Session 3: Modes of inheritance and constitutional genetics Flashcards
what are antisense oligonucleotides?
ssDNA or RNA 20bp that binds to mRNA blocking the translational mechanism. The can be used to block production of abnormal protein, correct aberration by exon skipping or correct splice mutations. they are checmically modified to prevent nuclease degradation
give examples of how antisense oligos have been used to treat diseases?
- DMD - Eteplirsen (Exondys 51) in clinical use. used as reading frame correction to induce exon skipping and produce smaller partially functional protein. requires repeated treatments. it is mutation specific but due to hotspots is applicable to wide number of patients. low efficiency in heart muscle and many patients die of heart complications so need to improve AO efficiency in heart muscles - would allow lower dosage and fewer administrations
- SMA - Nusinersen (Spinraza) in clinical use enhance exon 7 inclusion in SMN2 to produce functional protein and lessen SMA caused by loss of SMN1. this results from blocking intron 7 splice site to promote exon 7 inclusion.
- HD - IONIS-HTTRx in phase 3 trials - suppress translation of HTT mRNA containing CAG expansion. targets HTT-dependent SNPs so doesnt taget expansions in other genes.
what are the Challenges of using ASOs for the treatment of genetic diseases?
o Delivery to target tissue
o Achieve sustained effect. Chemically stabilised forms of ASOs will require re-administration for most applications.
o Difficult to achieve complete inhibition as there are large quantities of mRNA and lower levels of ASO within the cell.
describe CRISPR-Cas9 system and limitations
CRISPR-Cas9 is a highly cost-effective technique that allows specific targeting of gene manipulation via RNA-guided nuclease. once a cut is made, DNA with matching sticky ends can be incorporated by DNA repair mechanisms. Trials in b-thalassaemia, DMD, an
d freidreich ataxia.
limitations:
1. limited number of motifs to bind to in genome
2. delivery to target cells
3. although it has proofreading finction, some off target mutagenesis has been seen in similar sequences to target
describe small molecules for genetic treatment
- amnioglycosides promotes read-through of stop codons. amnioglycosides interact with A site of rRNA, altering conformation and reducing accuracy between mRNA-tRNA pairings allowing AA to be inserted instead of termination at stop codon. works best where low levels of functional protein can restore function. eg. Translana in DMD induces ribosomes to read through PTC. works on mRNA transcripts so patients with low mRNA levels may not respond. NICE approval
- corrects folding/transport or activation of protein eg. Ivacaftor for CFTR to improve chloride channel transport (class III) or enhance folding (class II) eg. phe508del Lumacaftor.
what are features of x-linked recessive inheritance?
- vertical transmission of carrier females to affected sons (50% chance)
- all daughters of affected males have the pathogenic variant (obligate carriers)
- daughters of female carriers have 50% chance of being a carrier
- affected homozygous females are rare
- affected males usually born to unaffected parents (may have affected male relatives)
- no male to male transmission
- pedigree mostly affected males, females are carriers only
why might females be affected by XLR disorder?
- skewed inactivation
- X chr deletion
- x chromo translocation
- variable penetrance/expressivity
- XO
- uPD
- compound heterozygosity
Give examples of X linked disorders?
- DMD, BMD,
-SBMA - androgen insensitivity syndrome
- XLRP (retinitis pigmentosa)
- haemophilia A and B - Christmas disease
what is DMD?
- 1/4000 births affected
- rapidly progressive muscular weakness proximal > distal & lower> upper limbs with calf hypertophy
- gower movement
- early childhood age of onset & first signs are delayed milestones, delayed sitting and standing
- cardiomyopathy >18 years, most common cause of death with respiratory complications
- wheelchair bound by 12
- few survive beyond 30 yrs
- males do not usually reproduce
- full penetrance in males, females can be unaffected to severe (manifesting carrier)
- > 10x creatine kinase levels, less in females. CK is an enzyme released from muscle into the bloodstream following damage
- out of frame deletions (be careful with duplications as dont always follow the rule)
what is BMD?
-1/18 000 male births
- in-frame deletions in DMD
- less severe & later onset
- longer life expectancy (mid 40s)
wheelchair bound >16
- heart failure from DCM still common cause of death
- females with DMD pathogenic variant at increased risk for DCM
- preservation of neck flexor muscle strength (differs from DMD)
- >5x creatine kinase levels , less in females
what is DMD-associated dilated cardiomyopathy (DCM) ?
