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Syndromes > Molecular Genetics > Flashcards

Molecular Genetics Flashcards

1
Q

Name an X-linked dominant disorder

A

Fragile X syndrome.

Alports syndrome.

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2
Q

Name an X-linked dominant lethal disorder

A

Rett syndrome.

Incontinentia pigmenti

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3
Q

What causes SBMA

A

CAG trinucleotide expansion (>35 rpts) of exon 1 of the AR gene Xq12

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4
Q

What are the features of SBMA

A

Age of onset: 30-50yrs. Progressive neuromuscular disorder (weakness, atrophy, fasciculations) of the lower motor neurons.
Gynecomastia. Testicular atrophy. Mild androgen insensitivity.

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5
Q

Describe features of Alports syndrome

A

Renal disease (progressive renal failure, haematuria, proteinuria).
Hearing loss.
Ocular lesions.

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6
Q

What’s causes Alports.

A

85% X-linked dominant: COL4A5 mutations.

15% autosomal recessive (10%) and dominant (5%): COL4A3 and COL4A4

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7
Q

Describe features of Retts

A

LoF MECP2 mutations. Usually male lethal.
Progressive neurodegenerative disease. Normal development until 18 months, then regression (language and motor). Characteristic hand flapping. Gait ataxia, panic attacks, autistic features.

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8
Q

Name an Autosomal dominant disorder: Gain of Function

A 
Huntingtons.
Myotonic dystrophy.
CMT2A.
BCR-ABL1 fusion.
Spinocerebellar ataxia.
Achondroplasia
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9
Q

Name an Autosomal dominant disorder: Loss of Function

A

Cytogenetics: DiGeorge, Williams, Cri du chat.
Cancer: BRCA, PTEN, TP53.
Single gene disorder: Aniridia, Alagille syndrome.

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10
Q

Name an Autosomal dominant disorder: Dominant Negative

A

TP53.
PML-RARA fusion.
Osteogenesis Imperfecta.
Autosomal dominant myotonia congentia

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11
Q

Name disease associated with PMP22 at 17p12

A

Over expression: Charcot Marie Tooth type 1a/Hereditary Motor & sensory Neuropathy type 1a.
Haploinsufficiency: Hereditary Neuropathy with liability of Pressure Palsies.

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12
Q

Name disease associated with AR at Xq12

A

Mutation: Androgen Insensitivity Syndrome.

CAG expansion: Spinal and Bulbar Muscular Atrophy.

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13
Q

Name disease associated with RET 10q22.21

A

LoF mut: Hirschsprung Disease.
GoF mut: MEN2 (multiple endocrine neoplasia type 2).
Somatic: NSCLC, Thyroid carcinoma.

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14
Q

What genes are associated with Lynch syndrome/ hereditary nonpolyposis colorectal cancer

A

DNA mismatch repair genes: MLH1, MSH2, MSH6, PMS2, EPCAM.

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15
Q

What genes are associated with Noonan syndrome

A

PTPN11 (50%). SOS1 (13%). RAF1 (3-17%). KRAS (1%). NRAS (1%). BRAF (1%).

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16
Q

What are the genes involved in SMA and how many copies are there. What do they express

A

SMN1 and SMN2 (pseudo gene). There’s 1-5 copies of SMN2 in tandem. 4% population have 2 copies of SMN1 in tandem.
SMN1 & 2 differ by 5nt in exon 7 so exon 7 isn’t transcribed from SMN2.
SMN1 expresses a full length transcript. SMN2 expresses a short transcript that’s non functional and rapidly degraded (it does produce a small amount of full length).

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17
Q

What’s the new mutation rate for SMN1 gene

A

2% SMA patients have a de novo mutation

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18
Q

What’s cystic fibrosis

A

Most common autosomal recessive disorder in Caucasians.

A multi system disorder affecting: pancreatic, pulmonary, gastrointestinal, reproductive.

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19
Q

Name two treatments for CF

A

Potentiators (directly activate CFTR protein): (G551D) IVAcaftor.
Correctors (promote correction of protein misfolding): (p.Phe508del) LUMAcaftor.

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20
Q

Name a treatment for SMA

A

Antisense oligonucleotide treatment: corrects SMN2 splicing resulting in restored SMN expression.
Quinazoline related compound: increases SMN2 promoter activity, altered SMN mRNA levels or splicing patterns leading to increased SMN protein levels.
Histone deacetylase inhibitors are being looked at.

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21
Q

Discuss SMA testing strategy

A

SMN1 exon 7 dosage analysis first (often done with exon8 for a control). If have 0 copies of exon 7 that’s the result. If 1 copy: sequence looking for intragenic mutation.

