Genetics Flashcards
Autosomal recessive inheritance - risk of 2 parent carriers
1:4 chance 2 normal genes (unaffected, non-carrier)
1:4 chance affected carrier
2:4 chance unaffected carrier
Features of Turner syndrome
- Short stature
- Lymphoedema of hands and feet in newborns
- Webbed neck, low-set ears, broad chest, widely spaced nipples
- Delayed puberty, primary amenorrhoea (gonadal dysgenesis - streak ovaries and infertility)
- Heart defects - bicuspid aortic vavle, CoA
- Increased risk of autoimmune disorders (hypothyroidism, coeliac)
Condition?
Turner syndrome - X,O (absence of all or part of one X chromosome)
Turner syndrome inheritance pattern
- Not typically inherited - occurs due to random meiotic error.
- 45,X karyotype, although some may have mosaicism with a 46,XX or 46,XY cell line.
- Not generally passed on to offspring; affected individuals are usually infertile.
- About half of the population with Turner syndrome have monosomy X (45,XO). The other 50% of the population has a mosaic chromosomal component (45,X with mosaicism).
- Rarely, Turner syndrome can result from a partial deletion of the X chromosome, and this can pass from one generation to the next.
Describe segregation and linkage analysis
Segregation analysis is used to determine the pattern of inheritance for a trait.
Linkage analysis is used to determine the genetic location of a disease gene (ie identify a piece of DNA of known location only inherited by affected family members). Once the DNA is found, one knows the disease is close by.
What is a phenotype?
An individual’s observable traits, such as height, eye colour, and blood type. The phenotype results from the interaction between the genotype and the environment. ‘Pheno’ means ‘observe’ and comes from the same root as the word ‘phenomenon’.
What is a genotype?
A genotype is an individual’s collection of genes.
What is a haplotype?
A haplotype is a set of DNA variations, or polymorphisms, that tend to be inherited together.
What is a karyotype?
A karyotype is an individual’s collection of chromosomes.
What is penetrance?
The proportion of a population of individuals who carry a disease-causing allele who express the related disease phenotype aka how likely it is that a condition will develop. Eg the penetrance for retinoblastoma is 90%, as 10% with the AD retinoblastoma causing mutation don’t develop it.
What is expressivity and variable expressivity?
Expressivity describes the extent to which a genotype shows its phenotypic expression in an individual aka the severity of the phenotype. Variable expressivity means the same genotype can have varying degrees of the phenotype.
Name 2 conditions with incomplete penetrance
Retinoblastoma, Huntington’s
Name 2 conditions with 100% penetrance
Achondroplasia
Conditions with AD pattern inheritance (7)
- Neurofibromatosis type 1&2 2. Tuberous sclerosis
- Marfan’s, achondroplasia
- Myotonic dystrophy
- Noonan’s syndrome
- Retinoblastoma
Conditions with autosomal recessive pattern (13)
- Phenylketonuria
- Homocystinuria
- Hurler’s syndrome
- Galactosaemia
- Tay-Sach’s disease
- Friedrich’s ataxia
- Wilson’s disease
- CF
- Sickle cell
- Thalassaemias
- MCAD deficiency
- Spinal Muscular Atrophy
- Alpha-1 Antitrypsin Deficiency
Conditions with x-linked dominant inheritance pattern (4)
- Vit D resistant rickets
- Rett syndrome
- Aicardi syndrome
- Alport syndrome
Conditions with x-linked recessive inheritance pattern (7)
- Duchenne muscular dystrophy
- Becker muscular dystrophy
- Haemophilia A&B
- G6PD deficiency
- Red-green colour blindness
- Hunter’s (MPS II)
- Lesch-Nyhan
Explain autosomal dominant inheritance pattern
- Conditions are expressed in individuals who have just one copy of the mutant allele.
- Affected M&F have an equal probability of passing on the trait to offspring, and M&F equally affected.
- Affected individual’s have 1 normal copy of the gene and 1 mutant copy of the gene, thus each offspring has a 50% chance on inheriting the mutant allele.
