Genetics Flashcards
(150 cards)
1
Q
Frameshift mutation
what is it? give example of condition
A
Insertion or deletion which alters the reading frame, which may lead to an entirely different protein or stop codon (ie. mutation is NOT in multiples of three)
= Most detrimental type of mutation eg. DMD
2
Q
DNA structure
A
Sugar-phosphate backbone (5’ end and 3’ end) with nitrogenous bases
2 strands (1 end 5’ to 3’ and complementary end is 3’ and 5”)
- > C paired with G, 3 H bonds ie harder to break and harder to sequence
- > A paired with T, 2 H bonds ie easier to break
Coiled tightly into chromosomes
3
Q
What is a codon
A
3 bases which codes for one amino acid via genetic code
how mRNA is read -> in blocks of 3 called codons
there are 64 different codon combinations (61 code for aa, 3 are stop codons)
The amino acids that result from reading of the code is dependent on the ‘reading frame’ (depends which base the reading frame starts from/where the polymerase starts from)
4
Q
DNA polymerase
A
Adds new nucleotides ot growing DNA single strand chain
5
Q
Point mutation
A
Substitution of one base pair by another
Alters the codon so that it changes from one aa to another (and thus causes different protein product) or may produce a stop codon where no protein product may be produced
6
Q
Missence mutation
A
Type of point mutation where single aa mutation results in production of different protein product
7
Q
Nonsense mutation
A
Type of point mutation
Change from one aa to another results in production of a stop codon and no protein product
8
Q
Splice site mutation
A
ABnormal splicing of introns and exons altering the mRNA
Mechanisms
- Excision of exon
- Inclusion of intron
9
Q
Expanded repeats
give examples
A
An increase in the normal tandem repeat (some genes are coded by triplet repeats where the gene sequence is made of a repetitive pattern of the same 3 base-pairs)
ex
- fragile x syndrome
- myotonic dystrophy
- freidrichs ataxia
- spinal muscular atrophy
- spinocerebellar ataxia
- Huntingtons Disease
10
Q
Whole gene mutation
-example
A
Charcot marie tooth disease
- 2 copies (duplication) of PMP22 gene which encodes myelin
11
Q
What is the genetic mutation in the most common form of CF
A
Delta 508 - 3 base pair deletion (CTT coding for aa ‘Phe’) at position 508 of cftr gene
12
Q
What is transcription
A
Process of forming mRNA from DNA nucleic acid sequence -> resulting in EXONS only (removes introns)
- > mRNA is single stranded with ribose sugar instead of deoxyribose and Uracil bases replacing T bases
13
Q
What is an intron vs exon
A
Intron- any nucleotide sequence between exons within a gene that is removed by RNA splicing during maturation of the final RNA product. In other words, introns are non-coding regions of an RNA transcript, or the DNA encoding it, that are eliminated by splicing before translation.
Exons - coding segments of DNA which will encode a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing.
-> codes for protein
14
Q
What is translation
A
mRNA is translated into amino acids (3xpairs = 1 aa) which will form protein
15
Q
What is this condition?
Butterfly distribution of photosensitive telangectatic facial rash
Malar hypoplasia
Short stature
Syndactyly
Recurrent infections
Risk of malignancy
A
Bloom syndrome
- chromosome 15q defects: BLM protein, which is a helicase involved in DNA repair.
= fragile chromosome disorder
- increased number of chromosomal breaks with sensitivity to UV radiation
- > risk of malignancy (squamous cell skin cancer, leukemia, lymphoma, and gastrointestinal tract cancer)
- > BLM protein required for normal development of B and T cells -> low number of lymphocytes (B mostly), but the immunodeficiency seems relatively mild since they have no severe or opportunistic infections (more recurrent ear and resp infx)
16
Q
FISH
A
Fluorescence in situ hybridization (FISH) is a laboratory technique for detecting and locating a specific DNA sequence on a chromosome. The technique relies on exposing chromosomes to a small DNA sequence called a probe that has a fluorescent molecule attached to it.
Used for detection of specific submicroscopic deletions (ie WIlliams syndrome) and duplications and translocations
17
Q
Non-disjunction
A
Failure of chromosomes to separate (usually during meiosis)
18
Q
Mechanisms of trisomy 21
A
- Non-disjunction - 95% of cases
- 1 parental chromosome (usually maternal in setting of incr age) fails to separate at meiosis
- > resulting in 3x chromosome 21 (rather than 2; 2 from mo, 1 from fa) - Robertsonian translocation - 4% of cases
- a chromosome 21 is transloated onto another chromosome where they are joined to one another (14, 15, 21 or 22) = ie they have 2x normal ch 21 and 1x robertsonian translocation
- results in 45 chromosomes - Mosaicism (1%)
- these kids have some normal cells and some trisomy 21 cells resulting from non-disjoining occuring during mitosis AFTER fertilisation
- usually phenotypically affecte to lesser disease
19
Q
Clinical feautres of t21
A
Hypotonic baby
Small stature
CNS: Dev delay, Early onset AD
Facial: upslanting palpebral fissures (eyes)
epicanthic folds
cataracts and brushfield spots (speckled irises)
small ears
dental hypoplasia, protruding tongue
short nekc
Hands and feet: shot fingers, 5th finger abnormally bent/curved
single palmar crease
sandal gap (wide gap) btwn 1st and 2nd toes
CVS: CHD - AVSD, VSD, PDA, ASD, valve prolapse
REsp: incr chest infx
Haem: incr incidence leukaemias (AML)
Endo: incr incidence hypothyroidism
Skin: loose neck folds in infancy
Genitalia: small penis/testes, infertility common
20
Q
what do you see with alpha fetoprotein in T21?
A
LOW alpha fetoprotein
21
Q
what are the features of trisomy 18/edwards syndrome?
A
General LBW, fetal inactivity, single umbi artery, skeletal muscle and adipose hypoplasia, ID
-key: overlapping inex finger and rockerbottom feet (see image)
***Serious cardiac defects*** ex: VSD, ASD, PDA, bicuspid aortic/pulm valves
Also assoc w R lung malsegemtnation or abscence and GI/renal abnormalitieis
Prognosis
- 50% die within 1st weak and only 5-10% survive the first year
22
Q
spot diagnosis
A
Edwards syndrome/T18 (47xy+18)
- note overlapping index finger
- low set abnomrla eas
- small mouth
- micrognathia
- epicanthic folds
- prominent occiput
23
Q
Spot diagnosis
What are the other features of this condition?