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22
Q

Discuss testing strategy form CF

A

Test using mutation panel (commercial usually) of approx 30 mutations - detects about 90% mutations.
Could sequence CFTR if haven’t detected mutation from panel.
PolyTtract for 5T if testing for CVAD.
could test for TG (12/13) repeat if 5T is detected in CVAD.

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23
Q

When test for CF

A

Neonate with meconium ileus.
Neonate with elevated IRT.
Positive sweat test.
Features of CF.

24
Q

Name an X-linked recessive disorder

A

Duchenne muscular dystrophy/Becker muscular dystrophy.
Spinal and bulbar muscular atrophy.
Androgen insensitivity syndrome.

25
Q

What are the features of duchenne muscular dystrophy

A

Progressive and symmetrical muscle weakness often with CALF HYPERTROPHY and SEVERE JOINT CONTRACTURES.

Classic feature: gowers sign.Age of onset: 2-5yrs.
1st signs: impaired motor development and delayed milestones.
5th affected makes have MR.

Wheelchair bound by 12yrs and dies of respiratory failure/cardiomyopathy late teens/early twenties (have cardiomyopathy by 18yrs).

Referral reason: delayed milestones, waddling gait, difficulty climbing.

26
Q

What are the features of Becker muscular dystrophy

A

Similar progression to DMD (progressive symmetrical weakness, often calf hypertrophy.

Older onset to DMD: 5-15yrs
Slower rate of disease progression (wheelchair bound by 16yrs).

Milder phenotype: activity induced cramps, flexion contractures of elbows, preservation of neck flexor muscle.

Heart failure is the most common cause of death at about 40yrs.

27
Q

What are the features of DMD-associated dilated cardiomyopathy (DCM)

A

Dilated cardiomyopathy with congestive heart failure.
NO skeletal involvement.

Typically males 20-40yrs (females in later life).
Rapid progression to death in males/ slower (over a decade) in females.

28
Q

What causes DCM

A

caused by DMDmut that affects muscle promotor and associated with exon 1 only which results in no dystrophin transcripts produced in cardiac muscle.

29
Q

What causes DMD/BMD, discuss the gene

A

DMD Xq21 dystrophin.
2.4Mb. 79 exons.

Expression controlled by 3 independently regulated promoters (B- brain, M-muscle, P-purkinje).

2 deletion hotspots: (screening 19 exons account for 98% all deletions)
Central Region (exon 44-53) (80% del/ 20% dup).
5' region (exon2-20) (20% del/80%dup)
30
Q

What is the general DMD mutation rule for DMD and BMD

A

90%cases:

Out-of-frame mutation : DMD.
In-frame mutation : BMD.

single point mutation/ small in/del: 25% DMD and 10-20% BMD.

31
Q

Treatment for DMD

A

Not curative.
Aims to alleviate symptoms with steroids, physio, anticongestives.

Dystrophin restoration approaches:
Stop codon read through (GENTAMICIN).
Exon skipping (MORPHOLINO OLIGONUCLEOTIDE).
32
Q

What’s the difference in terms of proteins between DMD and BMD

A

DMD: lack dystrophin protein.

BMD: reduction in amount of protein, alteration in size of protein.

Lack of dystrophin protein causes progressive fibre damage and membrane leakage.

33
Q

What’s the role of dystrophin

A

One of the major roles of dystrophin is a glycoprotein complex where it stabilises sarcolemma and protects muscle fibres from long term contraction induced damage and necrosis.

34
Q

What can cause of female DMD Carrie to exhibit a phenotype

A

Non random X inactivation.
X-auto some translocation.
UPD of X chromosome.
Deletion involving other X / compound heterozygote of two DMD pathogenic variants

35
Q

What type of mutations are seen in the DMD gene in DMD

A

60-65% are large insertions or deletions that cause a frameshift.
40% are point mutations or small frameshift rearrangements including pure intron deletions.

36
Q

How are DMD mutations tested for

A

Most widely used method now is MLPA.
Analyse all exons which increases mutation detection rate. It’ll detect whole exon deletions and duplications and will characterise breakpoints to an exon level and can be used for female carriers.

37
Q

What influences the severity of the DMD/BMD phenotype

A

The principle factor is the reading frame.

Severity of clinical symptoms does vary according to which exons and how many are involved.

38
Q

Discuss CBAVD and infertility

A

Congenital bilateral absence of the vas deferens.
OBSTRUCTIVE AZOOSPERMIA.
1-2% of all infertility.

Caused by mucus clogging the vas deferens as they’re for wing leading to deterioration before birth.

CFTR: mutated in 70-90% cases.

88%: 1 severe mutation (p.Phe508del, R117H) and 1 mild mutation (5T polyT tract allele).
12%: 2 mild mutations.

