Genetics Flashcards
Define Lyonization
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?
1:70
What is incidence of autosomal recessive kidney disease?
1:20 000
What type of inheritance does this pedigree demonstrate?
What are the characteristics of this type of inheritance?
Autosomal Dominant
- 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.
Aneuploid
What syndrome does this girl have and what are the features?
- 1:2500
- Normal intelligence
- 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
- Low hairline
- Shield chest with wide spaced nipples
- Cubitus valgus
- 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.
- Fertility normal
- 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
- Brachycephaly
- Eyes - upslanting palpebral fissures, epicanthic folds, Brushfield spots on the iris
- Protruding tongue
- Hands - single palmar crease, fifth finger clinodactly
- Feet - wide sandal gap b/w first and second toes
- Hypotonia
- 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.
- Hypothyroidism
- 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
Remember CATCH-22
Cardiac Abnormality (esp TOF)
Abnormal facies
Thymic aplasia
Cleft palate
Hypocalcemia/Hypoparathyroidism.
Williams syndrome is due to microdeletions involving the elastin gene on chromosome 11. What are the features of this syndrome?
- Supravalvular aortic stenosis
- Hypercalcaemia
- Stellate irides
- Learning disability
- Characteristic facial appearance
What is this syndrome and what are the characteristic facial features?
Williams Syndrome
- 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.
What is this syndrome and what are the typical facial features?
Fragile X
- Relative macrocephaly (head circumference >50th percentile for age and sex)
- Strabismus
- Pale blue irises
- Midface hypoplasia with sunken eyes
- Prominent forehead and jaw
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?
Noonans Syndrome
- Hypertelorism
- Broad forehead
- Ptosis
- 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?
CHARGE 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?
Alagille 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
You see a child with multiple cafe au lait patches and axillary freckling. Below is an image of what is seen on slit lamp examination.
What is his diagnosis and what is the diagnostic criteria?
Neurofibromatosis (NF-1)
Diagnostic criteria is any two of the following 7:
- Six or more café-au-lait macules
- >5 mm in prepubertal
- >15 mm in postpubertal
- Café-au-lait spots are the hallmark of neurofibromatosis and are present in almost 100% of patients.
- Axillary or inguinal freckling.Usually appears between 3 and 5 yr of age. (Frequency >80% by 6 yr of age).
- Two or more iris Lisch nodules (image shown)
- Two or more neurofibromas or 1 plexiform neurofibroma.
- A distinctive osseous lesion
- Optic glioma
- A first-degree relative with NF-1 whose diagnosis was based on the aforementioned criteria
NF-1 is autosomal dominant and has an incidence of 1 in 3000. It is the more common of NF-1 and NF-2.
This child has an autosomal dominant disorder caused by mutations in the fibrillin-1 gene on chromosome 15.
The incidence of this disorder is about 1/5,000-10,000 births. About 30% of cases are sporadic, due to de novo mutations; new mutations often associate with advanced paternal age.
He is diagnosed with a multisystem disorder. What is his diagnosis and what are the clinical features of this syndrome?
Marfan Syndrome
Musculoskeletal
- Tall stature with disproportionately long limbs (dolichostenomelia)
- Characteristic facial appearance
- Arachnodactyly
- Pectus carinatum or excavatum
- Scoliosis
- High, narrow arched palate with dental overcrowding
- Pes planus
Heart
- Aortic root dilatation and dissection
- Mitral valve prolapse
Eyes
- Lens dislocation (ectopia lentis)
- Myopia
Skin
- Striae
Lungs
- Spontaneous pneumothorax
- Apical bullae
A 6 year old boy was brought in to see you for easy bruising and delayed wound healing and abnormal scarring. While examining him, he is proud to show you his flexible thumb (image).
What is his diagnosis?
What are the features of this syndrome?
Ehlers Danlos Syndrome
A group of genetically heterogeneous connective tissue disorders.
Clinical features:
- appear normal at birth
- skin hyperelasticity
- fragility of the skin and blood vessels
- delayed wound healing
- joint hypermobility
The essential defect is a quantitative deficiency of fibrillar collagen.
There are 6 clinical forms, 4 are autosomal dominant and 2 are autosomal recessive.
- Classic
- Hypermobile
- Vascular
- Kyphoscoliosis (AR)
- Arthrochalasia
- Dermatospraxis (AR)
Stickler Syndrome is an Autosomal Dominant connective tissue disorder related to Marshall Syndrome and may include a Pierre Robin sequence.
What are the clinical features of Stickler Syndrome?
- Characteristic orofacial and ophthalmologic abnormalities, deafness, and arthritis
- Flat midface with a depressed nasal bridge, short nose, anteverted nares, and micrognathia.
- Midline cleft palate can occur, and ranges in severity from a cleft in the soft palate to the Pierre Robin sequence
- Abnormal architecture of the vitreous gel is pathognomonic of this disorder, and is usually associated with high myopia.
- Retinal detachment occurs frequently.
- Joint hypermobility is present in infancy and decreases with age.