A
Trisomy 13 - Patau syndrome
Other ft:
- Single umbi artery adn LBW
- CNS: Scalp defect w varying degrees of incomplete forebrain development; seizures, severe ID
- Craniofacial: cleft lip +/- palate, abnormal low set ears, micropthalmia
- Fingers/toes: polydactyly; clenched fist w overlapping fingers
- Cardiac: 80% VSD, ASD, PDA, hypoplastic L heart
- GI: omphalocoele/umbi hernia w single umbi artery
- Genitals: cryporchidism, bicronuate uterus
80% die within first month
24
Q
Turner syndrome karyotype
A
45xo
25
Spot diagnosis + what are the features of this condition
Turners syndrome
26
Management of turners syndrome
may be given growth hormone (to help them reach normal height) and HRT at around 12/on reaching adolescence (oedstrogen replacement for development of secondary sexual characteristics +/- small doses androgens for development of normal pubic hair and to help reach normal height)
Monitoring for cx
- Yearly: Thyroid, BP, weight, lipid profile and OGTT
- Every 5 years: echo, audiology, dexa, gynae US and thyroid Ab
27
What is imprinting?
Genetic mechanism by which the genes are selectively expressed (turned on or off) from the maternal or paternal chromosome
How does this occur
Genes are 'imprinted' by either methylation of genes -\> turns genes off
or by histone modification -\> this also affects activity of a particular gene
example of imprinting disorders: prader willi and angelman syndrome
28
Microcephaly
Spontaneous laughter
Seizures
FTT
Hypopigmentation
what is this condition?
What is the genetic inheritance?
Angel**MA**n syndrome (MA = Maternally Active gene)
- imprinting disorder of chromosome 15 q11-13 locus
- Normally, a fetus inherits an imprinted paternal copy of PW genes and a _functional maternal copy_ of PW genes. Due to imprinting, the paternally inherited copies of these genes are virtually silent, and the fetus therefore relies on the expression of the maternal copies of the genes.
Methods:
1. **deletion of maternal copy (70%)**
2. **mutation** on maternal gene (10%) -\> inactivation
3. **imprinting defect** (2-3%)
4. **paternal uniparental disomy** (2%) - both copies of chromosome 15 from the father -\> only paternally-expressed genes (intactive) in this region
29
Polyhydramnios; Hypotonic baby, poor feeding and hypogonadism
Obesity and Hyperphagia later in life w behaviour difficulties
What is this condition?
What is the inheritence pattern?
Features
Management
Prader Willi syndrome
Imprinting disorder **chromosome 15**
Normally, a fetus inherits an imprinted maternal copy of PW genes and a functional paternal copy of PW genes. Due to imprinting, the maternally inherited copies of these genes are virtually silent, and the fetus therefore relies on the expression of the paternal copies of the genes. In PWS, however, there is **mutation/deletion of the paternal copies** of PW genes (70%), leaving the fetus with no functioning PW genes.
Alternally can occur becuase of **maternal uniparental disomy** (28%)
_Features:_ hypotonia, feeding difficulties in infancy w gradual developemt of obesity, hyperphagia, dev delay, cognitive impairment, behavioral problems, short stature (GH responsive) and hypogonadism
_Facial feautres:_ almost shaped eyes, thin upper lips, downturned corners of mouth
_Diagnosis_ on DNA methylation studies (detects ALL cases); microarray only detects deletion
_Treatment:_ GH increases lean body mass, reduces fat mass, incr mobility and improves neurodevelopment
30
Imprinting conditions of chromosome 15 (x2)
* Praderwilli and angelman syndrome
* Both affect _15q12 region_
* Both conditions result from _failure to inherit the active gene/loss of gene product_
**Prader Willi syndrome -**
* Normal set up: paternally active genes (genes active on paternal copy of gene) and **matenrally imprinted (**inactive) gene.
**Mechanisms:**
* When you get deletion on paternal copy of gene, you get prader willi wyndrome (beacuse then you have no active gene, as maternal gene is turned off) - 75% of cases
* If you have maternal UPD - you also don't have the actiev paternal copy of the gene, which also results in PWS - 25% of cases
**Angelman syndrome**
* Opposite of prader willi (maternally active genes, **paternal genes imprinted**/silenced)
* -\> 70% of genes are deletion of gene on maternal copy. 5-10% mutation on maternal copy
* -\> 5% paternal UPD
31
**What is this condition and how is it diagnosed?**
Supravalvular aortic stenosis, pulmonary stenosis
Hypercalcaemia, hypothyroidism, early puberty
Hypotonia, ligament laxity
Developmental delay
Variable level ID in 100%
Dysmorphic features - periorbital fullness, short nose, long philtrum, hick vermilion of the upper and lower lips, wide mouth, stellate iris
ID and 'cocktail party' personality - friendly ++ empathy
What is this condition and the inheritance
What test to diagnose it?
what is the risk of surgery?
Williams syndrome
-microdeletion 7q11.23 which should be picked up on microarray/FISH
assoc w high risk of MI w geneal anaesthetic!
32
Tall forehead
'Receding' hairline
Macrocephaly, tall with advanced bone age
Premature ertuption of teeth
**Sotos syndrome**
genomic sequencing
* Physical
* Distinctive facial appearance include a long, narrow face; a high forehead; flushed (reddened) cheeks; and a small, pointed chin
* Hypotonia
* **Overgrowth** in childhood (adv bone age)
* Stabismus (Cross eye)
* Premature eruption of teeth
* Scoliosis
* Cancer predisposition - no particular type
* Developmental
* Learning disabilities
* Autism
* Dev delay
* ADHD
33
**What is this condition? Cause? How to diagnose it?**
- Widely set eyes (ocular hypertelorism)
- a small jaw (micrognathia)
- a short nose with broad base; and low-set
- posteriorly rotated ears (pinnae)
Short stature
Low posterior hairline
Curly/Wooly hair in adolescents
Excess nuchal skin
Widely spaced nipples
CHD - Pulm valve stenosis
Cryptorchidism
Noonan syndrome
Mutations in the RAS/mitogen-activated protein kinase (MAPK) pathway, which is essential for cell cycle differentiation, growth, and senescence
Diagnosis on whole exome sequencing (usually won't find it on microarray)
34
What is this condition? Who is it dignosed?
microcephaly
severe dev delay
severe feeding difficulty with reflux
monobrow
short, uprutrned nose
long curved philtrum
thin upper lip
downturned corners of lip
Cornella De Lange syndrome
requires exome sequencing
35
What is this condition?
COngenital heart defect
Hypoplastic thymus, thyroid and parathyroid
Distinct facial features: small lowset ears, enlarged nose tip, hooded eyes, thin upper lip and small mouth
cleft palate +/- lip
22q11 deletion syndrome
= di george syndrome or cardiovelofacial disorder
dignosed on **microarray**
**Ft**
* CHD (TOF 20%)
* Palatal abnormalities - 67%
* immune deficiency - 77%(mostly mild)
* HypoCa/hypoparathyroidism
* psychiatric disorders (schizofrenia in 20%)
* dev delay in 90%
* renal abnormalities 15%
* SNHL 15%
36
What is this condition?
