Inactivation of one X chromosome
Horizontal transmission is characteristic of what type of inheritance?
Autosomal recessive. Multiple affected family members in same generation but none in other generations. Males and females equally affected.
What is the carrier frequency of PKHD1 gene that leads to autosomal recessive kidney disease?
What is incidence of autosomal recessive kidney disease?
What type of inheritance does this pedigree demonstrate?
What are the characteristics of this type of inheritance?
- Vertical pattern of transmission
- Can appear in multiple generations
- 50% recurrence risk
- Males and females equally affected
- Male-to-male transmission (can occur with y linked also, but rare)
What is incomplete penetrance
Carrying mutation without phenotypic manifestations. Can appear as a skipped generation.
What is variable expression?
Manifesting a disorder to varying degrees.
What is a somatic mutation?
Spontaneous genetic mutation in a cell in the developing embryo.
A karyotype with too many, or too few chromosomes where the total is not a multiple of 23.
What syndrome does this girl have and what are the features?
Streak ovaries - failure of menstruation, low oestrogen, high gonadotrophins and infertility.
Normal secondary sexual characteristics may develop normally or be induced with oestrogens.
Uterus is usually normal and pregnancy possible with donated ova.
Short stature throughout childhood with failure of pubertal growth spurt.
Webbed or short neck
Shield chest with wide spaced nipples
Cardiovascular abnormalities (esp aortic coarc in 10-15%)
Renal anomalies (horseshoe, duplicated ureters, aplasia) in 1/3
Non pitting lymphoedema on 1/3
Features of triple x syndrome
1:1000 live-born girls
Little phenotypic abnormality but tend to be tall
Intelligence in normal or low-normal range but reduced cf siblings
Mild developmental and behavioural difficulties are more common.
Increased incidence of early menopause
Features of Klinefelter syndrome (47,XXY)
1:600 live-born boys
Phenotypic abnormalities rare prepubertally
Tend to be tall
Spontaneous expression of secondary sexual characteristics is variable
Poor growth of facial and body hair
Testes are small & assoc w/ azoospermia
Testosterone production is around 50% of normal and gonadotrophins are raised.
Gynaecomastia in 30%
Increased risk of male breast cancer
Female distribution of fat and hair and high pitched voice common but not typical.
Intelligence in normal or low-normal range but reduced cf siblings
Mild developmental and behavioural problems are more common.
Phenotypic features of Trisomy 21
Eyes - upslanting palpebral fissures, epicanthic folds, Brushfield spots on the iris
Hands - single palmar crease, fifth finger clinodactly
Feet - wide sandal gap b/w first and second toes
Moderate learning difficulty
Genetics of trisomy 21
1 in 700 live births
Secondary to meotic non dysjunction during oogenesis, more common with increasing maternal age
3% have detectable mosaicism usually resulting in milder phenotype
Common systems problems in trisomy 21
Cardiovascular malformations 40%, esp AV septal defects
GI abnormalities 6%, esp duodenal atresia and Hirschprungs Disease
Haem abnormalities esp ALL, AML and transient leukaemias.
Cataracts in 3%
Alzheimer's disease in majority by 40 years.
What are features of the microdeletion syndrome 22q11?
AKA DiGeorge syndrome
- Parathyroid gland hypoplasia with with hypocalcaemia
- thymus hypoplasia with t-lymphocyte deficiency
- congenital cardiac malformations esp interrupted aortic arch and truncus arteriosis
- cleft palate
- learning disability
- Increased incidence of psychiatric disorders esp schizophrenia
Cardiac Abnormality (esp TOF)
Williams syndrome is due to microdeletions involving the elastin gene on chromosome 11. What are the features of this syndrome?
Supravalvular aortic stenosis
Characteristic facial appearance
What is this syndrome and what are the characteristic facial features?
- Sunken nasal bridge
- Periorbital puffiness
- Epicanthic folds visible
- Stellate irides
- Long philtrum
- Small and widely spaced teeth
- Wide mouth
- Prominent lower lip
- Small chin
What is the risk of having another child with trisomy 21?
1% above maternal age related risks
Age 36, background risk is 0.5%
Parents with a Robertsonian translocation involving chromosome 21 have a much higher recurrence risk.
Mutations in the tumor suppressor gene APC (adenomatous polyposis coli) may result in what?
Familial adenomatous polyposis and potentially Colorectal CA
A mutation to the gene NF1 on the long arm of chromosome 17 is likely to result in which disorder?
Neurofibromatosis type 1. NF1 causes non cancerous lumps. Often assoc w/ scoliosis, learning difficulties, eye problems and epilepsy.
p53 is located on the short arm of chromosome 17. What is the significance of this gene?
Known as the "guardian of the genome" p53 is a tumour suppressor protein which regulates the cell cycle. More than 50% of human tumours have a mutation or suppression of p53.
How does the RB1 protein on 13q14.1-14.2 prevent excessive cell growth?
RB1 is a tumour suppressor gene that inhibits cell cycle progression until the cell s ready to divide. Mutation in this gene results in retinoblastoma.
Other cancers associated with mutations in this gene include bladder cancer, lung cancer, breast cancer, osteosarcoma, melanoma.
A loss of function mutation of the RET proto-oncogene results in what disease?
A gain of function mutation of the RET proto-oncogene results in what disease
MEN 2a& 2b carcinomas
Medullary thyroid carcinoma
What is this syndrome and what are the typical facial features?
1. Relative macrocephaly (head circumference >50th percentile for age and sex)
3. Pale blue irises
4. Midface hypoplasia with sunken eyes
5. Prominent forehead and jaw
Noonan syndrome is an autosomal dominant disorder that has a birth incidence of 1 in 1000-2500 live births. It may present in utero with fetal nuchal oedema.
What are the main features of Noonan Syndrome?
Short neck with webbing or redundancy of skin
Characteristic chest deformities - pectus carinatum superiorly and pectus excavatum inferiorly, broad chest with wide spaced nipples
Self-limited feeding problem (25%)
PS, HCMO, VSD, ASD, TOF
- PS, HCMO, VSD, ASD, TOF
This child has an autosomal dominant syndrome and on presentation has short stature, a webbed neck, a cardiac murmur and pectus carinatum.
What is the syndrome and what are the classic facial features?
- Broad forehead
- Down-slanting eyes in infancy
- epicanthic folds
- posteriorly rotated ears
- Characteristic cupids bow upper lip
This boy has atresia choanae and genital hypoplasia. He has been found to have a new mutation of the CHD7 gene on chromosome 8. What sydrome does he have and what are all the features of this syndrome?
C - Colobomas
H - Heart malformations
A - Atresia of the choanae
R - Retardation of growth and development
G - Genital hypoplasia
E - Ear abnormalities (of pinna, deafness)
Cleft lip/palate abnormalities are also common.
This girl was found to have icteric sclera and posterior embryotoxon. You diagnose her with an autosomal dominant syndrome which results from deletions or mutations in the JAG1 gene on chromosome 20.
What is her diagnosis and what are the features of this syndrome?
- Hepatic - cholestatic jaundice, paucity of intrahepatic bile ducts
- Cardiac - peripheral pulmonary stenosis +/- complex malformations
- Eye - posterior embryotoxon (image shown), abnormalities of the anterior chamber
- Vertebral - butterfly vertebrae, hemivertebrae, rib anomalies