Genetic Diseases

Question 1

Prader-Willi Syndrome
Genetic causse
Symptoms

Answer 1

Genetic cause: Paternal mutation/deletion on chromosme 15 (Maternal imprinting)

**Symptoms: **Hyperphagia, obesity, intellectual disability, hypogonadism, hypotonia

Question 2

Angelman Syndrome
Genetic causes
Symptomology

Answer 2

**Genetic Causes: **Maternal gene is deleted/mutated (Paternal imprinting)

**Symptom: **Inappropriate laughter, seizures, ataxia, severe intellectual disability

Question 3

Duchenne’s muscular dystrophy
Genetic cause
Molecular change
Muscles targeted
Age of onset
Cause of death

Answer 3

**Genetic Cause: **X-linked frameshift truncates dystrophin protein (DMD gene)

Molecular change: Dystrophin dysfunction causing myonecrosis (Cytoskeletal issues)

**Muscles: **Pelvic gridle weakness followed with pseudohypertrophy of calf muscles

Age: 5 years old

**Cause: **Dilated Cardiomyopathy

Question 4

Becker’s Muscular Dystrophy
Genetic Causes
Relative severeity to Duchenne
Onset age

Answer 4

**Genetic cause: **X-linked point mutation

Less severe

**Onset: **Adolescence/early adulthood

Question 5

**Myotonic Type 1 **
Genetic Causes
Molecular cause
Symptoms

Answer 5

**Genetic Causes: **DMPK trinucleotide CTG expansion

**Molecular Causes: **Abnormal expression of the myotonin protein kinase

**Symptoms: **Myotonia, muscle wasting, frontal balding, cataracts, testicular atrophy, arrhythmia

Question 6

Fragile X Syndrome

• *Genetic Cause**
• *Significance**
• *Other symptoms/findings**

Answer 6

**Genetics: **X-linked defect affecting methylation/expression of FMRI due to a trinucleotide repeat disorder

**Significnace: **2nd most common cause of genetic intellectual disabilitiy (after Down syndrome)

**Findings: **Post-pubertal macroorchidism (enlarged testes), long face with a large jaw, large everted ears, mitral valve prolapse

Question 7

What are the 4 trinucleotide repeat expansion disorders? What are their corresponding expansions?

Answer 7

Fragile X Syndrome - CGG
Friedrich ataxia - GAA
Huntington disease - CAG
Myotonic dystrophy - CTG

Question 8

Down syndrome
Genetic cause
Mechanism of genetic cause
Findings
In utero findings

Answer 8

Genetic Cause: **Trisomy 21 (Think Drinking age - 21)

**Mechanism of genetic cause: **95% due to meiotic nondisjunction of homologous chromosomes (especially in older women, 1:25 > 45 yo)
4% due to Robertsonian translocation
1% due to mosaicism (no maternal association, post-fertilization mitotic error)

**Findings: **Intellectual disability, flat facies, prominent epicanthal folds, single palmar crease, gap between 1st 2 toes, duodenal atresia, Hirschsprung disease, congenital heart disease (ASD mainly), Brushfield spots
Increased risk of ALL, AML, and Alzheimer’s disease (>35 yo)

**In utero: **First-trimester US reveals increased nuchal translucency and hypoplastic nasal bone, serum PAPP-A decreased, free B-hCG increased
Second-trimester quad screen shows: Decreased a-fetoprotein, increased B-hCG, decreased estriol, increased inhibin A

Question 9

Edwards Syndrome
Genetic cause
Findings
Age of Death
In-utero findings

Answer 9

Genetic cause: **Trisomy 18 (Think Election age)

**Findings: **Severe intellectual disability, rocker-fbottom feet, micrognathia (small jaw), low-set ears, clenched hands, prominent occiput, congenital heart disease

**Age of death: **Within 1st year of birth

**In-utero: **First trimester - Decreased PAPP-A and free B-hCG
Second-trimester quad screen shows: Decreased a-fetoprotein, B-hCG, estriol, inhibin A (inhibin can also be normal)

Question 10

Patau syndrome
Genetic cause
Findings
Age of death
In-utero

Answer 10

**Genetic Cause: **Trisomy 13 (Think Puberty ** **- 13)

**Findings: **Severe intellectual disability, rocker-bottom feet, microphthalmia, microcephaly, cleft lip/palate, oloprosencephaly, polydactyly, congenital heart disease, death usually occurs within 1 year of birth

**Age of death: **Within 1st year of birth

**In-utero: **First-trimester pregnancy screen shows decreased B-hCG and PAPP-A, increased nuchal translucency

Question 11

Robertsonian translocation
What is it?
Process
When is it problematic?

Answer 11

One of the most common types of nonreciprocal chromosomal translocations involving pairs 13,14,15,21,22 typically

Occurs when the long arms of 2 acrocentric chromosomes fuse at centromere and short arms are lost

Only problematic when unbalanced resulting in miscarriage, stillbirth, chromosomal imbalance (Down’s and Patau)

Question 12

Cri-du-chat syndrome
Genetic cause
Findings

Answer 12

**Genetic cause: **Congenital microdeletion of short arm of chromosome 5 (46,XX or XY,5p-)

Findings: Microcephaly, moderate to severe intellectual disability, high-pitched crying/mewing, epicanthal folds, cardiac abnormalities (VSD)

Question 13

Williams syndrome
Genetic cause
Findings

Answer 13

Genetic causes:** **Congenital microdeletion of long arm of chromosome 7 (deleted region includes elastin gene)

**Findings: **Distinctive “elfin” facies, intellectual disability, hypercalcemia (increased sensitivity to vitamin D), well-developed verbal skills, extreme friendliness with strangers, cardiovascular problems

Question 14

22q11 Deletion Syndromes
What is the pathophysiology?
Presentation
What is DiGeorge syndrome?
What is Velocardiofacial syndrome?

Answer 14

Due to aberrant development of 3rd and 4th branchial pouches

Presentation: CATCH-22
Cleft palate
Abnormal facies
Thymic aplasia (T-cell def)
Cardiac defects
Hypocalcemia (Secondary to Parathyroid aplasia)
Resulting from microdeletion at 22q11

• *DiGeorge Syndrome: **Thymic, parathyroid, and cardiac defects
• *Velocardiofacial syndrome**: Palate, facial, and cardiac defects