IUGR -\> short stature
Macrocephaly
Asymmetry between R and L sides of body
Triangular shaped face
Cafe au lait spots
Syndatctyly, clinodactyly 5th finger
**Russel Silver syndrome**
= NO IGF2 production
Imprinting disorder of _chromosome 11_ (normal is maternally imprinted/silenced genes with **paternally active copy)**
Disease state is due to _errors in imprinting/methylation (50%)_ or _maternal uniparental disomy (10%)_
37
What is uniparental disomy?
uniparental disomy, an abnormality in which a person receives both copies of a chromosome from one parent instead of receiving one from each parent
important in imprinting conditions such as angelman, russel silver, Beckwith wiederman
38
Neonatal hypoglycaemia, abdominal wall defect -\> hemihypertrophy, macroglossia, visceral organ hyperplasia. risk of embryonal tumours (Wilms, NB, HB)
ear pits and creases
what is this condition and mechonism of genetics?
Beckwith wiederMAn syndrome (Maternally Active)
Imprinting defects on chromosome 11 - normally **paternally imprinted/silenced** with **maternal gene copy active.**
* maternal copy **methylation defect** (50%)
* either **paternal uniparental disomy** (20%; no maternally active genes)
* maternal gene deletion
Risk of tumours lowest w mutaiton IC2 LOM - no routine screening req
For other mutations, requrie abdo USS Q3mo until 7yo
39
What is this condition?
FTT -\> **Trunkal Obesity** by mid-childhood (no hyperphagia)
Microcephaly and short stature
Hypotonia (low muscle tone)
Intellectual disabilities
**Myopia and retinal dystrophy**
**Friendly** disposition, cheerfulness
Distinctive facial features with prominent upper central teeth, low anterior hairline, thick wooly hair and eyebrows, downslanting palpebral fissures, gum enlargement, long eyelashes, microcephaly and micrognathia
Abnormalities of the hands and feet (long slender fingers)
**Cohen syndrome**
Note - also assoc w **neutropenia** with r_ecurrent infections and aphthous ulcer_s in some; a cheerful disposition; j**oint hypermobility**
G-CSF can be helpful for neutropaenmia
40
syndactyly
fusion of digits
41
clinodactyly
curved/bent digit
42
Noonan syndrome features
AD - mutations (often de novo) in more than 8 genes (RAS pathway) - diagnosis on WES
Variable presentation
**Features**
CNS: mild ID (10-20%)
Dysmorphisms: *ptosis, epicanthic folds*, hypertelorism, downslanting palpebral fissures, low nasal bridge, low set abnormal eaers, prominent upper lip
curly/wooly hair, low posterior hairline, *short webbed nec*k, widely spaced nipples
MSK: short stature, *shield chest*, pectus excavatum, *cubitus valgus*
Cardiac: *pulmonary valve stenosis, branch stenosis of pulm arteries*; HOCM (20-30%); VSD/ASD/PDA
Genitals: small penis, cryptorchidism 60-80%
Risk of childhood malignancy: NB, JMML (juvenile myelomonocytic leukemia)
43
What is Leigh's syndrome
Cause
Presenration
ix findings
A progressive neurometabolic degenerative condition - genetic condition -\> defective oxidative phosphorylation
* AR mitochondrial form inherited from mo
* XLR form - defective pyruvate dehydrogenase complex
Age of onset: **3 mo to 2 years**
Sx: **Developmental regression** (loss of motor skills particularly), dysarthria if older; dysphagia and FTT, irritability, **seizures**
OE: Geneal weakness, hypotonia, spasticity, loss of deep tenden reflexes ; can be assoc w HCM
Ix: Episodes of lactic acidosis (elevated lactate levels in blood, urine, CSF) resulting frmo excess pyruvate frmo dysfunctional oxidative phosphorylation +/- hypercapnoeic resp acidosis (hyperventilation/apnoea)
44
Features of angelman syndrome and inheritance
Imprinting/inactivation of paternal chromosome 15q12 region (condition is inherited via deletion in normal maternal copy or paternal uniparental disomy)
Features
* Dev delay/balance problems
* Microcephaly
* Severe ID
* Happy personality and characteristic broad smile (happy puppet syndrome) - laughing fits, excitability, hand flapping
* Epilepsy/seizures (80%, usually before age 3) - characteristic large amplitute slow spike waves on EEG
Diagnosis: need to do both DNA methylation studies and microarray
45
Chromosome structure
DNA wound around histones (nucleosome = DNA/histone complex) -\> coiled very tightly into chromosomes
2 sister chromatids joints at centre by centromere
46
Aneuploidy
Abnormal number of chromosomes - losing or gaining an extra chromosome
ex - trisomy 18/13/21 or turners (XO)
47
Diagnosis of T21
Karyotype
FISH
48
Unbalanced vs balanced translocation
use T21 as example
Balanced translocation - parent is clinically phenotypically normal and has 1x chromosome 21 and other chromosome 21 stuck on end of Chromsome 14 (robertsonian translocation)
Unbalanced translocation - child has 2x normal chromosome 21s but has also inherited the robertsonian translocation (chromosome 14 w chr 21 on end of it) -\> child has 3xchromosome 21 and therefore has Downs syndrome (may also be a nevo mutation; only 25% inherited from parent)
49
47XXY
What is this condition and what features does it have\>
**Kleinfelter syndrome (1:600)**
- hypogonadism, small testes , delayed puberty
- low testosterone
- infertility (azoospermia), incomplete verilisim/reduced secodnary sexual characteristics, gynecomastia
- tall stature, generally slim with low upper: lower segment ratio (long legs)
- mild learning difficulties, emotionally immature, shy (usually normal IQ but reduced c/w siblings)
- incr risk osteoporosis, t2dm, cvd
- malignancy risk (NHL, breast ca)
Tx: testosterone tx if deficient
50
45xo
turners syndrome
short stature
web neck
cardiac defects - bicuspid AO valve, Coarctation of aorta
ovarian dysgeneiss, infertility
normal intellect
51
Microarray
examination of chromosome at higher level of resolution compared with karyotype - looks at all chromosomes ~15% diagnostic yield but more variants of uncertain significance
Can look at **aneuploidy, large and small deletions and duplications (eg diGeorge, Williams syndrome), unbalanced rearrangements**
Does NOT detect triplet repeats (ie fragile X) or balanced translocations
_Does not require specific hypothesis (unlike FISH)_
2 types:
1. SNP array - looks at SNPs across whole genome
2. Array CGH - comparison of patient and control DNA labelled different colours
52
Fish
locus-specific fluorescent tags
'fishing' for a certain condition
used for localisation of a gene and looking for balanced rearrangements
53
Karyotype
direct visualisation of chromosomes
can detect aneuploidy, large imbalances only, balanced and unbalanced rearrangements
3% diagnostic yeild (lower) but most detected anomalies are pathogenic
54
How do you make protein from genes?