Using standard CF mutation detection methods only 47% CBAVD must will be detected.

39
Q

What percentage of female permutation carriers have POI

A

21%

40
Q

What are the 2 disorders associated with having an pre-mutation of FMR1

A

FXTAS: fragile X associated tremor-ataxia syndrome.

FXPOI: fragile X associated premature ovarian insufficiency.

41
Q

How is Kallman linked to infertility and what genes are involved

A

Endocrine disorder. So reduced t
Levels of GnRH- hypogonadotrophic hypogonadism: undeveloped gonads and incomplete secondary sexual maturation.

Males: undeveloped testes/ lack second sex charc/ infertile.

Females: little or no breast development/ primary amenorrhea.

Gens: KAL1: Xp22.33. FGFR1 (8p21 (AD)). GnRHreceptor (4q13.2 (AR)).

42
Q

How is Noonan associated to infertility.

A

Males: uni and bi-lateral cryptorchidism (77%) resulting in azoospermia/oligospermia.

Female: normally fertile.

43
Q

In terms of fertility discuss SBMA.

A

Progressive androgen insensitivity. Severe oligospermia. Infertility. Testicular atrophy.

44
Q

What are the symptoms of Huntingtons

A

Progressive neurodegenerative disorder.
Motor symptoms. Cognitive impairment. Psychiatric disturbances.

First symptoms manifest: 35-60yrs. Disease duration: 15-20yrs.

45
Q

Discuss HTT huntingtin

A

It’s ubiquitously expressed and required for normal development. 2 alternatively polyadenylated forms: larger 13.7Kb expressed in adult and fetal brain; smaller 10.3Kb s widely expressed.

Expansion causes of gain of function: acquires a deleterious effect casting neuronal dysfunction and degeneration.

46
Q

Discuss HTT expansions

A

CAG expansion

Less than 27 rpts: normal.

27-35 rpts: intermediate (family at increased risk)

36-39 rpts: incomplete penetrance (diagnosis confirmed) (family at increased risk)

40 and over: pathogenic (diagnosis confirmed) (family at increased risk)

Repeat expansion are usually paternal (risk of offspring developing HD is highest in dads carrying intermediate rpts and over 35yrs old).

47
Q

Discuss HD and anticipation

A

Increase in disease severity/reduction image of onset is observed in successive generations.

Repeat numbers correlate inversely with mean age of onset. Longer repeats= earlier onset.

Very large expansions (>60) present with juvenile HD - before 20yrs.
Shorter expansions (36-39) can be asymptomatic..

Number of repeats accounts for about 70% of variance in age of onset

48
Q

What considerations for HD if getting homozygous result

A

Genotype to establish of real.
Consider age of onset (large expansion: Southern blot).
STR allele analysis (check for two allele).
Polymorphism under biding site

49
Q

What causes phenotype on FXTAS and FXPOI

A

Excess of FMRI mRNA causes a toxic build up- gain of function phenotype.

50
Q

Where’s the expansion in FMR1

A

CCG repeat in the first untranslated exon of FMR1

51
Q

What are the expansion sizes in fragile x

A

Normal: 6-45 rpt. Stable allele (98% popn: model number: 30rpts).

Intermediate: 46-58 rpt: less than 50: likely stable; 50-58: may show instability.

Premutation: 59-200rpt UNMETHYLATED: distinction between pre and full is methylation status..

Full mutation: 200-1000 rpts METHYLATED: 20% full muts are mosaic

52
Q

What’s the significance of AGG repeats in CGG repeats of FMR1

A

Stability of intermediate expansion correlates to the presence of two or more AGG interspersions.

Unstable repeats tend to late AGG or have only one. Therefor it’s assumed it’s the presence of these that maintain the stability.

53
Q

What percentages of permutation carriers manifest FXPOI and FXTAS

A

FXTAS: 16.5% women; 45,0.5% men.

FXPOI: 20% women.

54
Q

What’s the phenotype of a female full FMR1 expansion carrier

A

Variable: 50% apparently normal- 50% moderate mental and social impairment

Due to differences in proportions of active and inactive normal and mutation X chromosome in relevant tissues.

55
Q

What the phenotype of FXPOI

A

Amenorrhea before 40yrs for over 4 months in association with FSH level in menopausal range.

Varying degree of ovarian function seen in 50% women.

56
Q

What’s the phenotype of FXTAS

A

Late onset neurodegenerative disorder. Late onset cerebellar ataxia and intention tremor.

Severity of symptoms and reduction in age of onset proportional to increase number of repeats.

Clinical symptoms less severe in females

57
Q

What tests are carried out to detect fragile x

A

Most common: fluorescent PCR across CGG repeat. Southern blotting. Long range PCR.

Syndromes (7 decks)

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