- DCM between 20-40 years in males and later in females
- usually no skeletal muscle disease
- rapid progression to death in males and slower progression in females
-increased creatine kinase levels , less in females
how do you test for DMD without genetics?
immuno staining shows lack of dystophin in skeletal muscle, cardiac and smooth muscle cells. Dystrophin plays a role in sarcolemma stability. In DMD it is absent but in BMD it is 20-100% - may be normal levels but reduced function
how do you genetically test for DMD?
- MLPA (80% mutations) - QF-PCR required or single del/dup or SNP array can offer higher resolution may be done solely by NGS in future
- sequencing, NGS allows mosaics to be detected. sanger for familial mutations
- RNA analysis deep intronic variants or complex rearrangements. usually muscle or urine but need to confirm in genomic DNA. can also confirm splicing outcomes and orientation of duplications
Two deletion hotspots: 30% exons 2-19 and 70% exons 45-55
What is traditional treatments for D/BMD (before gene therapies)?
steroids (improve muscle strength and motor function), physical therapy, anti-congestives and cardiac transplant in severe cases
what gene therapy is available for D/BMD?
- stop codon readthrough eg. translana. 15% of patients have PTC. Tretments allows alternative amino acids to be inserted at the site of the mutated stop codon & results in dystophin expression at 10-20% providing some function
- exon skipping eg. exondys51 (80% of patients in theory). Interferes with splicing skipping the specific exon in DMD pre-mRNA to restore open reading frame and allow expression of shorter but functional protein
what is SBMA?
X linked disorder affecting males 1/300 000
caused by CAG repeat in exon 1 of AR gene
progressive neuromuscular disorder with degeneration of motor neurons resulting in muscle weakness and muscle atrophy and reduced fertility (due to mild androgen insensitivity)
GOF mutation. the more repeats there are the earlier the age of onset
only occurs in Europeans or Asians
females not usually affected
what is androgen insensitivity syndrome (AIS)?
complete = total insensitivity to androgen and child develops female genitals. abnormal secondary sexual development at puberty and infertility in those with a 46, XY karyotype
partial = level of insensitivity determines how genitals develop (predominantly female, male or ambiguous)
mild = typically male genitalia
Affects 2-5/100 000 who are genetically male
infertility
What causes androgen insensitivity syndrome?
- pathogenic sequence variants in AR gene (XLR)
- androgen receptors allow cells to respond to androgens (hormones such as testosterone) that direct male sexual development
- AR mutations present receptors from working properly and makes cells less responsive to androgens
WHat is haemophilia A and B (christmas disease)?
XLR disorders caused by mutations in F8 (A) and F9 (B) causing F8 and F9 to be inefficient at coagulation in the blood. Disorders are indistinguishable clinically. Clotting deficiency results in prolongued bleeding after injury. 10% of female carriers are at risk for bleeding. 1/6000 males have haem A and 1/30 000 males have haem B.
what is Fabry disease?
XLR lysosomal-storage disorder caused by mutations in GLA which encodes the galactosidase enzyme (breaks down a fatty substance). pathogenic variants prevent the enzyme from breaking down this substance leading to it damaging cells. symptoms include pain in hands and feet, inability to sweat, cloudiness in eye, angiokeratomas *dark red spots on skin), GI problems, tinnitus and hearing loss. life-threatening complications include kidney damage, heart attack and stroke. 1/5-10 000 affected. childhood onset. females may be affected
define anticipation?
give examples
trinucleotide repeat expansions in successive generations in which the signs and symptoms of some genetic conditions tend to become more severe, more frequent or occur at an earlier age
- these dynamic expansions are unstable and expand on transmission to next generation
- eg. FRAX (XL) maternal CGG expansion
- HD HTT CAG AD paternal
- DM1 CTG DMPK maternal expansion
what causes trinucleotide repeats to expand?
replication slippage - mispairing, hairpin loops causing replication fork blockage, unequal crossing overresulting in one expanded and one contracted tract
define Age-related mosaicism?
