Genetics Flashcards Preview

Paeds Exam > Genetics > Flashcards

Flashcards in Genetics Deck (54):

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?



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


  1. Vertical pattern of transmission
  2. Can appear in multiple generations
  3. 50% recurrence risk
  4. Males and females equally affected
  5. 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?

  1. 1:2500
  2. Normal intelligence
  3. Streak ovaries - failure of menstruation, low oestrogen, high gonadotrophins and infertility.
  4. Normal secondary sexual characteristics may develop normally or be induced with oestrogens.
  5. Uterus is usually normal and pregnancy possible with donated ova.
  6. Short stature throughout childhood with failure of pubertal growth spurt.
  7. Webbed or short neck
  8. Low hairline
  9. Shield chest with wide spaced nipples
  10. Cubitus valgus
  11. Cardiovascular abnormalities (esp aortic coarc in 10-15%)
  12. Renal anomalies (horseshoe, duplicated ureters, aplasia) in 1/3
  13. Non pitting lymphoedema on 1/3


Features of triple x syndrome

  1. 1:1000 live-born girls 
  2. Little phenotypic abnormality but tend to be tall
  3. Intelligence in normal or low-normal range but reduced cf siblings
  4. Mild developmental and behavioural difficulties are more common.
  5. Fertility normal
  6. Increased incidence of early menopause


Features of Klinefelter syndrome (47,XXY)

  1. 1:600 live-born boys
  2. Phenotypic abnormalities rare prepubertally
  3. Tend to be tall
  4. Spontaneous expression of secondary sexual characteristics is variable
  5. Poor growth of facial and body hair  
  6. Testes are small & assoc w/ azoospermia
  7. Testosterone production is around 50% of normal and gonadotrophins are raised.
  8. Gynaecomastia in 30%
  9. Increased risk of male breast cancer
  10. Female distribution of fat and hair and high pitched voice common but not typical.
  11. Intelligence in normal or low-normal range but reduced cf siblings
  12. Mild developmental and behavioural problems are more common.


Phenotypic features of Trisomy 21

  1. Brachycephaly
  2. Eyes - upslanting palpebral fissures, epicanthic folds, Brushfield spots on the iris
  3. Protruding tongue
  4. Hands - single palmar crease, fifth finger clinodactly
  5. Feet - wide sandal gap b/w first and second toes
  6. Hypotonia
  7. Moderate learning difficulty


Genetics of trisomy 21

  1. 1 in 700 live births
  2. Secondary to meotic non dysjunction during oogenesis, more common with increasing maternal age
  3. 3% have detectable mosaicism usually resulting in milder phenotype


Common systems problems in trisomy 21

  1. Cardiovascular malformations 40%, esp AV septal defects
  2. GI abnormalities 6%, esp duodenal atresia and Hirschprungs Disease
  3. Haem abnormalities esp ALL, AML and transient leukaemias.
  4. Hypothyroidism
  5. Cataracts in 3%
  6. Alzheimer's disease in majority by 40 years.


What are features of the microdeletion syndrome 22q11?

AKA DiGeorge syndrome

  1. Parathyroid gland hypoplasia with with hypocalcaemia
  2. thymus hypoplasia with t-lymphocyte deficiency
  3. congenital cardiac malformations esp interrupted aortic arch and truncus arteriosis
  4. cleft palate
  5. learning disability
  6. Increased incidence of psychiatric disorders esp schizophrenia

Remember CATCH-22

Cardiac Abnormality (esp TOF)
Abnormal facies
Thymic aplasia
Cleft palate


Williams syndrome is due to microdeletions involving the elastin gene on chromosome 11. What are the features of this syndrome?

  1. Supravalvular aortic stenosis
  2. Hypercalcaemia
  3. Stellate irides
  4. Learning disability
  5. 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.


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?

Hirschprungs disease


A gain of function mutation of the RET proto-oncogene results in what disease

  • MEN 2a& 2b carcinomas
  • Medullary thyroid carcinoma
  • Phaeochromocytoma
  • Parathyroid hyperplasia


What is this syndrome and what are the typical facial features?

Fragile X

1. Relative macrocephaly (head circumference >50th percentile for age and sex)

2. Strabismus

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 stature
  • Short neck with webbing or redundancy of skin
  • Facial dysmorphism
  • Characteristic chest deformities - pectus carinatum superiorly and pectus excavatum inferiorly, broad chest with wide spaced nipples
  • Self-limited feeding problem (25%)
  • Cryptorchidism
  • Learning difficulties
  • Cardiac
  • Bleeding diathesis
  • Leukemia
  • Neuroblastoma
  • Non-Hodgkins Lymphoma


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:

  1. 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. 
  2. Axillary or inguinal freckling.Usually appears between 3 and 5 yr of age. (Frequency >80% by 6 yr of age).
  3. Two or more iris Lisch nodules (image shown)
  4. Two or more neurofibromas or 1 plexiform neurofibroma. 
  5. A distinctive osseous lesion
  6. Optic glioma
  7. 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.