- Osteoarthritis in the third or fourth decade.
- Sensorineural deafness.
- Mitral valve prolapse may occur.
The child in the image below has been diagnosed with Pierre Robin sequence.
What are the clinical features of Pierre Robin?
- Micrognathia
- Glossoptosis
- Cleft palate
Achondroplasia usually arises as a new mutation to normal parents and behaves like an autosomal dominant trait. It occurs due to mutations in FGFR3 codon 380.
What are the clinical features of achondroplasia?
- Delayed motor milestones, often not walking alone until 18-24 mo (due to hypotonia and large head on normal trunk)
- Normal intelligence unless CNS complications
- Gibbus usually gives way to exaggerated lumbar lordosis after starting to walk
- Large heads (few with hydocephalus)
- Stenotic spinal canal with possible spinal cord compression at foramen magnum and lumbar spine
Compression at foramen magnum usually occurs in infants and small children. It may be associated with hypotonia, failure to thrive, quadriparesis, central and obstructive apnea, and sudden death. Surgical correction may be required for severe stenosis
What is the diagnosis?
What are the characteristic facial features?
Myotonic dystophy
- Facial weakness
- Inverted V-shaped upper lip
- Thin cheeks
- Loss of muscle mass in temporal fossa
This 11 year old girl presents with increasing numbers of erythematous papules on her cheeks. There has been no improvement with oral tetracycline and topical benzyl peroxide gel.
What is this disease and how do you treat it?
Angiofibromas from Tuberous Sclerosis Complex.
Improvement using CO2 laser treatment.
2008A Q15
This family presents due to an apparent familial predisposition to a disorder.
What is the most likely explanation for the apparent normal health of II:1?
A. Anticipation.
B.Imprinting.
C.Non-paternity.
D. Non-penetrance.
E. X-linked inheritance.
D. Non-penetrance.
I:1 and his wife I:2 are screened for Tay Sachs and are both found to be carriers. The children have not been tested. The frequency for the heterozygous state in the population these people are from is 1:30.
What is the chance of the fetus at III:1 will be affected?
1 in 180.
Person II:2 has a 2/3 chance of being a carrier (since not affected so not 2/4).
Person II:3 has a 1/30 chance of being a carrier (population frequency).
The fetus has a 1/4 chance of being affected if both parents are carriers.
So 2/3 X 1/30 X 1/4 = 2/360
2/360 = 1/180
(to multiple fractions, multiply all top numbers, and multiply all bottom numbers)
What kind of inheritance is this?
What are the key features?
Mitochondrial inheritance
Passed on from mother b/c sperm contribute no mitochondria.
Passed on from mother to both male and female offspring.
Affected male CANNOT pass onto offspring
A 12-year-old boy is referred for investigation of a first episode of acute psychosis. He has a past history of mild developmental delay, with recent psychometric testing indicating that he is functioning in the borderline range of intellectual handicap. He had a small ventricular septal defect identified in infancy, for which surgical correction was not required. His facial features are shown in the photograph below:
What is the most likely diagnosis?
Velocardiofacial syndrome
Features suggestive of VCFS (22q11 deletion syndrome) include
- mild developmental delay/intellectual disability,
- ventricular septal defect and
- psychosis.
The deletion on chromosome 22q11.2 found in VCFS is 80 times more common in adults with schizophrenia and 240 times more common in childhood-onset schizophrenia
The photograph shows tubular nose, widened nasal tip, small palpebral fissures, minor structural ear abnormality.
Describe Smith-Lemli-Opitz Syndrome
Smith-Lemli-Opitz Syndrome
- autosomal recessive disorder caused by a defect in cholesterol biosynthesis.
- elevated serum cholesterol precursor (7-dehydrocholesterol), as well as low blood cholesterol levels.
Cholesterol is both a major component of myelin and contributes to signal transduction in the developing nervous system, therefore low levels of cholesterol can cause severe neurodevelopmental impairment.
It is unclear how impaired cholesterol synthesis causes congenital malformations, but there are many phenotypic features commonly found in these children including pre and postnatal growth retardation, structural organ anomalies (cardiac, GI, renal, genital), dysmorphism (low set ears, ptosis, broad nasal tip with anteverted nares, 2-3 toe syndactyly, postaxial polydactyly), cleft palate, intellecutal impairment and seizures
A four-year-old boy has global developmental delay. He has a past history of severe gastrooesophageal reflux in infancy. His facial appearance and the appearance of his hands are shown below.
What is the most likely diagnosis?
Cornelia de Lange syndrome
Cornelia de Lange syndrome is characterised by pre- and postnatal growth retardation, distinctive facial features and upper limb defects, which range from mild phalangeal abnormalities to oligodactyly (missing digits). The boy in this picture has the typical facial features – synophyrys (unibrow), long eyelashes, short upturned nose, thin downturned upper lip and missing fingers. His history of severe gastro-oesophageal reflux disease is typical of the condition. Almost all children have cognitive impairment with many being severely affected.