Mosaicism is defined as the presence in an individual, or in a tissue, of two or more cell lines that differ in genetic constitution. As we age, somatic/germline mutations accumulate over the course of a person’s life resulting in age-related mosaicism
eg. loss of X in males and females is normal age-related anaphase lag
eg. cancer is an example of age related mosaicism - mutations accumulate as we age
define Variable expressivity
give examples
degree to which phenotype is expressed varies between individuals with same genotype
eg. MArfan FBN1 - some are just tall and thin whilst others have heart conditions
eg. NF1 - mildly affeected have cade au lait skin but more severely affected have neurofibromas. may also develop tumours. may also have ID, short stature or seizures.
define penetrance
give examples
proportion of individuals carrying a particular variant of a gene (allele or genotype) that also expresses an associated trait (phenotype)
eg. BRCA1 - penetrance = 80% risk of BC. also affected by environmental modifiers such as smoking, diet, pregnancies etc
what is Age-related penetrance
penetrance is often expressed as a frequency, determined cumulatively, at different ages
define Sex-limiting
give an example
Sex-limited genes are genes which are present in both sexes but expressed only in one sex, and causes the two sexes to show different traits or phenotypes
eg. Familial Male Precocious Puberty - males only have signs of puberty at 4 years
define epistasis
give an example
interaction between nonallelic genes in which one combination of such genes has a dominant effect over other combinations eg. Bombay phenotype
define pleiotrophy
give an example
Pleiotropy occurs when one gene influences two or more seemingly unrelated phenotypic traits eg. usually metabolic pathway that affects different phenotypes such as PKU. depending on mutation involved may have reduced conversion of phenylalanine to tyrosine or ceased entirely. the failure to convert normal levels of phenylalanine to tyrosine results in less pigmentation being produced causing the fair hair and skin typically associated with phenylketonuria. also causes mental retardation and abnormal gait and posture.
what is antagonistic pleitropy?
the expression of a gene resulting in competing effects, some beneficial but others detrimental to the organism.
Antagonistic pleiotropy hypothesis – some genes responsible for increased fitness in the younger, fertile organism contribute to decreased fitness later in life. An example is the p53 gene, which suppresses cancer, but also suppresses stem cells, which replenish worn-out tissue.
define: Amorphic, Hypomorphic Hypermorphic Antimorph and Neomorphic
Amorphic = LOF
hypomorphic = partial loss through reduced function. usually recessive but occasionally dominant due to haploinsufficiency eg. Friedreich’s ataxia homozygous GAA repeat expansion. some cases are compound het with a point mutation. Homozygosity for inactivating mutations is embryonic lethal.
hypermorphic = GOF - increased activity of normal function
antimorph = dominant negative (gene product adversely affects the normal, wild-type gene product)
NEOMORPHIC - DOMINANT GAIN OF GENE FUNCTION that is different from normal function
what is a transition substitution?
a pyrimidine for a pyrimidine (C for T or vice versa) or a purine for a purine (A for G or vice versa)—
what is a transversion substitution?
Substitution of a pyrimidine by a purine or vice versa (C to an A)
define haploinsufficiency
A situation in which half amount of a gene product is not enough to maintain normal function for instance, individual with heterozygous mutation or hemizygous at a particular locus is clinically affected.
define linkage disequilibrium
give a CF example
: Linkage disequilibrium is the phenomenon by which there is a non-random association of alleles at two or more loci i.e. when variants co-occur together in an allele more than should be expected if random distribution of variants was occurring.
Phe508del 98% occurs in cis with 9T - important if patient also has c.350G>A p.(Arg117His) and 5T (causes CF with 5T only)
give an example of XLD disorder?
Fragile X, - CGG trinucleotide repeat in FMR1
X linked Alport syndrome - COL4A5. most common. kidney disease, hearing loss and eye abnormalities
give an example of an X-linked dominant disorder with male lethality
rett syndrome
Intercontinentia pigmenti
what are the features of XLD inheritance?
- expressed in males and females
- an affected female has a 50% chance of having an affected child
- an affected male has affected daughters and unaffected sons
- higher proportion of females affected than males
- affected males have more severe phenotype - variability in females
- may be mistaken for AD, unless there is an affected male who will have all affected daughters and no affected sons
When the mother is affected with an X-linked lethal disease what is the expected offspring ratio of M:F affected vs unaffected?
1/3 affected females, 1/3 unaffected females and 1/3 affected males
what are the features of an X-linked dominant disorder with male lethality in pedigrees?