- Transmitted from one generation to the next (vertical transmission)
- Parents usually one affected heterozygote and one unaffected homozygote.
- If only one parent affected there is a 50% chance that a child will inherit the mutated gene.
Pattern of inheritance?
Autosomal dominant
Explain autosomal recessive inheritance pattern
- Conditions are clinically manifest only when an individual has 2 copies of the mutant allele. When just one copy of the mutant allele is present, an individual is a carrier of the mutation, but does not develop the condition.
- F&M equally affected.
- When two carriers mate, each child has a 25% chance of being homozygous wild-type (unaffected); a 25% chance of being homozygous mutant (affected); or a 50% chance of being heterozygous (unaffected carrier).
- Both parents’ usually unaffected heterozygotes.
Pattern of inheritance?
Autosomal recessive
Explain x-linked recessive pattern of inheritance
- Not clinically manifest when normal copy of the gene.
- Traits fully evident in males b/c they have only one x chromosome, but women are rarely affected (but are when have 2 copies of the mutant allele).
- No father to son transmission, but there is father to dtr and mother to dtr/son transmission.
- If male affected with an x-linked recessive condition, all dtrs will hv one copy of the mutant gene
- A female carrier has a 50% chance of having affected sons and a 50% chance of having carrier dtrs
Pattern of inheritance?
X-linked recessive
Explain x-linked dominant pattern of inheritance
- Traits manifest if have one affected chromosome.
- No transmission from father to son
- All dtrs of a carrier male will be affected
- 50% of M&F a carrier mother will be affected
Pattern of inheritance?
X-linked dominant
Explain y-linked pattern of inheritance
- Every son of an affected father will be affected.
- Females of affected fathers are never affected.
Explain mitochondrial inheritance
- Mitochondria are inherited only in the maternal ova and not in sperm
- M&F affected, but always being maternally inherited
- All children of affected F will inherit the condition
- An affected M does not pass on his mitochondria to his children, so all his children will be unaffected
- Poor genotype : phenotype correlation - within a tissue or cell there can be different mitochondrial populations (heteroplasmy)
Explain horizontal transmission
Horizontal transmission implies that the condition can be seen in multiple siblings within the same generation, which is a characteristic of autosomal dominant inheritance. This occurs because an affected individual has a significant chance (50%) of transmitting the disorder to each child.
What gene is impacted in Marfan’s syndrome?
Fibrillin-1 gene
What genes are affected in the following trisomies?
1. Patau
2. Edward
- 13 (Patau)
- 18 (Edward)
What features on antenatal screening (at 14 weeks) would be noted in trisomy 21?
- Decreased serum AFP (alpha fetoprotein)
- Elevated hCG (human chorionic gonadotropin)
- Low uE3 (unconjugated oestrodiol)
- Increased nuchal translucency measurement
What is the most common cause of aneuploidies?
Non-disjunction of chromosomes during meiosis I
What physical features are associated with Down syndrome?
- Single transverse palmar crease
- Hypotonia
- Short broad hands
- Short incurved little fingers
- Sandal gap btwn 1st & 2nd toes
- Dislocation of knee
- Short stature
- Up slanting palpebral fissures
- Prominent epicanthic folds
- Protruding tongue
- Flat nasal bridge
- Small ears
- Round/ flat face
- Flat occiput
- Short neck
What cardiac complications are associated with T21?
- Endocardial cushion defect (aka AV septal canal defects) ~40%
- VSD ~30%
- Secundum atrial septal defect ~10%
- Tetralogy ~5%
- PDA ~5%
What abdominal conditions are associated with T21?
Hirschsprung’s disease
Intrahepatic biliary hypoplasia
Duodenal atresia/stenosis
What features are associated with William’s syndrome?
- Elfin facial appearance
- Cheerful demeanour
- Low nasal bridge
- Idiopathic hypercalcaemia
- Behavioural problems
- Dvpmtl delay, low IQ
- Prenatal, postnatal growth delay, FTT, short stature
- Recurrent middle ear infections, sensorineural hearing loss
- Congenital heart disease
- Abnormal joint mobility
- Hernias
- Diverticula
- Squint
What features are associated with Marfan’s syndrome?
