Cytogenetics / Microarrays (TRANSFERRED) Flashcards
Reference: Genetics residents in-training examination - March 2020 (Spring 2020)
What is the role of the XIST gene?
What is the consequence of the heterozygous XIST deletion in women?
X inactivation process.
Biased X inactivation, X chromosome which carries the XIST deletion cannot inactivate, symptomatic XLR genetic conditions if the mutation is on the XIST deleted chromosome.
Reference: Genetics residents in-training examination - March 2020 (Spring 2020)
You have evaluated at 12-month-old child with failure to thrive and mild hypotonia. An array CGH was requested and yielded the following results:
arr[GRch37] 7q31.2(117021908_117406888)x1.
This copy number variation involves, at a minimum, exons 4 to 15 of the CFTR gene.
a. Explain this result.
b. In what context could this result explain your patient’s phenotype?
c. Name two tests that you would recommend to clarify the situation.
a. Heterozygous deletion conferring a carrier state for cystic fibrosis.
b. Since CF is an autosomal recessive condition, a point mutation on the other allele would be necessary.
c. CFTR sequencing
Sweat test
Reference: Genetics residents in-training examination - March 2020 (Spring 2020)
A 26-year-old man comes in for a consultation because he is a carrier of a chromosomal inversion, discovered through familial screening. He has brought a cytogenetic report done at a different hospital centre, which reads: 46,XY,inv(7)(p14.2q36.3). (Total 3 points)
a. What kind of inversion is this?
b. Name two possible unbalanced recombinants while specifying the nature of the imbalance in each case.
c. Name an important criterion with respect to the viability of embryos carrying a chromosomal imbalance.
a. Pericentric inversion
b. Recombinant 1 : deletion 7p14.1->pter and duplication 7q36.3->qter
Recombinant 2 : deletion 7q36.3->qter and duplication 7p14.1->pter
c. The HAL percentage, used in many different kinds of disequilibria. The lower the percentage of HAL involved, the greater the viability.
Reference: Genetics residents in-training examination - March 2020 (Spring 2020)
Name the 5 laboratory steps necessary to obtain chromosomes for analysis using any specimen type.
Initiate cell culture in a medium appropriate to the tissue.
Culture cells for a period of time appropriate to the tissue.
Arrest cell cycle in mitosis with Colcemid.
Extract chromosomes with hypotonic chock and fix cells
Spread on slide.
Stain the chromosomes (GTG or else)
Reference: Genetics residents in-training examination - March 2020 (Spring 2020)
Regarding recurrent chromosomal microdeletion syndromes:
a. What mechanism explains the existence of recurrent chromosomal microdeletion syndromes?
b. Name a recurrent chromosomal microdeletion syndrome and its chromosomal region, as well as 4 key (i.e. frequent) clinical characteristics of this syndrome (other than developmental delay).
a. Non-allelic homologous recombinations in meiosis due to flanking low-copy repeats (LCRs).
b. Answer will vary based on the syndrome chosen.
Reference: Genetics residents in-training examination – Fall 2020
You see a 42-year-old pregnant woman at 16 weeks’ gestation. She had declined prenatal screening in this pregnancy, but had some bleeding and an HCG level and viability scan were done at 15 weeks. The HCG level was relatively high for gestational age, which the patient found reassuring. The ultrasound reports that the fetus is small for gestational age (overall size is less than 5th centile). All the long bones measure about 3 weeks’ behind the confirmed gestational age. The biparietal diameter, head circumference, and abdominal circumference measure about 2-3 weeks behind. The fetal scan is otherwise unremarkable, but the placenta appeared enlarged and multicystic. You suspect a triploid fetus.
A. What makes you suspect this?
B. Do you expect diandric or digynic tripolidy? Why?
C. What is another name for this condition?
D. What are the possible karyotypes for the baby?
E. Are there long-term maternal health concerns related to this finding? How would you manage this?
A. Any of High HCG, enlarged cystic placenta, poor fetal growth, vaginal bleeding, advanced maternal age.
B. Diandric, due to enlarged and cystic placenta.
C. Partial Mole.
D. 69, XXY; 69, XXX; 69, XYY
E. Risk of invasive mole (or gestational trophoblastic disease). Requires follow up after pregnancy by OB/MFM to ensure HCG returns to normal. (Ok to say would refer to OB/MFM for follow up)
Reference: Genetics residents in-training examination – Fall 2020
You receive the microarray results on a newborn female in the Intensive Care Unit presenting with microcephaly, preauricular tag, high-arched palate and a congenital heart defect. Microarray has shown a terminal gains of approximately 18 Mb on the long arm of chromosomes 11 (11q23-qter), and a gain of approximately 3 Mb on the proximal centric portion (22q10-22q11.2) of the long arm of chromosome 22.
a) What is the most probable clinical diagnosis in this patient?
b) What cytogenomic test(s) would you recommend as follow-up and what are you specifically looking for?
c) What is the expected karyotype of the proband?
d) Draw the pachytene diagram from a balanced carrier parent to show the segregation that would lead to this abnormality.
e) List two regions that do not have probe coverage on microarrays and that are relevant to the interpretation of the array results obtained on this newborn.
a) Emanuel syndrome
b) Karyotype or metaphase FISH of the proband and both parents should be recommended. The presence of terminal gain of chromosome 11 and gain of the centric portion of chromosome 22 suggests a supernumerary derivative chromosome 22 from a 3:1 segregation of a parental balanced t(11;22).
c) The proband is expected to have the karyotype: 47,XX,+der(22)t(11;22)(q23;q11.2). Microarray or quantitative PCR on the parents would NOT be appropriate, as these tests do not detect balanced structural rearrangements.
d) Should show 3:1 segregation of a parental balanced t(11;22)(q23;q11.2)
e) The centromeric regions of all chromosomes and the short arms of acrocentric chromosomes do not have probe coverage on clinical microarrays.
Reference: Genetics residents in-training examination – Fall 2020
A patient is referred to genetics at 20 weeks’ gestation for a split hand foot malformation. They proceed with amniocentesis. All testing, including a microarray, shows a normal result. They also have a 4-year-old child with autism, who was found to have a 0.2kb deletion of uncertain clinical significance on microarray 6 months earlier. Parental testing was done and it was paternally inherited. The family is now asking if the prenatal testing is satisfactory in ruling out the variant in the fetus.
- Does the prenatal microarray answer their question?) Why or why not?
- Is there another test that should be offered to clarify the status of the CNV? If so, what?
- No
Prenatal arrays have a higher threshold for reporting CNVs, and therefore this CNV was most likely missed. - It is a CNV, so unless it is clinically indicated, there is no reason to test with postnatal microarray.