DNA -\> transcription -\> RNA -\> translation -\> Protein
55
Promotor regions
upstream of 1st exon/5' end of DNA
defined by 'TATA' box
5' TATAA 3'
56
Enhancer/silencer regions of gene
bits of dna that can further modiify expression of a particular gene
tissue specific
fine tuning at any given time/tissue of a particular organism
57
Inheritance of Rett synrome
X linked dominant (males die in utero)
MECP2 gene mutation
58
frameshift mutation
change in DNA where you alter the reading frame -\> results in totally different sequence of aa and completely alters the protein or results in a downstream premature STOP codon (truncated protein product)
59
PEnetrance
On/off binary 1:0
Either you have the phenotype of the disease or you don't
Genotype positive but phenotype negative = incomplete penetrance (this can be age-dependent; ie 2 year old with breast cancer or HD gene will be incompletely penetrant, but can develop disease as an adult and thus be penetrant for the condition)
60
Expressivity
Variabiilty in clinical features in individuals with the same genotype (ie expressiviety is variable phenotype despite same mutation/genes)
ex: NF1, Hypertrophic cardiomyopathy vs dilated cardiomyopathy in individuals with same familial mutation
61
Define
Locus
Allele
Locus - position of a gene on a chromosome
Allele - alternative variant of a particular gene (A vs a)
62
Co-dominance
effects of both alleles are seen in heterozygote
ex: Blood groups (AB etc)
63
Skipped generation in pedigree of likely AD condition?
= Incomplete penetrance
64
1st individual with an AD ocndition has arisen from?
de novo mutation
65
More than 1 affected child with AD or X linked condition but parents unaffected, none of their family has the condition is due to ?
give example
Gonadal mosaicism
ie: osteogenesis imperfecta and DMD
66
X inactivation
* Females have 2 X chromosomes but only 1 is active in any one cell
* One of the x chromosomes is inactivated ie those genes are not expressed
* The inactive chromsome is a dense chromatin mass called a **'barr body'**
* This occurs randomy in **_early embryonic development_**, so females are mosaic for X chromosome and explains why *X linked disorders are variably expressed in females* (why carrier females may be phenotyically affected)
Example: DMD - mother of a boy with DMD can express symptoms of muscle weakness/cardiomyopathy due to random inactivation of normal X chromsomomes and expression of the diseased X
67
Epigenetics
how is this done
changes in gene function/expression that occurs separate to changes in gene sequence
heritable information that is NOT carried in the gene DNA sequence itself
ie - the way an orchestra might play/interpret a piece of music (the actual music score is fixed but the way it is played is variable)
Expression is modified by
1. Histone packaging/coiling into nucleosomes. How tightly the DNA is coiled around histones -\> tighter coiling leads to reduced gene expression as it is unable to be read
2. Methylation of DNA inactivates/silences the gene expresion
68
Girl wiht normal prenatal growth and development upto 6-18months of age with regression in development (first hand movements/coordination and speech and social skills) in early childhood, acquired microcephaly
- \> stereotyped repetetive hand movements
- \> ataxia
- \> autistic like traits
- \> regression in intellect
what is this condition?
Rett syndrome
90-95% of Rett syndrome cases are caused by identifiable mutations of the MECP2 gene
69
Transmission pattern of AD inheritance in pedigrees
Vertical inheritance - disease seen in every successive generation (except in case of incomplete penetrance where it may skip a generation)
Both sexes affected Appx 50% of each gen affected
70
Example of triplet repeat conditions
Fragile X
Friedrich ataxia
Spinocerebellar ataxia
HD
Myotonic dysrophy
71
Key concepts of triplet repeat conditoins
- what affects phenotype severity
repeat size and stability
gender of transmitting parent (ie if one gender passes it on, child will be phenotypically more affected and repeats will get longer; ex fragile X, mat transmission)
anticipation - phenotype worsens with each generation (ex: myotonic dystrophy)
larger the repeat, earlier the onset but does not necessarily correlate w severity of sx
72
What is Whole Exome sequencing
Give an example of a condition that can only be picked up with WES
Whole genome DNA -\> shear into small fragments -\> capture all exomes -\> sequence those exomes
Can either order targeted panel (ie looking for causes of long QT syndrome)
Indications:
1. Ultra rare diagnoses
2. Early presentation, non specific presentation
3. Inconsistent gene lists/presenting sx
ex: Noonan syndrome
73
Myotonic dystrophy
triplet repeat condition (CTG repeat)
-\> \<37 no problem; \>50 - disease; congenital form as repeat \>1000 (generally inherited frmo mo)
Most severe form is congenital MD
- \> RFM and polyhydramnios
- \> born very floppy, mouth open; respiratory insufficiency; may need ventilator frmo birth
- \> froglike position, fixed talipes
If survives neonatal period, ID
74
Fragile X syndrome
* X linked Triplet repeat (CGG) disease
* X chromsomes have a 'FRAGILE' site and may develop breaks when cultured in a medium deficient in folic acid
* Repeat size correlates w expression of disease
* \<55 repeats normal w no risk for offspring
* 55-200 - _'premutation';_ normal intellect but _risk of transmission to **offspring of females**_ (passed on through female line).