- disorder observed exclusively in females
- affected males rarely seen (except XXY)
- history of miscarriages as 50% of males die
- sex ratio of offspring is therefore skewed
describe X-linked male lethal Intercontinentia pigmenti
- affects hair, skin, nails. teeth eyes and CNS
- wart-like skin growths
- Majority of males spontaneously abort
- NEMO gene with common deletion
- without NEMO protein, cells triggered to self-destruct
- high penetrance and highly variable
describe X-linked male lethal rett?
- neurological and developmental disorder with repetitive, stereotypic hand movements
- mecp2
- de novo
- high variability in females
- males with XXY or somatic mosaics survive
why is XLD Craniofrontonasal syndrome caused by variants in EFNB1 more severe in females?
-Cellular ‘interference’ between wild-type and mutant cell populations is the cause for the severe disease manifestation in CFNS females
-males are asymptomatic/mild phenotype
why might an XL disorder present in a female?
- skewed x inactivation
- variants in PAR regions are expressed on both X’s as escape X inactivation and can behave in AD manner eg. SHOX on PAR1
- XLD
- XO
- deletion on one X
ADD TO CARDS what is a microdeletion? give examples of reciprocal, interstitial and terminal microdeletion syndromes.
<5-10 Mb, can be recurrent
-monosomy and haploinsufficiency of dosage sensitive –genes. Also involves imprinted genes, unmasking recessive mutation, and positional effects
- can result in clinically recognisable syndrome
can be mendelian or contiguous eg. di george syndrome
for every deletion there should be a duplication - reciprocal microdeletion/duplications from NAHR eg. HNPP/CMT1A 17p12 and Smith-Magenis syndrome (SMS)/Potocki-Lupski syndrome (PTLS) (17p11.2)
Interstitial microdeletions:
Di GEorge 22q11.2
PWAS 15q11-q13
NF1 17q11.2
Miller-Dieker 17p13.3
williams syndrome 7q11.23
terminal microdeletions: wold-hirschorn del4pter
cri du chat del 5pter
what is a microduplication
<5-10 Mb, can be recurrent
regional trisomy and effects dosage sensitive genes
eg. mendelian -PMP22 HNPP,
- milder than deletions as cells more tolerant to gain than loss
- FISH less sensitive for duplications
-variable expressivity and reduced penetrance
Interstitial eg. Duplication 7q11.23 (williams syndrome region duplication syndrome)
what causes microdeletions/microduplications?
- low copy repeats up to 0.5Mb that have high homology >97% and result in structural aberrations from NAHR. NAHR hotspots cause recurrent CNVs
- may be interchromosomal
- intrachromosomal (between 2 chromatids)
- intrachromatid (within chromatid)
- results in deletions, duplications, inversions and dicentric
what methods can be used to identify microdeletions and duplications?
- FISH
- arrayCGH
- MLPA
- Q-PCR
- Optical Genome Mapping (Next gen cyto)
where is Charcot-Marie-Tooth (CMT1A)/Hereditary neuropathy with liability to pressure palsies (HNPP) located and what causes the syndromes? what are clinical features of the syndromes?
17p11.2
- reciprocal 1.4Mb duplication/deletion including PMP22- caused by NAHR between two LCRs with 99% homology
CMT1A (80% of CMT1) = PMP22 duplications. CMT1 is a demyelinating peripheral neuropathy. distal muscle weakness and atrophy, slow nerve conduction. slowly progressive. foot drop, calf hypertrophy.
HNPP - milder neuropathy. numbness, tingling and muscle weakness in the limbs. deletion of PMP22 (80%). other 20% have pathogenic mutation.
ADD TO CARDS where is smith magenis/Potocki-Lupski syndrome located and what causes the syndromes? what are clinical features of the syndromes?
17p11.2
3.7Mb recurrent del/dup generated by NAHR between LCRs. common del/dup occurs due to NAHR between proximal and distal low copy repeats.
smith-magenis syndrome = developmental delay, hypotonia and distinctive facial features. caused by de novo 17p11.2 deletions. (70%)
potocki-lupski syndrome - dev delay, autism and hypotonia. de novo duplications of 17p11.2
what causes Prader-Willi syndrome (PWS)/Angelman syndrome (AS) del 15q11-q13 and what are clinical features?
PWS = hypotonia, feeding difficulties, obesity, dev delay, insatiable appetite.
