Genetics Flashcards
Common single gene conditions (7)
- Hereditary haemochromatosis (1 in 300)
- Familial hypercholesterolaemia (1 in 500)
- BRCA1/2 (1 in 1000)
- Alpha-1-antitrypsin deficiency (1 in 1700)
- HNPCC (1 in 2000)
- Cystic fibrosis (1 in 3000)
- Neurofibromatosis (1 in 3000)
Autosomal dominant inheritance
- No difference whether you are male or
female - A 50/50 chance that a child will inherit
- There may be incomplete penetrance, variable expressivity
- A single affected person in a family may have a ‘de-novo’ AD mutation in a gene
Autosomal recessive inheritance
- No difference whether male or female
- Both parents must carry mutation for children to be at risk
- In that situation each child has a 1 in 4 chance of inheriting the disease
- Usually only one generation in a family is at risk. [Exceptions: highly consanguineous families or high gene frequencies in the general population]
Autosomal recessive disorders (11)
- Deafness
- Albinism
- Wilson disease
- Sickle cell disease
- Thalassaemia
- Cystic fibrosis
- Homocystinuria
- Friedreich ataxia
- Phenylketonuria (PKU)
- Haemochromatosis
- Alpha-1-antitrypsin deficiency
X-linked inheritance
- Affected males linked by unaffected females (x-linked dominant can mean female shows phenotype, or skewed x-inactivation)
- No male to male transmission
X-linked recessive disorders (9)
- Haemophilia A
- G6PD deficiency
- Fabry disease
- Ocular albinism
- Testicular feminization
- Chronic granulomatous disease
- Fragile X syndrome
- Colour blindness
- Duchenne and Becker muscular dystrophy
X-linked dominant disorders (3)
- Vitamin D resistant rickets
- Rett syndrome
- Incontinentia Pigmenti
Polygenic inheritance
Threshold for disease needs to be met with many genes playing an additive role
- These conditions cluster in families but do not follow predictable inheritance patterns.
- Environmental factors also often contribute to disease development
Klinefelter syndrome
47XXY
Tall stature
Infertility
Low testosterone
Mild learning difficulties
Turner syndrome
45X0
Short stature
Ovarian dysgenesis
Infertility
Heart and renal defects
Normal intellect
Robertsonian translocation
Afrocentric chromosomes (13, 15, 15, 21, 22) - don’t have a p arm and thus with two q arms can lead to trisomy in offspring
Prader-Willi syndrome (and…)
Absence of paternally functioning genes
- 70% paternally derived deletion of 15q12
- 25% maternal uniparental disomy 15
- <1% imprinting defect
Angelman - absence of maternally functioning genes
Trinucleotide expansions (5)
Features = intergenerational instability, anticipation, permutations, genotype-phenotype correlation
- Fragile X syndrome
- Friedrich Ataxia
- Huntington
- Spinocerebellar ataxia
- Myotonic dystrophy
Myotonic dystrophy
Muscle Weakness / Cataract / Myotonia / Infertility
CTG Repeat
<37- No Problem
>50- Disease
50-100- Generally Mild
Congenital Form Often >1000
Congenital Form Almost Always Maternally Inherited
Worse With Succeeding Generations (Anticipation)
fragile X syndrome
CGG Repeat
<50- Normal and No Risk for Offspring
50-200= ‘Premutation’- shy, 20% premature ovarian failure, risk to Offspring of Females, in males ataxia, tremor FAXTAS
>200 = ‘Full mutation’- Males have intellectual disability but intellect in females is variably affected (50% intellectual disability)
Huntington Disease 1
1:10 000, autosomal dominant neurodegeneration
Chorea, Cognitive impairment, Psychiatric/ personality changes
CAG Repeat»_space; Polyglutamine
Intergenerational instability
- Male > Female Transmission
- Juvenile Onset HD Almost Always Paternally Inherited
- Repeats >29 Unstable
- 36-39 = reduced penetrance
- 40+ = huntigton
Protein = Huntingtin- Unknown Function
Likely That Expansion Confers A Toxic Gain Of Function
Onset > death = 15 years
Mitochondrial inheritance + unique features
- Affected mothers pass on the mutation to all children (though mutant loads may vary)
- Males cannot pass on the disorder
- Variable expressivity is common
Unique features
- heteroplasty = coexistence of mutant & wt
- bottleneck = small number of genomes selected to repopulate oocyte
- threshold effect = critical number of mutant DNA needed for each tissue to become dysfunctional
Mitochondrial diseases (7)
- MELAS (Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like episodes)
- MERRF (Myoclonic Epilepsy with Ragged Red Fibres)
- Leber Hereditary Optic Neuropathy (LHON)
- External Ophthalmoplegia
- Kearns-Sayre syndrome
- Chronic progressive external ophthalmoplegia
- NARP (Neurogenic weakness Ataxia with Retinitis Pigmentosa)
A single nucleotide polymorphism (SNP) with 2 alleles, A and B, has been shown to be associated with an increased risk of celiac disease in homozygotes of allele B.
