Genetics Flashcards
What are the down syndrome features present at birth?
Typical facial appearance Hypotonic Flat occiput Single palmar creases Incurved fifth finger Wide 'sandal' gap between the big and second toe
What is the typical craniofacial appearance in down syndrome?
Round face and flat nasal bridge
Upslanted palpebral fissures
Epicanthic folds (a fold of skin running across the inner edge of the palpebral fissure)
Brushfield spots in iris (pigmented spots)
Small mouth and protruding tongue
Small ears
Flat occiput and third fontanelle
What are the anomalies associated with down syndrome that don’t involve the typical craniofacial appearance?
Short neck Single palmar creases Incurved fifth finger Wide 'sandal' gap between toes Hypotonia Congenital heart defects (AV canal defect) Duodenal atresia Hirschsprung disease
What are the long-term medical problems associated with downs syndrome?
Delayed motor milestones
Moderate to severe learning difficulties
Small stature
Increased susceptibility to infection
Hearing impairment from secretory otitis media
Visual impairment from cataracts, squints, myopia
Increased risk of leukaemia and solid tumours
Risk of atlanto-axial instability
Increased risk of hypothyroidism and coeliac disease
Epilepsy
Alzheimer’s disease
What is the main cytogenetic cause of down syndrome?
Meiotic non-disjunction
What are some other chromosomal abnormalities apart from down syndrome?
Edwards syndrome
Patau syndrome
Turner syndrome
What are the clinical features of Edwards syndrome?
Low birthweight Prominent occiput Small mouth and chin Short sternum Flexed, overlapping fingers 'Rocker-bottom' feet Cardiac and renal malformations
What are the clinical features of Patau syndrome?
Structural defect of brain Scalp defects Small eyes (microphthalmia and other eye defects) Cleft lip and palate Polydactyly Cardiac and renal malformations
What are the clinical features of Turner syndrome?
Lymphoedema of hands and feet in neonate, which may persist Spoon-shaped nails Short stature - a cardinal feature Neck webbing or thick neck Wide carrying angle (cubitus valgus) Widely spaced nipples Congenital heart defects (coarctation of the aorta) Infertility Hypothyroidism Renal anomalies Pigmented moles Recurrent otitis media Delayed puberty Normal intellect function in most
How do you treat Turners syndrome?
Growth hormone therapy
Oestrogen replacement for development of secondary sexual characteristics at the time of puberty
What are the clinical features of Klinefelter syndrome?
Infertility Hypogonadism with small testes Pubertal development may appear normal Gynaecomastia in adolescence Tall stature Intelligence usually in the normal range, but some have educational and psychological problems
What is Mendelian inheritance?
The transmission of inherited traits or diseases caused by variation in a single gene in a characteristic pattern.
What are some examples of autosomal dominant disorders?
Ehlers-Danlos syndrome Familial hypercholesterolaemia Huntington disease Marfan syndrome Myotonic dystrophy Neurofibromatosis Osteogenesis imperfects
What is the most common mode of Mendelian inheritance?
Autosomal dominant
Chromosomally, how would you summarise autosomal dominant inheritance?
Affected individual carries the abnormal gene on one of a pair of autosomes
What are the chances of inheriting the abnormal gene from an affected parent in autosomal dominant inheritance?
1 in 2 chance, 50%. But there may be variation in expression (severity), non-penetrance, no family history (new mutation, parental mosaicism, non-paternity)
What is non-penetrance?
It refers to the lack of clinical signs and symptoms in an individual who has inherited the abnormal gene.
What is parental mosaicism?
A healthy parent harbours the mutation only in some of their cells e.g. in their gonads
What are some examples of autosomal recessive disorders?
Congenital adrenal hyperplasia Cystic fibrosis Freidreich ataxia Sickle cell disease Thalassaemia
Chromosomally, how would you summarise autosomal recessive inheritance?