* ****Note that expansions of premutation to full mutation _do not occur in male transmision._
* **\>200: full mutation, affected,** males will have clinical signs but only 1/3 of females will have clinical signs and this is due to x inactivation
* **Features**
* *Learning difficulties* (milder in females than males - x linked)
* 2-3% of ASD, ADHD
* Dysmorphic facies (large ears, long face, prominent jaw)
* Large testicular volume
* Hypermobile joints
* Recurrent OM in 50%
* Seizures 12%
* Can have MV prolapse
* Premutation carriers
* Tremor and ataxia in 45% males and 16.5% females \>50yo
* Premature ovarian insufficiency (-\> conception difficulity)
75
Friedchreich ataxia
**Genetics**
* AR hereditary ataxia (most common hereditary ataxia)
* Bigger the size of the smaller allele (2 triplet repeats inherited, one from each carrier parent) corresponds with higher rate of complications and earlier age of onset
**Pathophys:**
* GAA triplet repeat (\>600) within intron 1 of FXN gene -\> codes protein frataxin (helps to assemble iron-sulphur complexes required for mitochondrial ATP production)
* Reduction in normal frataxin results in impaired mitochondrial function
**Features develop w time, age onset 10-15yo**
- Progressive ataxia of limbs
- Absent lower limb reflexes and plantar response
- Reduction in vibration and proprioception (starting with lower legs then moving to torso)
- Scoliosis
- Foot deformity from contractures
**Associated:**
- Hypertrophic cardiomyopathy (most common cause of death)
- Diabetes
NOTE: Normal intellect
76
Reccomendations around predictive testing in minors
Guidelines recommend against
Insurance and discrimination reasoning
77
NF1 diagnostic criteria
2 or more of:
\>= 6 **cafe au lait patches** (\>5mm prepubertal; \>1.5cm postpubertal)
\>= 2 **neurofibroma** or 1 **plexiform neurofibroma**
**Axillary or inguinal freckling**
**Optic glioma** (slow growing generally benign tumour of optic nerve +/- chiasm - Gradual, painless, unilateral proptosis associated with loss of vision and an afferent pupillary defect is a common presentation)
\>= **lisch nodules** (brown spots in iris of eye, best seen via slit lamp)
**Distinct osseous lesions** (pseudoarthrosis appearing as broken bone on xray or sphenoid wing dysplasia)
**Parent with NF1** _(AD inheritance)_
78
Role of surgery for neurofibromas
Limited value due to tendancy towards regrowth
Indicaitons:
- sudden growth and painful
- Malignant
- Cosmetic reasons
79
NF1 compliocations
Mild ID
Seizures
1. Plexiform neurofibroma becoming malignant -\> neurofibrosarcoma (usually present w pain and rapid growth)
2. Scoliosis
3. Aqueduct stenosis (headache -\> signs ICP -\> MRI, tx w shunt)
4. HTN (most commonly due to essential HTN; renal artery stenosis in 1.5%; pheochromocytoma in 0.8%)
5. Precocious or delayed puberty, often assoc w CNS tumour
6. Lifespan reduced (~50s)
7. CNS tumours (note tend to be low grade and indolent excpet in case of optic nerve gliomas)
- optic nerve gliomas -\> opthal review regularly -\> treat w carboplatin if becomes symptomatic
- meningiomas
- astrocytomas
80
Genetics of NF1
AD mutation in NF1 gene -\> protien is neurofibromin
30-50% are de novo mutations
100% penetrance by 2-5 years of age
81
TImeline for NF1 sx
0-2: cafe au lait patches, plexiform neurofibromas
1-6: symptomatic optic nerve glioma, skinfold freckling
\>2: HTN
\>6: neyrofibromas, neurofibrosaromas (malignant transformation)
6-16: scoliosis (During period of rapid growth)
82
Management of child with NF1
Annual review for
- learning eval
- neuro assessment
- BP
- Scoliosis
6 monthly opthal review
Routine neuroimaging not reccommended unless clinical concern
83
What tumour types can NF1 patients develop?
GI stromal ttumours
pheochromocytomas
breast cancer
rhabdomyosarcoma
astrocytoma
Neuroblastoma
MPNST
84
_What is a ddx (not NF) in a young child w:_
- multiple cafe au lait patches
- flexural freckling
- macrocephaly and some learning difficulties
- NO neurofibromas, optic nerve gliomas, bone lesions
_What is the responsible gene and clinical significance of this?_
**Legius syndrome**
Due to mutations in SPRED1 (if doing genetics for NF1, also order SPRED1)
- clinical significance - **don't** have to monitor for **opthal/malignancy** as would with NF1
85
Tuberous sclerosis diagnostic criteria
Diagnosis is with: 2 major or 1 major + 2 minor
**Major features**
- facial angiomas (A) or forehad plaques (B) - 90%
- ungal or periungal fibroma (C; side of nail) - 80%
- \>3 hypomelanotic macules (D; best seen under UV lamp w woods lamp) - 70%
- shagreen patch (E; often lower back)
- multiple retinal nodular hamartomas
- cortical tumour (H) - 80%
- subependymal nodules (I)
- subependymal giant cell astrocytoma -\> can cause hydrocephalus
- cardiac rhabdomyoma \>1 (usually asymptomatic but can cause arrhythmia or CCF)
- lymphangiomyomatosis -80%
- renal angiomyolipoma (G; fatty lumps, usually asymptomatic but can bleed causing pain) -90%
**Minor feaures**
- pits in teeth (F) - 90%
- rectal polyps
- teeth enamel pits
- bone cysts
- gingival fibromas
- non renal hamartomas
- retinal achromic patches
- confetti skin lesions
- multiple cysts
Associated CNS problems
- 75% seizures (note 20% of infantile spasms -\> TS)
- 50% ID mild-severe
- Behaviour problems - ADHD, Autism, sleep
86
Genetics of Tuberous sclerosis
AD
2/3 de novo and 1/3 inherited
Mutation in TSC1 or TSC2 (both tumour suppressor genes) in 80%
87
Prenatal genetic testing options
CVS - piece of placenta removed, from 11 weeks (1:500 m/c)
Amniocentesis - fluid from around baby removed for testing - from 15 weeks (1:1000 m/c)
Both involve needle into womb
Preimplantation genetic testing
- can be done with IVF
- bx embryo (in lab at day 5, 100 cell stage) and test for what you're interested in (single gene disorders only; CF most common indication)
88
47XYY
What are the features of this condition?
Jacobs Syndrome
NOT kleinfelters (=47XXY)
Often undetectable as phenotypically normal males; may have slightly raised testosterone
**Features**
- CNS: learning difficulties, poor fine motor coordination, speech delay, behaviour problems (hyperactive, temper tantrums; minor incr risk of antisocial and criminal behaviour)
- ACNE
- MSK: long fingers and toes, pectus excavatum
89
Examples of conditions caused by microdeletions
Williams syndrome -chromosome 7 (up to 28 genes involved region 7q11.23, including elastin gene)
DiGeorge syndrome - chromosome 22
90
Inheritance pattern G6PD
X linked recessive
91
Inheritance and mutation that causes Marfans
AD
Mutations in FBN1 gene (codes for fibrillin protein) on chrom 15q21.1
-\> Fibrillin is a connective tissue protein found in microfibrils, a constituent of elastic tissue and abundant in tissues affected in Marfan's syndrome, including the aorta, the suspensory ligament of the lens, and the periosteum
92
inheritance of NF1
AD
93
Inheritance of CF
AR
94
X linked dominant disorders inheritance pattern
Uncommon - may be lethal in males and seen only in females (have 1x normal x chromosome which modifies expresion of disease)
ex: familial hypophosphataemic rickets, incontinentia pigmentii
95
Inheritance of Noonan syndrome
AD
96
Inheritance of galactosaemia
AR
97
Inheritance of homocystinuria
AR
98
INheritance of polyposis coli
AD
99
Inheritance of phenylketonuria
AR
100
INheritance of friedrich ataxia
AR
101
**Congenital adrenal hyperplasia** - compare presentations of the following causes:
1. 21-hydroxylase deficiency
2. 11-beta hydroxylase deficiency
3. 17-alpha hydroxylase or 17,20 hydroxylase deficiency
AR condition
1. 21-hydroxylase deficiency = Classical CAH with virilisation, adrenal insufficiency (hypotension, hypoglycaemia, hypoNa, hyperK)
2. 11-beta hydroxylase deficiency = CAH with hypertension, hypoglycaemia and virilisation
3. 17-alpha hydroxylase or 17,20 hydroxylase deficiency = CAH with hypertension, hypoglycaemia and hypoandrogenism
102
inheritance pattern of AR conditions in pedigree
horizontal (seen in multiple siblings but not parents)
conditions almost always inherited (rarely de novo)
103
AR conditons - offspring of 2 carriers.
