Biochem - Genetics (Special genetic disorders)

Question 1

What are 4 examples of trinucleotide repeat expansion diseases?

Answer 1

(1) Huntington disease (2) Myotonic dystrophy (3) Friedreich ataxia (4) fragile X syndrome; Think: “Try (trinucleotide) Hunting for My Fried Eggs (X)”

Question 2

What is the trinucleotide repeat sequence of Fragile X syndrome?

Answer 2

Fragile X syndrome = (CGG)n

Question 3

What is the trinucleotide repeat sequence of Freiderich ataxia?

Answer 3

Friedreich ataxia = (GAA)n

Question 4

What is the trinucleotide repeat sequence of Huntington disease?

Answer 4

Huntington disease = (CAG)n

Question 5

What is the trinucleotide repeat sequence of Myotonic dystrophy?

Answer 5

Myotonic dystrophy = (CTG)n

Question 6

What genetic term/property may apply to trinucletoide repeat expansion diseases?

Answer 6

May show genetic anticipation (disease severity increases and age of onset decreases in successive generations)

Question 7

Name the 4 trinucleotide repeat expansion diseases and give the specific repeat sequence of each.

Answer 7

(1) Fragile X syndrome = (CGG)n (2) Friedreich ataxia = (GAA)n (3) Huntington disease = (CAG)n (4) Myotonic dystrophy = (CTG)n; Think: “X-Girlfriend’s First Aid Helped Ace My Test”

Question 8

Name 3 Autosomal trisomies.

Answer 8

(1) Down syndrome (trisomy 21) (2) Edwards syndrome (trisomy 18) (3) Patau syndrome (trisomy 13)

Question 9

What is the genetic defect in Down syndrome? What are the chances of a patient having this condition?

Answer 9

Down syndrome (trisomy 21), 1:700; Think: “Drinking age (21)”

Question 10

What is the genetic defect in Edwards syndrome? What are the chances of a patient having this condition?

Answer 10

Edwards syndrome (trisomy 18), 1:8000; Think: “Election age (18)”

Question 11

What is the genetic defect in Patau syndrome? What are the chances of a patient having this condition?

Answer 11

Patau syndrome (trisomy 13), 1:15,000; Think: “Puberty (13)”

Question 12

What are 9 clinical findings of Down syndrome?

Answer 12

Findings: (1) intellectual disability (2) flat facies (3) prominent epicanthal folds (4) single palmar crease (5) gap between 1st 2 toes (6) duodenal atresia (7) Hirschsprung disease (8) congenital heart disease (most commonly ostium primum-type atrial septal defect [ASD]) (9) Bruschfield spots.

Question 13

What are 3 conditions for which Down syndrome patients have an increased risk?

Answer 13

Associated with increased risk of ALL, AML, and Alzheimer disease (> 35 years old).

Question 14

What chromosomal event causes most Down syndrome cases? What percentage of cases does it cause? With what factor is this event associated, and what are the related statistics?

Answer 14

95% of cases due to meiotic nondisjunction of homologous chromosomes (associated with advanced maternal age; from 1:1500 in women < 20 to 1:25 in women > 45 years old).

Question 15

What are 2 less frequently occurring (than meiotic nondisjunction of homologous chromosomes) events that cause Down syndrome? What percentage of cases does each of these cause?

Answer 15

4% of cases due to Robertsonian translocation; 1% of cases due to mosaicism (no maternal association; post-fertilization mitotic error)

Question 16

What is the most common viable chromosomal disorder? Of what else is this the most common cause?

Answer 16

Down Syndrome; Most common viable chromosomal disorder and most common cause of genetic intellectual disability

Question 17

What does first-trimester ultrasound of Down syndrome baby commonly show?

Answer 17

Increased nuchal translucency and hypoplastic nasal bone

Question 18

What are 2 lab findings associated with Down syndrome in the first-trimester?

Answer 18

(1) serum PAPP-A is low (2) free beta-hCG is high

Question 19

What 4 findings does second-trimester quad screen show in Down syndrome?

Answer 19

Second-trimester quad screen shows: (1) low alpha-fetoprotein, (2) high beta-hCG, (3) low estriol, (4) high inhibin A

Question 20

What are 7 clinical findings associated with Edwards syndrome?

Answer 20

Findings: (1) severe intellectual disability (2) rocker-bottom feet (3) micrognathia (small jaw) (4) low-set ears (5) clenched hands (6) prominent occiput (7) congenital heart disease

Question 21

What is the usual prognosis/outcome of Edwards syndrome?