- Tall stature
- Learning disability (50%)
- Lens subluxation (usually upwards)
- Femoral hernia
- Hemivertebrae
- Cardiac - aortic/mitral regurgitation, aneurysms
- Joint hypermobility
- Arachnodactyly
Congenital meaning
Condition or anomaly present at birth
Hereditary meaning
Conditions that are genetically transmitted from parent to offspring. All hereditary conditions are genetic, but not all genetic conditions are hereditary (if affects reproduction)
Familial meaning
Conditions that cluster in families. Can include genetic and non-genetic (eg ADHD, hypertension)
Unbalanced translocation meaning
Unequal exchange of chromosome material, resulting in extra or missing genes
Genotype meaning
Genetic constitution, or different forms of a gene (alleles) at a given locus on a chromosome.
Describe imprinting
Imprinting turns off genes. If a gene is paternally imprinted, the allele from the father is inactive and only the maternal allele is expressed. Eg Prader-Willi (paternally derived 15q11-13 deletion) and Angelman (maternally derived 15q-13 deletion).
Pleiotropy meaning
Genes that produce many effects eg Marfan syndrome (eyes, CVS, skeletal)
Mosaicism meaning
Presence of 2 or more genetically different sets of cells in the same person caused by an error in mitosis eg Turner syndrome 45,X
Heterozygous meaning
2 different alleles at a gene locus on a pair of homologous chromosomes
Homozygous meaning
Identical alleles at a particular gene locus
Autosome meaning
All chromosomes except the x and y chromosomes (22 autosomes + 2 sex chromosomes). The majority of the population has a total of 46 chromosomes.
Nondisjunction meaning
Homologous chromosomes or chromatids fail to separate, resulting in aneuploidy (an abnormal number of chromosomes in the dtr cells)
Syndrome meaning
A recognisable pattern of structural defects, due to a known single genetic etiology, with a predictable natural history that remains relatively consistent with unrelated patients
Association meaning
Anomalies seen together that do not have a known single genetic or developmental etiology eg VACTERL association
Sequence meaning
A pattern of multiple anomalies caused by a single identifiable event in development eg Pierre Robin
Genetics of Beckwith-Wiedemann syndrome
Most common overgrowth syndrome
>50% caused error in imprinted gene expression in chromosome 11p15.5 region
20% due to paternal disomy
Usually sporadic, may be inherited in autosomal dominant fashion
Features of Beckwith-Weidman syndrome
Macrosomia, premature birth
Macroglossia
Hepatosplenomegaly
Nephromegaly (renal medullary hyperplasia)
Pancreatic B-cell hyperplasia (excess insulin and hypoglycaemia)
Abdominal wall defects (eg omphalocele, umbilical hernia, diastasis recti)
Puberty, episeal fusion (early symptoms)
Embryonal tumours (eg Wilms, hepatoblastoma, neuroblastoma, rhabdomyosarcoma)
Features NF1
90% of NF, on chr 17q
Diagnosis if TWO OR MORE of:
* ≥ 6 café-au-lait macules (prepubertal >5 mm, postpubertal >15 mm).
* ≥ 2 neurofibromas, or one plexiform neurofibroma
* Freckling in the axillary or inguinal regions.
* Optic glioma
* ≥ 2 Lisch nodules (iris hamartomas).
* Bony lesion – sphenoid dysplasia (pulsating exophthalmos), or dysplasia of a long bone cortex.
* First-degree relative with NF1, based on the above criteria
Features NF2
10% of NF, on chr 22q
Diagnosis with ONE of the following
* Bilateral VIII nerve acoustic neuromas (i.e. vestibular schwannomas) (~90%)
* Unilateral VIII nerve mass, in a/w any 2 of: meningioma, neurofibroma, schwannoma, juvenile posterior subcapsular cataracts, glioma.
* Unilateral VIII nerve acoustic neuroma (or any two other brain/spinal tumours as above) and a first-degree relative with NF2
Clinical features include: cerebellar ataxia, hearing loss, facial neve palsy, headache.
Skin lesions less common than in NF1.
