing water to exit cell by osmosis
5 classes of CF variants
- No synthesis, usually protein truncating nonsense/frameshift/splicing e.g. Gly542X
- Block in processing leading to protein degradation e.g. Phe508del
- Block in regulation, usually in R domain e.g. G551D
- Altered conductance, usually in transmembrane domains e.g. Arg1152His
- Regulation of other ion channels
Severe / mild classes
Class 1/2 homozygotes or compound hetz are more severely affected with worse survival. No or severely reduced CFTR protein
Class 4 usually have mild symptoms (more panc/GI, less respiratory). Some functional CFTR protein
CF testing strategy
Level 1 = multiplex commercial kit e.g. ARMS. Allele specific PCR assay. 2 reactions, common primer + WT or mutant specific primer. Sizing and use of fluorophores allows detection of many muts in one test. Cross reactivity can occur at codons with multiple muts
Level 2 = sequencing and CNV analysis (if non-Caucasian population or 1 variant identified by level 1)
Explanation for a homozygous proband with CF but one parent is not a carrier?
UPD(7), hetz deletions of locus or non-paternity
2 examples of CFTR modulator therapy
Ataluren (stop codon readthrough)
Ivacaftor
What is the prior chance of an unaffected person being a CF carrier if they have an affected sibling?
2/3
SMA incidence & carrier frequency (UK)
Incidence = 1 in 6000-10000
Carrier freq = 1 in 50
SMA clinical features
Widespread synaptic defects at NMJs in anterior horn motor neurons of spinal cord
Progressive proximal and symmetrical limb/trunk weakness, breathing difficulties due to intercostal muscle paralysis, finger tremors, poor suck/swallow, aspiration pneumonia, neonatal hypotonia
5 types of SMA
Prenatal
Arthrogryposis and no movements in utero due to contractures. Lethal in neonatal period if birth survived
Type 1, acute infantile - 60%
Dx <6m, death early childhood. Hypotonia & symmetrical floppy paralysis, little motor development
Type 2, chronic infantile - 27%
Dx 6-12m, 70% reach adulthood
Unable to walk unaided
Type 3, chronic juvenile - 12%
3a = Dx <3yo; 3b = Dx >3yo
Usually sit/walk unaided but with leg weakness
Type 4, adult - 1%
Similar to type 3 with later onset. Normal life expectancy
Describe the 5q12.2q13.3 region
Complex unstable region
SMN1 and SMN2 pseudogene, originate from inverted duplication in tandem
Differ by 5bp (same aa sequence). Key change in SMN2 = c.840C>T disrupts an ESE and decreases splicing of exon 7 = truncated protein that is rapidly degraded. Can produce some functional protein
Can have up to 5 copies of SMN2 in tandem
4% of general population have 2 copies of SMN1 on same chromosome - silent carriers
SMN protein function
Molecular chaperone for assembly of small nuclear riboproteins and vital for spliceosome function
SMA genetic cause
95-98% = homozygous SMN1 deletion (of at least exon 7)
True deletion or gene conversion event (non-reciprocal exchange of DNA with SMN2 = hybrid SMN with splicing defective exon 7 from SMN2)
2-5% = compound hetz for SMN1 deletion and SNV
1% = homozygous SNV