What is teh chance the offspring will inherit the disease?
What is the chance of them being an asymptomatic carrier?
disease - 25%
asymptomatic carrier - 50%
not a carrier, no disease - 25%
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Anticipation
What is this concept?
Give examples of conditions in which it is seen
Disease expression/phenotype becomes more severe through successive generations
Seen in diseases caused by genes w trinucleotide repeats as teh number of repeats incerases through generations and correlates w severity of disease
ex: myotonic dystrophy, fragile X, Huntingtons disease
105
MArfan syndrome features
**1. Skeletal:** tall, thin habitus, muscle hypotonia, *joint laxity*, decreased upper:lower segment ratio (short torso, long legs), *long fingers and toes (arachnodactyly)*, pes planus (flat feet), pectus excavatum (indented breastbone), scoliosis/kyphosis, *high arched palate*
**2. Eyes**: myopia, retinal detachment, ectopia lentis (lens displacement)
**3. CV:** most common cause of death. Dilation of aorta, aortic aneurysm, dissection, mitral valve prolapse
106
Inheritance of haemophilia A
X linked recessive
107
Inheritance of Fabry's disease
What is this condition /presenting ft?
X linked recessive
Lysosomal styorage disease (affected enzyme is alpha-galactosidase -\> build up of sphingolipids)
Elevated GAGs in urine
Ft
* decr sweating
* peripheral neuropahty - burning/tingling to extremities
* angiokeratomas to skin (back, bathing trunk distribution)
* Eyes: verticillata to cornea (slit-lamp exam)
* Renal failure and early death if untreated
* Also causes GI and CV disease
108
Inheritance of familial hypophosphataemic rickets
X linked dominant
109
Inheritance of mitochondrial disorders
Mitocondria contain their own chromosomes which are **maternally derived**
Ie inheritance through maternal line
Ex: mitochondrial myopathies - MELAS, MERRF
110
What is the concept of a premutation? give an example of such a condition
A feature of trinucleotide repeat conditions (fragile x, myotonic dystrophy, HD, spinocerebellar ataxia)
triplet repeats can be normal and are found at many places in genome however repeat number above a certain size can make the gene unstable (=premutation) and more likely to expand further to a size that interferes w the function of the gene (full mutation)
111
Beckwith wiederman inheritance
* Autosomal dominant with variable expresison in phenotype and incomplete penetrance
* Imprinted condition (m_aternal gene copy imprinted_/inactive)
* Disease results from _overexpression_ of gene product (IGF2)
* Affects gene located at chromosome 11p15.5 -\> codes for IGF2 gene
* Inheritance - mutation or deletion in inactive maternal copy or paternal uniparental disomy results in **OVERPRODUCTION of IGF2 -\> resulting in overgrowth phenotype**
112
Achondroplasia
inheritance pattern
GEne mutation
* AD inheritance (often de novo mutation)
* Heterozygous (notę - homozygous is lethal inutero -\> miscarriage)
* Involves FGFR3 - fibroblast growth factor receptor normally INHIBITS bone growth
* Mutation results in ACTIVATION of this so it is always on
* Results in inhibition of long bone growth
* Doesn’t affect flat bones (skull, ribs)
* Results in disproportionate growth (long torso, short legs)
* Short phalanges and short MC
* Large head
* Normal organs, intelligence, lifespan, intelligence
* Prenatal dx: larger skull width: femur length ratio on US
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Li fraumeni syndrome
* Tumour predisposition syndrome
* Autosomal dominant
* _Germline_ mutation in p53 tumour suppressor gene
* Results in increased risk of following cancers
* Sarcomas
* Breast
* Leukaemia
* Adrenal gland tumours
* The risk of developing any invasive cancer (excluding skin cancer) is about 50% by age 30 (1% in the general population) and is 90% by age
114
FAP
* AD condition
* Mutation in tumour suppression gene APC gene making it less effective
* Results in formation of (100s of 1000s of) adenomatous polyps in epithelial lining of LI
* Start out benign but turn malignant (7% risk by age 21)
* Screening colonoscopies from 12 years of age (or from 18 years if attenuated form)
* Prophylactic ileostomy/(partial) colectomy (not in paediatric population, occurs generally in young adults or older)
115
Lynch syndrome
* = Hereditary non polyposis colorectal cancer
* Most common cause of inheritable colon cancer
* AD inheritance pattern
* Mutation in MLH1, MSH2, MSH6, PMS2 or EPCAM gene (these are mismatch repair genes - normally repair errors in DNA replication)
* Increased risk of colonic cancer (but also stomach cancer and in women uterine and ovarian cancers)
* Routine colonscopies every 1-2 years from age 25-30 (depending on specific mutation) or 5 years earlier than youngest person affected
* Routine gastroscopies every 2 years from age 30
* Treatment is partial vs complete colectomy
* Aspirin can reduce risk
116
When is genetic testing offered for familial cancer syndromes?
When risk of pathogenic cancer predisposition mutation is more than 10%
117
118
119
Genetics of HOCM
* AD condition
* Missense mutation - single nucleotide is swapped resulting in a different amino acid and thus diff protein product (make up sarcomere of myocytes)
* Beta myosin heavy chain the most common mutation
120
Familial HOCM
- pathophys
- treatment
* AD genetic condition affecting proteins that make up sarcomeres in muscle cells
* Results in assymmetrical thickening of ventricle walls (interventricular wall grows larger relative to free wall) -\> thick, heavy and hypercontractile.