In the general population, 36% of the population is homozygous for allele A. In the same population, what proportion of the population is at increased risk of celiac disease as a result of homozygosity for allele B?
A. 6%
B. 16%
C. 36%
D. 64%
Hardy-Weinberg
1 = p2 + 2pq + q2
where p is and q are frequencies of alleles
B
Melanie has 2 brothers affected with Duchenne muscular dystrophy. Melanie’s daughter is pregnant. What is the risk to Melanie’s grandchild of developing DMD?
A.1 in 2
B.1 in 4
C.1 in 16
D.1 in 32
C. 1 in 16
John and Rita are having their first child together. They are unrelated. John’s niece and Rita’s brother both had cystic fibrosis.
What is the risk to their child of developing cystic fibrosis?
A. 1 in 36
B. 1 in 18
C. 1 in 16
D. 1 in 12
D. 1 in 12
Bill and Cindy are planning to have a child and are concerned about having a child with phenylketonuria (PKU). Bill had a son with a previous partner that died from PKU. Cindy has no family history of PKU. The couple are non-consanguineous. The carrier frequency of PKU in the general population is 1 in 50.
What is the risk of the couple having a child affected with PKU?
A.1⁄4
C.1/100
D.1/200
E. 1/300
D.1/200
A recessive condition is known to have a carrier frequency of 1/8 in the community. What is the likelihood that a couple with unknown carrier status will have an affected child?
A) 1/32
B) 1/64
C) 1/128
D) 1/256
D) 1/256
Familial cancer syndromes and genes associated (4)
- Hereditary Non-polyposis Colorectal Cancer
(HNPCC) - MLH1/MSH2/MSH6 - Familial Adenomatous Polyposis (FAP) - APC
- Hereditary Breast/Ovarian Cancer - BRCA1, BRCA2
- Neurofibromatosis type 1 - NF1
Rarer familial cancer syndromes
- Neurofibromatosis type 2 = NF2
- Li-Fraumeni syndrome = p53
- MEN1
- MEN2A, 2B, Familial Medullary Thyroid Cancer = RET
- Retinoblastoma = RB1
- Von Hippel-Lindau syndrome
- Basal cell naevus syndrome (Gorlin syndrome) = PTCH
- Cowden syndrome = PTEN
- Familial melanoma = P16
- Hereditary Diffuse Gastric Cancer = CDH1
- Autosomal recessive colorectal adenomatous polyposis = MUTYH (MYH)
Hereditary Non-Polyposis Colorectal
Cancer
Main features:
- Autosomal dominant in DNA mismatch repair: most often MLH1, MSH2, MSH6 (Most families have unique mutations) resulting in microsatellite instability
- Tumour suppressor genes thus accelerated transformation of normal polyps to colon cancer
Lifetime cancers risks:
- Colorectal Ca ~80%, median age 44 years, 2/3rds ‘right’ sided
- Endometrial Ca ~40%
- Ovarian Ca ~10%
- Gastric, small intestine, renal pelvis/ureter, pancreatic, gliomas (Turcot syndrome), hepatobiliary - each < 10%
Diagnosis
- family history most sensitive
- microsatellite instability - 90% in HNPCC while 10% in sporadic
- tumor IHC for mismatch repair
Familial Adenomatous Polyposis
- Autosomal dominant, mutations in APC gene (Most unique family mutations, 95% are truncating mutations)
- 10% have ‘attenuated FAP’ with later onset (more right sided)
Clinical features
- Onset of polyposis 12-25 years - 100% risk (most left sided)
- Extra-colonic features:
