Cytogenetics and Aneuploidy

Question 1

Trisomy 21

Question 2

Trisomy 13

Question 3

Trisomy 18

Question 4

The only trisomies compatible with live birth

Answer 4

13, 18, and 21

Question 5

Klinefelter Syndrome

Answer 5

XXY Syndrome

Question 6

Turner Syndrome

Answer 6

XO

The only monosomy compatible with life. Often diagnosed when female patients fail to go into puberty or have gonadal failure. ~1/2000 births

Short stature as a result of haploinsufficiency of SHOX.

Question 7

Aneuploidy is the result of ____% of miscarriages.

Answer 7

Aneuploidy is the result of >60% of miscarriages.

Question 8

5p^-

Answer 8

Cri du Chat Syndrome

Missing the short arm of chromosome 5 on one copy.

Question 9

Philidelphia chromosome karyotype

Answer 9

Translocation between chromosome 9 and 22.

Causative for chronic myelogenous leukemia (CML)

Question 10

Nonallelic homologous recombination

Answer 10

Question 11

NAHR duplication and deletion pair for PMP22

Answer 11

Question 12

Pericentric Inversions

Answer 12

Span a centromere

The type that you may see in clinic.

Often result in haploinsufficiency of certain genes and triplicate copies of others.

Question 13

Paracentric Inversions

Answer 13

Do not span a centromere

Either lead to normal chromosomes or extremely unstable chromosomes that will not give gametes.

Question 14

Ring Chromosomes

Answer 14

Due to homology at ends (likely telomeres)

Cuts off the very ends of the chromosome and creates a ring structure with one centromere.

Question 15

Balanced Translocation

Answer 15

Likely will go unnoticed in the proband, but descendants are likely to have dosage abnormalities.

Question 16

Note to self:

Go over BC Genetics textbook on inversion cross-over and meiosis.

Question 17

Robertsonian Translocation

Answer 17

Acrocentric chromosomes have very little information on the p-arm, and as a result the p-arm is mostly telomere.

Because of this, acrocentric chromosomes are more prone to becoming stuck to one another via the telomeres. This may result in a Robertsonian Translocation, where the short arms of two chromosomes break off and a hybrid chromosome is formed from the longer (q) arms.

The acrocentric chromosomes 14 and 21 are particularly vulnerable to Robertsonian translocations.

Question 18

Metacentric vs Submetacentric vs Acrocentric

Answer 18

Refers to relative location of centromere.

Question 19

Karyotyping may test for. . .

Answer 19

Aneuploidy or other large chromosomal deletions, inversions, or translocations.

Karyotyping misses all of the smaller-scale genetic changes.

Question 20

Array Cytogenetic H (Array CGH)

Answer 20

Test for copy number of DNA. Patient DNA and control healthy DNA are labeled with different fluorophores, then subjected to an array of genetic probes that hybridize with certain genes. If the copy number is the same, the fluorescence intensity will be the same. If the patient DNA fluoresces more, there is an extra copy of something. If less, there has been a deletion.

May test for changes in chromosomal number or smaller deletions and duplications than may be detected by karyotype.

However, it misses many point mutations, and all inversions and translocations. It will also miss very small scale deletions and duplications.

Question 21

Fluorescent In-Situ Hybridization tests for. . .

Answer 21

Deletions, translocations, and inversions.

It misses point mutations and small deletions.

Utilizes a control probe to hyridize near the centromere of the target chromosome, then an experimental probe which hybridizes on the target gene.

Question 22

Syndrome

Answer 22

Question 23

Dysmorphology

Answer 23

Search for bbnormal physical findings, often part of a genetic syndrome.

Takes into account multiple “minor malformations”, but in any healthy invidual one or two are expected.

Question 24

Marfan Syndrome

Answer 24

Aortic root dilation may lead to aortic dissection (rupture) and sudden death.

Arachnodactyly: long fingers.

Mutation in FBN1, which encodes fibrulin-1, a structural protein that plays a rule in TGF-beta signaling. Loss of FBN1 disrupts the TGF-beta signaling pathway.

Autosomal dominant.

Question 25

19 year old, male college freshman, 6' 3", wants to play intermural basketball. On physical exam, presents with long fingers and loose joints. Grandfather died suddenly at age 54 from a "heart problem." What is the diagnosis? What steps should be taken?

Answer 25

Diagnosis: Marfan syndrome Steps: Sequence FBN1, echocardiogram to look for aortic root dilation. Keep on monitor for heart issues. If necessary, place on therapy to prevent aortic dissection.

Question 26

19 year old, male college freshman, 6' 3", wants to play intermural basketball. Passed out suddenly last week playing basketball. Normal hands and joints on physical exam. Grandfather died suddenly at age 54 from a "heart problem." What is the diagnosis? What steps should be taken?

Answer 26

Obtain an electrocardiogram (ECG) to check for prolonged QT interval. If so, diagnose with **Long QT Syndrome**. Long QT Syndrome is typically caused by ion channel mutations. Order sequencing of ion channel genes. -\> find a mutation in ***KCNQ1***. Test other family members. -\> Father is also affected. Place both on **beta-blockers**, father considered for implantable defribrillator.

Question 27

Patient presents with missing index finger on both hands upon physical exam. Patient of short stature with noticeable craniofacial dysmorphology. What is the potential diagnosis? What steps should be taken?

Answer 27

Potential diagnosis: **Diamond Blackfan Anemia** Do a blood test for macrocytic anemia **25%** of patients have a mutation in ***RPS19***, most others have mutations in other **ribosomal genes**. ***RPL5*** and ***RPL11*** more often cause malformations. (don't need to remember 5 and 11)

Question 28

Aniridia

Answer 28

No iris, all pupil.

Question 29

Four year-old child comes into clinic with patients due to concerns over recent haematuria. Physical exam reveals asymetrical lump on right side of abdomen, as well as aniridia. Heart and lung function normal. Patient is well-nourished and GI function appears normal. What is the diagnosis? What steps should be taken?

Answer 29

Diagnosis: **Wilms' tumor and associated aniridia** Steps: Order sequencing of ***PAX6*, *BDNF*,** and ***WT1***. Order CT scan to visualize tumor. **Nephrectomy** likely a necessity, with post-operative antibiotics. Discussion: ***Wilms' tumor gene 1*** lies close to ***BDNF*** ***and PAX6***, the human equivalent of the D. melanogaster ***eyeless,*** on chromosome 11, and they are often deleted together. Deletion of ***WT1*** results in high likelihood of heritable pediatric kidney tumor. Patients with ***BDNF*** mutations are at risk for severe obesity in adulthood.

Question 31

Fragile X Syndrome and Anticipation-pattern Inheritance

Answer 31

One of the most common causes of intellectual disability in males. Caused by **triplet repeat** on X chromosome. Mostly recessive, partially penetrant. Disease is increasingly severe and penetrant as generations go by. -\> **Anticipation** Unaffected carriers carry a "**premutation**", a triplet repeat, which progresses into worse mutations, longer triplet repeats, after multiple waves of reproduction. **In the case of triplet repeats, the longer they are, the less stable they are during replication, and they get longer with each generation.**