Answer 21

Death usually occurs within 1 year of birth

Question 22

What are 8 clinical findings associated with Patau syndrome?

Answer 22

Findings: (1) severe intellectual disability (2) rocker-bottom feet (3) microphthalmia (4) microcephaly (5) cleft liP/Palate (5) holoProsencephaly (6) Polydactyly (7) congenital heart disease

Question 23

What is the usual prognosis/outcome of Patau syndrome? What other autosomal trisomy condition shares this?

Answer 23

Death usually occurs within 1 year of birth; Edwards syndrome

Question 24

What is the second most common trisomy resulting in live birth? What is the first?

Answer 24

Edwards syndrome is the Most common trisomy resulting in live birth after Down syndrome

Question 25

What are 2 key lab findings in first trimester with Edwards syndrome?

Answer 25

PAPP-A and free beta-hCG are decreased in first semester

Question 26

What are 4 key findings of Edwards syndrome in quad screen?

Answer 26

Quad screen shows: (1) low alpha-fetoprotein (2) low beta-hCG (3) low estriol (4) low or normal inhibin A

Question 27

What 3 findings does first-trimester pregnancy screen show in Patau syndrome?

Answer 27

First-trimester pregnancy screen shows: (1) low free beta-hCG (2) low PAPP-A and (3) high nuchal translucency.

Question 28

Draw visuals depicting nondisjunctions in meiosis I versus meiosis II.

Answer 28

See p. 90 in First Aid 2014 for visuals at bottom of page

Question 29

What is Robertsonian translocation? What 5 chromosome pairs does it commonly involve?

Answer 29

Nonreciprocal chromosomal translocation that commonly involves chromosome pairs 13, 14, 15, 21, and 22.

Question 30

In general, how common is Robertsonian translocation?

Answer 30

One of the most common types of translocation

Question 31

What causes Robertsonian translocation?

Answer 31

Occurs when the long arms of 2 arocentric chromosomes (chromosomes with centromeres near their ends) fuse at the centromere and the 2 short arms are lost

Question 32

What phenotype results from balanced Robertsonian translocation?

Answer 32

Balanced translocations normally do not cause any abnormal phenotype

Question 33

What are 3 consequences unbalanced Robertsonian translocation?

Answer 33

Unbalanced translocations can result in miscarriage, stillbirth, and chromosomal imbalance (e.g., Down syndrome, Patau syndrome).

Question 34

What causes Cri-du-chat syndrome?

Answer 34

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

Question 35

What are 5 clinical findings of Cri-du-chat syndrome?

Answer 35

Findings: (1) microcephaly (2) moderate to severe intellectual disability (3) high-pitched crying/MEWING (4) epicanthal folds (5) cardiac abnormalities (VSD); Think: “Cri du chat = cry of the CAT”

Question 36

What causes Williams syndrome?

Answer 36

Congenital microdeletion of long arm of chromosome 7 (deleted region includes elastin gene)

Question 37

What are 6 clinical findings of Williams syndrome?

Answer 37

Findings: (1) distinstinctive “elfin” facies (2) intellectual disability (3) hypercalcemia (high sensitivity to vitamin D) (4) well-developed verbal skills (5) extreme friendliness with strangers (6) cardiovascular problems

Question 38

Describe the presentation of 22q11 deletion syndromes. Give 5 examples of signs/symptoms.

Answer 38

Variable presentation, including Cleft palate, Abnormal facies, Thymic aplasia –> T-cell deficiency, Cardiac defects, Hypocalcemia secondary to parathyroid aplasia, due to microdeletion at chromosome 22q11; Think: “CATCH-22”

Question 39

What are the genetic and embryological causes of 22q11 deletion syndromes?

Answer 39

Due to microdeletion at chromosome 22q11; Due to aberrant development of 3rd and 4th branchial pouches

Question 40

Give 2 examples of 22q11 deletion syndromes.

Answer 40

(1) DiGeorge syndrome (2) Velocardiofacial syndrome

Question 41

What are 3 signs/symptoms in the presentation of DiGeorge syndrome?

Answer 41

DiGeorge syndrome - thymic, parathyroid, and cardiac defects

Question 42

What are 3 signs/symptoms in the presentation of Velocardiofacial syndrome?

Answer 42

Velocardiofacial syndrome - palate, facial, and cardiac defects