- paternal contiguous gene deletion resulting from NAHR between low copy repeats (75%) of 15q11q13 leading to absence of expression of paternally-imprinted genes. also caused by mat UPD and IC deletion. there are 4 large clusters of complex repeats termed BP1-4, with common deletion ranging from BP1 or 2 to BP3. SNURF-SNRPN, MAGEL2, C15orf2 involved.
angelmann = severe developmental delay/intellectual disability, severe speech impairment, gait ataxia , happy demeanor, microcephaly, sezures. Disruption of UBE3A in 15q11q13. 70% have maternal deletion.
what causes Neurofibromatosis type 1 (NF1)? where is the location? what are clinical features?
del 17q11.2
multiple café-au-lait spots, neurofibromata, learning difficulties
heterozygous loss of function mutations in the NF1 gene at 17q11.2 as well as by an LCR-mediated 1.5Mb deletion that encompasses NF1 and other flanking genes and pseudogenes
what is the location of Wolf-Hirschhorn syndrome , what causes the syndrome and what are the clinical features?
del 4pter
craniofacial features (greek warrior helmet appearance
dev delay, growth delay, ID, seizures
contiguous gene deletion
up tp 60% de novo and 40% have unbalanced translocation with deletion of 4p and partial trisomy of different chromosome arm.
may require FISH for detection
Candidate genes that may contribute to the WHS phenotype include WHSC1, LETM1 (seizures) and FGFRL1 (craniofacial phenotype).
what is the location of cri du chat syndrome , what causes the syndrome and what are the clinical features?
del 5pter
cat-like cry
severe dev delay/ID
microcephaly, hypotonia, hyperterlorism,
variable seized deletions of 5p from 5p13-5p15
size of del correlates with phenotype
85% are de novo deletion and 15% are unbalanced translocation
CTNND2 causes ID
what is the SMA carrier frequency in uk?
1/50
what is the main clinical symptom of SMA?
- progressive proximal muscle weakness due to spinal cord and motor neuron degeneration
- earlier onset is more severe
- prenatally: Arthrogryposis (joint contractures), absence of movement, death from respiratory failure
describe the different SMA types? what is the most likely cause?
- type 1 = most common form <6 months
- floppy baby
death at early age - poor head control and unable to sit
- swallowing and feeding difficulties
- homozygous deletion
type 2 = <1 year
- low muscle tone
- may be able to sit, never able to walk
- 70% reach adulthood
- gene conversion in one allele and hemi deletion in other
- type 3 = >1 until adulthood
- can stand and walkprobability of being ambulatory decreases with age
- gene conversion in both alleles
type 4 = adult onset
normal life expectancy
<1% of patients
aytypical - non chromosome 5 related
floppiness, multiple fractures, high CK
if a baby presents as floppy, what is the testing triad?
SMA, myotonic dystrophy and PWS
new TD = R70 (separate referral from hypotonic infants which go for R69 DM1, PWS and microarray so now the consultant has to specify SMA)
what causes SMA?
homozygous or compound het deletions and mutations of SMN1
- 98% homozygous deletion of SMN1 exon 7 (deletions or gene conversions)
- 2% compound het for a deletion and mutation
- <1% have homozygous pathogenic mutation in SMN1
mutations may be deep intronic.
2% of deletions are de novo (unequal crossing over)
Incidence of SMA remains high due to high new mutation rate
- germline and somatic mosaicism have been described
why is the SMA gene difficult to test
- has SMN2 (centromeric) pseudogene
- complex region of high instability with repetitive sequences, retrotransposable elements, deletions and inverted duplications
- 4% of population have two copies of SMN1 on one chromosome (can have up to 5 copies)
- SMN1 and 2 differ by 5 base pairs
- critical difference is a synonymous variant in SMN2 exon 7 which alters ESE and 90% of transcripts lack exon 7 in SMN2 and produce truncated product and so is degraded
- SMN2 still produces some full length SMN protein (10%) but not sufficient to compensate for lack of SMN1
- homozygous SMN1 del patients have at least one copy of SMN2 as SMN null mice is embryonic lethal
- higher copies of SMN2 leads to milder phenotypes
what is the SMN protein a component of?
spliceosome
how do you test for SMA?