Affected individuals are homozygous for the abnormal gene, each unaffected parent will be a heterozygous carrier
What is the risk of two carrier parents having an affected child in an autosomal recessive disease?
1 in 4 risk. Risk of these disorders is increased by consanguity and within specific populations
What sort of pathways do autosomal recessive disorders usually affect?
Autosomal recessive disorders often affect metabolic pathways, whereas autosomal dominant disorders often affect structural proteins
How does X-linked recessive inheritance affect males and females?
Males are affected.
Females can be carriers but are usually healthy or have mild disease
How would offspring be affected in an X-linked recessive disorder?
Each son of a female carrier had a 50% risk of being affected.
Each daughter of a female carrier has a 50% risk of being a carrier.
Daughters of affected males will all be carriers
Sons of affected males will not be affected.
What are trinucleotide repeat expansion mutations?
A class of unstable mutations caused by unstable expansions of trinucleotide repeat sequences inherited in Mendelian fashion.
What are some examples of trinucleotide repeat expansion mutations?
Fragile X syndrome
Myotonic dystrophy
Huntington’s disease
Friedrich’s ataxia
What are the clinical features of Fragile X syndrome?
Moderate-severe learning difficulty
Macrocephaly
Macro-orchidism - post pubertal
Characteristic facies (long face, large everted ear, prominent mandible and broad forehead, most evident in affected adults)
Other features - mitral valve prolapse, joint laxity, scoliosis, autism, hyperactivity
What are some examples of X-linked recessive disorders?
Colour blindness
Duchenne and Becker muscular dystrophy
Fragile X syndrome
Why do mitochondrial disorders present in variable fashion?
The mutation may be present in all or only some of the mitochondria, so that the tissues affected and the severity of the condition can be highly variable
What is imprinting?
It has been shown that the expression of some genes is influenced by the sex of the parent who has transmitted it. This phenomenon is called ‘imprinting’. An example is Prader-Willi syndrome
What is a malformation?
A primary structural defect occurring during the development of a tissue or organ, e.g. spina bifida, cleft lip and palate
What is a deformation?
Implies an abnormal intrauterine mechanical force that distorts a normally formed structure, e.g. joint contractures or pulmonary hypoplasia due to fetal compression caused by severe oligohydramnios.
What is a disruption?
Involves destruction of a fetal part which initially form normally e.g. amniotic membrane rupture may lead to amniotic bands which cause limb reduction defects
What is a dysplasia?
Refers to abnormal cellular organisation or function of specific tissue types e.g. skeletal dysplasia, dysplastic kidney disease
What is a single-system defect?
Single congenital malformations, such as spina bifida, which are often multifactorial in nature with fairly low recurrence rates
What are some pathogenic mechanisms?
Malformation
Deformation
Disruption
Dysplasia
What are some clinical classifications of birth defects?
Single-system defects
Sequence
Association
Syndrome
What is a sequence?
A pattern of multiple abnormalities occurring after one initiating defect.
What is an association?
A group of malformations that occur together more often than expected by chance, but in difference combinations from case to case.
What is a syndrome?
A particular set of multiple anomalies occurs repeatedly in a consistent pattern and there is known or thought to be a common underlying causal mechanism.
What are some reasons for performing a genetic investigation?
Confirmation of clinical diagnosis
Detection of female carriers in X-linked disorders
Carrier detection in autosomal recessive disorders
Presymptomatic diagnosis in autosomal dominant disorders
Antenatal diagnosis of an increasing number of Mendelian conditions
What are the main aims of genetic counselling for the parents?
To understand their situation
To make their own decisions about managing the disease or risk of disease
To adjust to their situation of being affected by or at risk of the condition
What are the influences on decisions regarding options for genetic counselling?
Magnitude of risk
Perceived severity of disorder
Availability of treatment
Person’s experience of the disorder
Family size
Availability of a safe or reliable prenatal diagnostic test
Parental cultural, religious or ethical values
When should pre-symptomatic testing not be given?
It should not be performed until the individual can give informed consent