* Usually affects L ventricle causing:
* Decr stroke volume (less space in chamber and stiffer so less compliant so less preload/filling) -\> **diastolic heart failure**
* Obstructed L ventricular outflow tract during systole (muscle growth of interventricular septum gets in way of L ventricular outflow tract)
* Variable crescendo decrescendo murmur (this is due to obstructed outflow tract)
* Bifid pulse
* S4 heart sound
* Dangerously fast arrhythmias -\> risk of syncope or sudden death esp in young athletes
* Treatment
* Beta blockers to slow HR
* Ca channel blockers (verapamil or diltiazem)
* Cessation of high intensity sports/athletics
* Surgery
121
What do duchenne and beckers musc dystrophies have in common and how are they different
* Both dystrophin gene mutation
* Dystrophin stabilises the sarcolemma of myofibrils; dysfunctional dystrophin results in myofibril cell death and muscle atrophy
* Both x linked recessive, so more common in boys
* DMD - NO dystrophin gene
* nonsense or frameshift mutation
* more severe
* presents ~ age 5
* Beckers - Misshapen dystrophin protein
* missense mutation
* Less severe
* presents age 10-20
* Symptoms
* Waddling gait
* Calf pseudohypertrophy (Fat and fibrous tissue causes enlargement)
* Gower's sign (needing to use arms to help stand up from lying on floor due to weak legs)
* Wheelchair bound
* REsp failure (weak diaphragm(
* Scoliosis
* Heart (dystrophin also expressed in heart muscle)
* dilated cardiomyopathy
* arrhythmias
* High CK levels
* GEnetic testing looking for mutations in dystrophin
* Muscle bx - stain for dystrophin
* Treatment
* Steroids can slow progression
* PT and OT
* Genetic counselling
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SMA
- genetics
- symptoms/signs
- types
Genetic disorder that causes lower motor neurons in spinal cord die prematurely -\> muscles controlled by those cells atrophy
* AR
* Deletion of SMN1 gene resulting in NO SMN1 protein.
* Severity/type of SMA is from the number of copies of functional SMN2 gene
* SMN protein expressed in all cells but particularly important in alpha motor neurons
**Results in**
* Muscle weakness
* Flaccid/low-tone paralysis
* Fasiculations
* Absent/reduced deep tendon reflexes
* Ultimately results in muscle atrophy
**Types**
* Congenital/type 1a: most severe, starts before birth with reduced foetal movements
* Infantile/type 1b: babies appear normal at birth but develop hypotonia in first few weeks of life. evelopment of proximal weakness, worse in legs + weakness in sucking, chewing and swallowing -\> aspiration risk
* Resp/diaphragm muscle weakness -\> ultimately result in resp failure and death by ~2 years of age
* Types II -\> Type IV progressively mild forms
* Scoliosis
* Thin limbs due ot muscle wasting
123
**Retinoblastoma**
Genetics
Signs/sx
**Genetics**
* AD inheritance
* Mutation/defect/deletion in RB1 tumour suppressor gene on chromosome 13
* -\> disrupts protein product pRb -\> unregulated cell division/rapid abnormal cell growth
* 2 hit model: development of disease requires 2x copies of RB1 gene (2x alleles) nonfunctional (2 'hits')
* 50% hereditary - germline RB1 mutation, 2nd hit ocurs randomly after bith
* tends to be bilateral
* 50% sporadic - born with 2x normal RB1 genes so requires 2x random mutation in both RB1 genes after fertilisation (somatic events)
* Onset later age
* Tends to be unilateral
* Note - 1.4% of cases due to amplification of MYCN oncogene (non-hereditary, early onset, aggressive, unilateral retinoblastoma)
**Signs**
* Leucocoria (white pupil as light reflex instead of normal red)
* Strabismus
* Eye pain
* Eye redness
* Bulging of the eye
* Blindness
124
**Wilms tumour**
Genetics
Embryonal kidney cancer - most common kidney cancer in childhood
**Genetics**
* Bilateral tumours more likely to have genetic predisposition
* Syndromic causes -
* WNT 1 mutation -\> Incr Wilms risk
* WAGR (Wilms, Aniridia, Genital anomalies, mental Retardation)
* earlier age of onset wilms (by age 4) and ESRF by adolescence
* Denys-Drash syndrome
* diffuse mesangial clerosis leading to early onset renal fialuire and intersex disorders (hermaphroditism)
* Frasier syndrome
* undermasculinised external genitalia of varing severity in 46XY male
* FSGS
* Gonadoblastoma
* 11p15.5 imprinting disorder
* Beckwith-Wiedemann syndrome
* Bloom syndrome
* Fanconi anaemia
**Signs/sx**
* Abdominal mass, haematuria, HTN; fever, anaemia
125
What is this condition?
* Most common
* *Developmental delay*
* *Intellectual disability (mild to moderate)*
* *Macrocephaly*
* *Dysmorphic features*
* *Hypertelorism (widely spaced eyes)*
* *Frontal bossing*
* Less common
* Behaviour - ASD, ADHD
* Risk of psychiatric disorders - schizophrenia, depression
* Cardiac malformations - TOF
* GU abnormalities - Hypospadius
* MSK
* Club foot
* Hip dysplasia
Chromosome 1q21.1 duplication/deletion syndrome
126
Main features of 16p11.2
Deletion vs duplication
* Most common (to both)
* Global dev delay
* Intellectual disability
* Speech/Language impairment
* ASD spectrum and ADHD
* Broad forehead, macrocephaly
* Gene deletion - risk of obestiy and macrocephaly
* Gene duplicaiton - risk of LBW/FTT and microcephaly
127
Myotonic dystrophy
Types and sx/signs
**Nucleotide repeat expansion condition**
* Caused by 'slipped mispairing' where DNA polymerase gets confused and starts repeating a certain sequence over and over
* Affected by anticipation (amplification of repeats w subsequent generations)
**2 types**
* **DM1 (trinucleotide repeat CTG)**
* _Congenital form: sx begin at birth with babies too weak to even suck or breathe; early death_
* Adult form: muscle weakness later in life, mainly affecting facial muscles (hollow cheeks and drooping eyelids) and distal hand muscles and muscles of lower leg (-\> toe and foot drop)
* **DM2 (tetranucleotide repeat CCTG)**
* Adult onset
* Milder sx
* Proximal muscles of thighs and hips (difficulty climbing stairs or rising from seated position)
* Features of both
* Myotonic (sustained muscle contraciton and difficulty relaxating muscles after use)
* ex: unable to release grip after shaking someone's hand
* Cataracts
* Insulin resisttance -\> diabetes
* Cardiac conduction defects -\> may require pacemaker
128
**Cri du chat syndrome**
1. genetics
2. presentation
3. diagnosis
**Genetics**
* Deletion of segment of the small arm (p arm, p for petit) of chromosome 5 (5p deletion syndrome)
* 80-85%: de novo mutation
* 10%: balanced translocation
**Presentation**
* Characteristic high pitched cry of babies sounding like cry of a cat
* Due to structural abnormalities of larynx
* Facies: small round face
* round cheeks
* hypertelorism
* prominent supraorbital arches
* epicanthal folds
* flat nose with wide nasal bridge
* low set ears
* dropped jaw
* dental malalignment
* Cardiac: VSD
* Neuro: mod-sev ID and delayed motor milestones, clumsiness
* FTT
* Neonatal hypotonia -\> hypertonia later in life
* Swallowing difficulties -\> feeding difficulties
* Constipation
* Recurrent infections (ototis media, UTI, resp)
**Diagnosis**
* Karyotype
* FISH if karyotype neg but clinical suspicion is there
129
Osteogenesis imperfecta
- What is it?