Children 0-10 years age diagnosed with NF-1 should have an annual ophthalmologic review. Why?

Optic gliomas are present in approximately 15% of patients with NF-1 and represent mostly low-grade astrocytomas. They are the main CNS tumor with a marked increased frequency in NF-1.

When they progress, visual symptoms are produced because the tumors enlarge and put pressure on the optic nerves and chiasm resulting in impaired visual acuity and visual fields. Extension into the hypothalamus can lead to endocrine deficiencies or failure to thrive.


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


  • 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


  • Aortic root dilatation and dissection
  • Mitral valve prolapse


  • Lens dislocation (ectopia lentis)
  • Myopia


  • Striae


  • 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.

  1. Classic
  2. Hypermobile
  3. Vascular
  4. Kyphoscoliosis (AR)
  5. Arthrochalasia
  6. 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?

  1. Characteristic orofacial and ophthalmologic abnormalities, deafness, and arthritis
  2. Flat midface with a depressed nasal bridge, short nose, anteverted nares, and micrognathia.
  3. Midline cleft palate can occur, and ranges in severity from a cleft in the soft palate to the Pierre Robin sequence
  4. Abnormal architecture of the vitreous gel is pathognomonic of this disorder, and is usually associated with high myopia.
  5. Retinal detachment occurs frequently.
  6. Joint hypermobility is present in infancy and decreases with age.
  7. Osteoarthritis in the third or fourth decade.
  8. Sensorineural deafness.
  9. 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?

  1. Micrognathia
  2. Glossoptosis
  3. 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


What is the relationship between Turners Syndrome (45,X) and the SHOX gene?

SHOX gene is located on the X-chromosome and is important for long bone growth. Haploinsufficiency of the X chromosome in Turners Syndrome is part of the cause of short stature.


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.


What is Tuberous Sclerosis Complex?

  • autosomal dominant genetic disorder
  • incidence of approximately 1 in 5000 to 10,000 live births.
  • mutations in two separate genes, TSC1 and TSC2. 
  • benign tumors in multiple organs, including the brain, heart, skin, eyes, kidney, lung, and liver.
  • increased risk of malignancy in TSC.
  • characteristic cardiac feature of TSC is a rhabdomyoma
  • Epilepsy is most frequent and significant cause of morbidity.
  • Autism and behaviour problems
  • Learning difficulties


2008A Q9

Cystic fibrosis is an autosomal recessive disorder caused by mutations in a single gene on the long arm of chromosome 7. These mutations lead to abnormal functioning of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a chloride channel in the cell membrane. The most common mutation in the Australasian population is ∆F508.
What is the principal effect of this mutation on the function of CFTR? 

A.Abnormal adenosine triphosphate (ATP) gating of the chloride channel.

B.Abnormal protein folding and thus poor transportation to the cell membrane.

C.Abnormal splicing resulting in reduced amounts of functional protein.

D. Decreased conductance of the chloride channel.

E.Premature transcription termination signals resulting in a truncated or absent protein.



B.Abnormal protein folding and thus poor transportation to the cell membrane.


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.
D. Non-penetrance.
E. X-linked inheritance.


D. Non-penetrance.


2008A Q28

A three-year-old boy is evaluated because of delayed motor milestones. On examination he has muscle weakness with calf hypertrophy. He has a markedly elevated creatine kinase level of 15,400 I/U 
Which of the following is most likely to be found on testing of the dystrophin gene?

A. Deletion of one base pair causing a frameshift.
B. Deletion of several exons.
C. Duplication of several exons.
D. Missense mutation.
E. Splice-site mutation.

B. Deletion of several exons.


Cystic Fibrosis is the most common autosomal recessive disorder. The unaffected sibling of a person with cystic fibrosis wants to know the chance of them being a carrier.

Explain why this is the case.

Chance of being a carrier is 2/3.

In a recessive disorder, 50% chance of being a carrier, 25% chance of being affected and 25% of being unaffected and not carrier.

Remembering that the person is unaffected therefore leaves 3 options, not 4, so it is a 2/3 chance, not 2/4.

(do punnet square and remove affected person, 3 choices left)


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)


If a patient with minimal facial expression shakes your hand and is unable to let go, what diagnosis are you thinking of?

Myotonic dystrophy


Some common triplet repeat disorders include myotonic dystrophy and fragile X syndrome.

What is a triplet repeat disorder?

What can happen with subsequent generations?

Mother has a triplet repeat is a mutation in DNA replication.

As mother passes the gene on, the repeat can get bigger and become more severe with each generation which is known as anticipation.


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


What disorders are associated with defects at chromosome 22q11?

  • Di George syndrome
  • VCFS


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


What is Bardet-Biedl Syndrome?

Bardet-Biedl syndrome is an autosomal recessive disorder characterised by rod-cone dystrophy (>90%), truncal obestiry (72%), post-axial polydactyly, cognitive impairment, cystic renal anomalies and male hypogonadotrophic hypogonadism/complex female genitourinary malformations.


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.