Cytogenetics and Aneuploidy Flashcards
Trisomy 21
Trisomy 13
Trisomy 18
The only trisomies compatible with live birth
13, 18, and 21
Klinefelter Syndrome
XXY Syndrome
Turner Syndrome
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.
Aneuploidy is the result of ____% of miscarriages.
Aneuploidy is the result of >60% of miscarriages.
5p-
Cri du Chat Syndrome
Missing the short arm of chromosome 5 on one copy.
Philidelphia chromosome karyotype
Translocation between chromosome 9 and 22.
Causative for chronic myelogenous leukemia (CML)
Nonallelic homologous recombination
NAHR duplication and deletion pair for PMP22
Pericentric Inversions
Span a centromere
The type that you may see in clinic.
Often result in haploinsufficiency of certain genes and triplicate copies of others.
Paracentric Inversions
Do not span a centromere
Either lead to normal chromosomes or extremely unstable chromosomes that will not give gametes.
Ring Chromosomes
Due to homology at ends (likely telomeres)
Cuts off the very ends of the chromosome and creates a ring structure with one centromere.
Balanced Translocation
Likely will go unnoticed in the proband, but descendants are likely to have dosage abnormalities.
Note to self:
Go over BC Genetics textbook on inversion cross-over and meiosis.
Robertsonian Translocation
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.
Metacentric vs Submetacentric vs Acrocentric
Refers to relative location of centromere.
Karyotyping may test for. . .
Aneuploidy or other large chromosomal deletions, inversions, or translocations.
Karyotyping misses all of the smaller-scale genetic changes.
Array Cytogenetic H (Array CGH)
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.
Fluorescent In-Situ Hybridization tests for. . .
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.
Syndrome
Dysmorphology
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.
Marfan Syndrome
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.
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?
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.
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?
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.
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?
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)
Aniridia
No iris, all pupil.
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?
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.
Fragile X Syndrome and Anticipation-pattern Inheritance
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.