1. Gastric and duodenal polyposis/cancer-potential cause of mortality post- colectomy
2. Bone cysts (especially in jaw; previously called Gardener syndrome)
3. Desmoid tumours
4. Low risk of other cancers: medulloblastoma, biliary tract, thyroid, hepatoblastoma
Diagnosis = colonoscopy followed by genetic testing
Management - total colectomy with ilioanal pouch as teen, endoscopy 2 yearly
BRCA1 & BRCA2
- Increased risk of ovarian cancer: BRCA1 20-40%, BRCA2 2-20%
- BRCA2: risk of male breast cancer, small increased risk of prostate ca.
- Increased in the Ashkenazi Jewish population
Management
- mammogram from 30yo
- ovarian US from 35yo
- prophylactic mastectomy reduces risk by 90% (sapling-oophorectomy - less research but similar)
Gaucher disease - gene + features (5)
Autosomal recessive mutation of GBA1 leading to accumulation of glucocerbrosidases lipids
Features
- Hepatosplenomegaly may be asymptomatic or may be associated with early satiety, abdominal complaints (distension, discomfort, pain), and/or anaemia and thrombocytopaenia.
- Bone/ joint pain - Erlenmeyer flask deformity
- ILD
- Neurocognitive
- Associated with Parkinson disease
Hemophagocytic lymphohistiocytosis - what is it, triggers, findings
Life-threatening, hyper-inflammatory disorder via CD8 and NK cells
Triggers: autoimmune disorder, infection, malignancy, familial presents in newborn
Features
- fever
- cytopenias
- splenomegaly
- hypertriglyceridemia
- ferritin >500
- elevated sIL2Ra
Treat with immunosuppression followed by BM transplant
The genetics of complex diseases involves not a single gene mutation but multiple genes and
their interaction with environmental factors. Which of the following is true?
a. Twin studies are of little value in complex genetic disorders
b. ERAP-1 allele deletion is protective for Ankylosing spondylitis
c. Ulcerative Colitis is associated with NOD-2 allele
d. Genome wide association studies failed to identify risk loci for Schizophrenia
e. Heavy cannabis use has a causal role in the development of Schizophrenia
Answer: B
The development of Genome wide association studies (GWAS) has resulted in the identification of
risk alleles in a number of complex diseases with a strong familial risk.
Twin studies -especially in diseases with a strong familial tendency have been invaluable in identifying conditions where multiple genetic mutations are likely and where an environmental factor is also likely. Such diseases include, Type-1 diabetes, inflammatory bowel disease, ankylosing spondylitis and schizophrenia.
In Ankylosing spondylitis a functional ERAP-1 protein is necessary to present peptides to HLA-B27.
Individuals who are HLA-B27 positive but lack ERAP-1 are protected against the disease.
NOD-2 is a gene that is specifically associated with distal ileal Crohn’s Disease and thus identifies a specific subset of patients with this condition.
Schizophrenia has a familial predisposition in some
presentations.
Whilst cannabis use appears to precipitate or worsen schizophrenia on some individuals, it is not a universal environmental trigger and so is not strictly causal.