-98% are deletions so MLPA or real-time PCR for SMN1 exon 7 & 8 deletion
- MLPA uses probes specific to the SNV differences between SMN1 and SMN2
- multiplex real time PCR uses TaqMan probes specific to exon 7 SMN1 and a control probe
- 2% sequence variant - NGS, allele specific long range PCR and RT-PCR/cDNA sequencing are used for specific analysis of SMN1
why might a parent of a child with SMA have normal SMN1 dosage? how can this be confirmed?
- 4% of population have two copies of SMN1 on one chromosome - linkage analysis
- de novo deletion - 2% of patients, can do bayes calculation for normal dosage parent.
what therapies are available for SMA?
what are issues with these treatments?
drugs work by stabilising the SMN protein or modulating SMN2 expression
- Increasing protein:
Zolgensma - virus vector delivers SMN1 transgene to affected motor neurons
modulate SMN2:
Nusinersen/Spinraza is an antisense oligo to promote inclusion of exon 7 in SMN2 transcripts by blocking intron 7 splice site to increase SMN protein levels. highly stable and not toxic.
Risdiplam - oral (not injected)promotes inclusion of exon 7 in SMN2
Issues - usually diagnosedin advanced stages where motor degeneration has occured. screened for?
current pilot study to include SMA in UK newborn screening - March 2022
define haploinsufficiency?
both copies of a gene need to be functional in order to express the wildtype. 50% of the normal gene product/expression/activity is not enough. Inactivation/loss of a single allele (leaving the second allele unaffected) produces a clinical phenotype
A gene is likely to be haploinsufficient if all mutation types (missense, nonsense, gene deletion etc.) produce the same phenotype
give an example of a haploinsufficient single gene?
PMP22 - HNPP 80% caused by deletion of a ~1.5Mb region at 17p11.2 and 20% caused by mutation
repeated focal pressure neuropathies
HNPP is haploinsufficient whilst PMP22 dup CMT1A is GOF
give an example of a haploinsufficient contiguous gene deletion syndrome?
22q11.2 Di George syndrome - tbx1 HI causes heart defects and dysmorphology
give example of HI cancer gene?
TP53 - Thought to be typical two-hit model BUT LFS tumours analysed for LOH (loss-of-heterozygosity) show it occurs in ~60%, so ~40% of tumours have a presumably functioning second copy
what is a gain of function mutation?
what is a hypermorph and a neomorph?
- increase in gene expression or product develops new function
Hypermorph: an allele that produces an increase in quantity or activity of its product
Neomorph: an allele with a novel activity or product.
give examples of GOF mutations?
HD = CAG TNR exon 1 HTT polyglutamine tract 36 repeats or more. acquires novel deleterious function - deletions of region do not cause disease so GOF. forms inclusion bodies containing huntingtin which forms abnormal B sheets
DM1 - CTG toxic gain of function in DM1 and CCTG in DM2
Achondroplasia - inherited short stature FGFR3 tyrosine kinase receptor which negatively regulates bone growth. mutations activate the receptor, limiting bone growth. Gly380Arg) accounts for >99% of cases. high de novo mutation rate. FGFR3 mutations also cause thanatophoric dysplasia TD1 and 2, hypochondroplasia
BCR-ABL1 fusion gene in CML: t(9;22)(q34;q11) - novel tyrosine kinase. imatinib is TKI. MRD by RT-PCR quantifies levels of BCR-ABL1 mRNA transcripts in blood and bone marrow samples. determines treatment response.
CMT PMP22 - 1.5Mb duplication 17p11.2 - 80% of CMT1 cases. PMP22 codes for peripheral myelin protein. duplication generated by NAHR between sequences that flank the gene. reciprocal deletion causes HNPP
what is a dominant negative mutation?
mutations that reduce the function of the protein encoded by the normal copy of the gene
- only seen in heterozygotes and cause more severe effect than no gene product
- <50% residual function
-
give examples of dominant negative mutations
osteogenesis imperfecta
- COL1A1 or COL1A2 causes 90% of cases
- Haploinsufficiency (type 1): null variants and NMD results in milder phenotype as amount of collagen produced is reduced
- Dominant negative (Type 2): 80% caused by replacement of Glycine in Gly-X-Y in triple helix domain. disripts formation of triple helix and causes severe disease
Marfan - FBN1
- haploinsufficiency or dominant negative
- dominant negative: usually cysteine substitutions
Haploinsufficiency - nonsense/FS lead to NMD and decreased amount of fibrillin and aortic wall strength