- Genetics
Disease of brittle bones prone to fractures due to impaired type I collagen synthesis
AD mutation of COL1A1 or COL1A2 -\> misfolding of collagen proteins , loss of function -\> bone loss, fragility
130
What is cDNA?
* Used in gene cloning or as gene probes
* cDNA is synthesised from a single stranded RNA template in a reaction catalyzed by reverse transcriptase
Synthesis of cDNA
* Mature mRNA is extracted from a eukaryotic cell, and PolyA tailing to the 3’ end
* Reverse transcriptase is added along with deoxynucleotide triphosphates (AT,CG) -\> synthesis of one complementary strand of DNA (cDNA)
* DNA polymerase I and DNA ligase can be used to make double stranded DNA
* This cDNA can be used as a template for PCR
131
Define acrocentric chromosome
when the short arm contains insignificant genetic material – chromosomes 13, 14, 15, 21, 22
132
Define q arm
long arm of chromosome (vs p is short arm, p for petit)
133
Define aneuploidy
Gain or loss of a whole chromosome
* Monosomy
* Disomy – e.g. uniparental disomy
* Trisomy
134
Define balanced translocation
Exchange of genetic material without loss or gain overall
Abnormal genotype, normal phenotype
Risk to children
135
Inheritance of haemophilia A
X linked recessive
Mutation in F8 gene causing reduction in factor VIII levels -\> bleeding predisposition
136
Pedigree - clues towards translocation
Carriers are phenotypically normal
* Carriers (balanced) have an increased risk for **miscarriage** and **bearing affected children**
137
Define Brachydactyly
disproportionately short fingers nad toes
a feature of achondroplasia
138
What are the possible outcomes to offspring of 2 parents who both have achondroplasia
Achondroplasia is AD condition btu the homozygous form is lethal
so both parents are Aa
therefore
* 50% achondroplasia
* 25% normal
* 25% lethal homozygous form
139
Homocystinuria vs Marfan syndrome
1. inheritance
2. intelligence
3. joints
4. eyes
5. heart
6. diagnosis
7. treatment
Marfan
Homocystinuria
Inheritance
AD
FBN1 mutation – chromosome 15
AR
CBS mutation – chromosome 21
Intelligence
Normal
Intellectual disability
Joints
Hyperextensible joints
Rigid joints
Eyes
**Upward dislocation** of ocular lens (ectopia lentis)
**Downward dislocation** of ocular lens (ectopia lentis)
Heart
Aortic root dilation/dissection
Valvular insufficieny
Vaso-occlusive disease
Diagnosis
GHENT criteria
High plasma/urine levels of homocysteine and methionine
Treatment
Beta blockers for aneurysm
Surgery
High dose vitamin B6
140
GEnetics of homocystinuria
what is it?
**Genetics:**
* AR
* CBS mutation on chromosome 21
* Result in deficiency of the enzyme cystathionine beta synthase
**What is is:**
* Genetic disorder of the _metabolism of the amino acid methionine_ due to a deficiency of cystathionine beta synthase (CBS) or methionine synthase
* REsults in multi-systemic disorder of the connective tissue, muscles, central nervous system (CNS), and cardiovascular system.
* Ix: Elevated homocsteine levels in blood and urine
141
Genetic causes of long-QTc
1. **Long QT syndrome - *AD***
1. type 1 (KCNQ1) and 2 (KCNH2): caused by excessive K efflux
2. Type 3 (SCN5A): caused by excessive Na influx
2. **Jervell Lange – Nielsen syndrome - *AR***
1. ASsociated with congenital B/L SNHL
2. Mutation in KCNQ1 gene (excessive K efflux)
In both, risk of torsade de pointes (TdPs) -\> VF -\> sudden death
142
What triad of sx is associated w Kearns-Sayre syndrome? When do sx typically onset?
Mitochondrial disorder
Characterised by the _triad_ of:
1. External ophthalmoplegia (-\> B/L ptosis)
2. Pigmentary retinopathy
3. Cardiac conduction abnormalities.
Other features include sensorineural hearing loss, limb weakness.
Onset is typically later in childhood
143
What does CHARGE syndrome stand for?
What is the gene mutation?
**CHD7** gene mutation.
## Footnote
Coloboma (eye) - 80%
Heart defects
Atresia (choanal, also assoc w TOF-OA)
Retarded growth
Genitourinary defects
Ear abnormalities -\> diagnosis with MRI w fine cuts over temporal region to see abnormalities in inner ear (hypoplasic semicircular canals)
Also frequently have cranial nerve abnormalities (most often vestivular dysfunction from CN8 or anosmia from CN1)
144
What gene mutations cause the following conditions of copper transport/storage?
1. Menkes
2. Wilsons
1. ATP7A (A before B and M before W)
2. ATP7B
145
Conductive hearing loss and facial deformity
What is this condition and the gene mutation/inheritance pattern?
Treacher-Collins syndrome
AD, complete penetrance
TCOF1 mutation
146
SERPINA1 gene mutation =?
Alpha 1 antitrypsin deficiency
147
Costello syndrome
- Inheritance/genetics
- Features
AD
RASopathy- mutation in RASMAPK pathway HRAS
Features
- Infantile FTT (skin and bones)
- Short stature, delayed bone age - low levels GH
- Dev delay and ID
- Joint laxity and loose skin folds to hands, feet etc
- Warty growth to perinasal area
- Acanthosis nigricans
- HCOM, fetal SVT, valvular abnormalities
- Cancer predisposition (rhabdomyosarcoma and benign papillomas of mouth, anus)
148
Huntington's disease genetics and inheritance pattern
AD
CAG triplet repeat
\>40 (dad) \*Anticipation\*
149
AD - mutation in ARID1 or SMARC genes
Relatively common cause of ID
Hypertrichosis/hairyness
Thick eyebrows and long eyelashes
Low hairline w thick, sparse hair in infancy
Thick lips
75% central hypotonia
50% seizures
35% ea - renal and cardiac abnormalities
150
ID/mild global dev delay
ASD/ADHD/behavioual issues
Macrodontia
What genetic syndorme would you consider?
KBG syndrome
