Uniparental disomy

Question 1

Infertility is the inability to achieve a conception and sustian a pregnancy through to live birth

Of the possible causes, genetic causes are ___

Answer 1

THE MINORITY

chromosomal causes of infertility are the minority

Question 2

XX males and XY females are rare - how do they occur?

Answer 2

SRY translocation

Question 3

Name the chromosomal abnormalities associated with infertility.

Answer 3

XXY - Klinfelter’s; has azoospermia (absence) or oligospermia (low conc)

45, X - Turner’s

X chromosome abnormalities

Y chromosome microdeletions

Translocations - reciprocal and Robertsonian

Question 4

Autosomal abnormalities are an infrequent cause of infertility.

• ____ and ___ can be associated with oligospermia
• ____ also causes infertility probs

Answer 4

Reciprocal translocations & inversions can cause oligspermia

Robertsonian translcoations cause infertility issues

Question 5

There are 4 categories of female infertility:

• Fallopian tube obstruction/adhesion
• Anatomic abnormalities
• Endometriosis
• Ovulation disorders: hypothalamic, pituitary, and ovarian causes

cytogenic causes of infertility occur in which category?

Answer 5

Ovulation disorders

Question 6

Genetic causes

• Gene mutations
  
  • Ex)
• Chromosomal causes primarily involve ___

Answer 6

• Gene mutations
  
  • Ex) Carriers of the trinucleotide repeat –> premature ovarian failure
• Chromosomal causes primarily involve the X chromosome

Question 7

X chromosome abnormalities

Answer 7

• 45,X and 45,X mosaicism
• Y chromosome sequences found in 45,X and 45,X mosaics
• X chromosome deletions
• X chromsome/autosome translocations

–> ovarian dysfunction

Question 8

Which can get pregnant?:

45,X mosaic

45,X/ 46 X,Y mosaics

Answer 8

45,X mosaic

But there’s still a high risk of pregnancy loss, stillbirth, chromsomal abnormalities, and birth defects

30% of fetal loss

Question 9

What does this patient have?

idk if thsi will be on the test

Answer 9

Monosomy Xmosaic -

45,X / 46, X,i(X)q10

There are 3 copies of Xq and no copies of Xp due to deletions of Xp

Question 10

What is this?

idk if this will be on the test

Answer 10

Monosomy X mosaic -

45,X / 47, XXX

Question 11

In a balanced X;autosome tranloscation, the _____ X is inactivated

In an unbalanced X;autosome translocation, the ______ X is inactivated

Answer 11

Balanced X;autosome translocation –> normal X is inactivated

Unbalanced X;autosome translocation –> abnormal X is inactivated

Question 12

__% of males and ___% of females with X;A translocations are infertile.

Answer 12

ALL males

50% of females

Question 13

People with klinefelters are azoospermatic and have small firm testes and gynecomastia

90% have what karyotype? 10% have what karyotype?

Answer 13

90% - 47,XXY karyotype

10% - mosaic 46 XY / 47, XXY

Question 14

Carriers of balanced translocations are phenotypically ___.

Whats their fertility situation?

Answer 14

Phenotypically normal, but reduced fertility.

Question 15

Robertsonian translocation carriers are phenotypically __.

What’s their fertility situation?

Answer 15

phenotypically normal, but also infertile.

Question 16

Microdeletions of Y

Answer 16

One of the most common molecular genetic causes of male infertility.

Infertile because genes necessary for sperm production are on AZF (azoospermic factor), which is on Yq

Question 17

Genomic imprinting

Answer 17

Epignetic phenomenon where genes are expressed differently depending on the parent of origin.

Imprinted alleles are silenced. This can lead to differences in phenotype if a patient has UPD or heterozygous deletion for an imprinted region

Question 18

What are some of the epigenetic mechanisms that causes genomic imprinting?

Answer 18

Methylation, histone modification, noncoding RNAs

Re-set during gametogenesis

Question 19

Imprinting occurs on the entire chromosome or just the gene?

Answer 19

gene

Question 20

Uniparental disomy (UPD)

Answer 20

Inheritance of a pair of chromosomes from one parent with no copy of that chromosome from the other parent.

_{NOT THE SAME AS TRISOMY, where there are 2 copies from one parent and a third copy from another parent.}

Question 21

Mechanisms that cause UPD

Answer 21

Trisomy rescue: 21, 13, 18

Monosomy rescue

Genetic complementation

Somatic crossing-over

Roberstonian translocation

Question 22

Isodisomy vs heterodisomy

Answer 22

Note: In isodomy, any mutations would be expressed because you have 2 copies of the same homolog. You’d see dominant disorders.

Question 23

Trisomy rescue in UPD

Answer 23

to compensate for the trisomy, during mitosis, you will lose one of the 3 chromosomes

–> UPD results if 2 chromosomes from the same parent are kept; can be heterodisomy or isodisomy

Question 24

monosomy rescue in UPD

Answer 24

you cant survive with just one copy of genetic material, so the chromosome in a monosomic zygote duplicates itself-> isodisomy only

Question 25

\_\_\_\_ can cause trisomy and monosomy rescue, resulting in UPD

Answer 25

Nondisjunction

Question 26

Gamete complementation

Answer 26

A gamete with two copies of a chromosome (disomy) is fertilized by a gamete that has no copy of that chromosome (nullisomy) --\> UPD

Question 27

Robertsonian translocations cause UPD

Answer 27

Robertsonian translocations can give you a trisomy 14, which is unviable unless you lost the paternal copy --\> maternal UPD is viable

Question 28

Phenotypic consequences of UPD

Answer 28

* **Autosomal recessive (AR) disease** due to reduction in homozygosity * Transmission of **X-linked genes** from father to son * **Imprinted gene** effects for some chromosome regions

Question 29

What causes prader willi syndrome?

Answer 29

****_P_**aternal UPD imprinting**--\> loss of function of a group of genes on the paternal chromosome 15 **_p_**rader = **_p_**aternal!

Question 30

Characteristics of Prader-Willi Syndrome

Answer 30

**Hypotonia** **Hyp**_er_**phagia** **Hypogonadism** **\*Obesity\*** Deletion --\> **Hypopigmentation & skin picking** Maternal disomy --\> higher verbal IQ & better memory retention

Question 31

What are the 3 types of genetic abnormalities that can cause the loss of function on paternal chromosome 15 that give rise to prader-willi?

Answer 31

**Deletion of parental chromosome 15** (70%) **Maternal disomy for chromosome 15** (25%) **Imprinting center defect** (5%)

Question 32

Angelman syndrome

Answer 32

**Maternal UPD imprinting** --\> loss of function of maternal chromosome 15

Question 33

Characteristics of Angelman Syndrome

Answer 33

**Severe intellectual impairment\*** **Seizures & jerky, ataxic movements** **Handclapping** WIde mouth & protruding tongue Absence of speech Microcephaly

Question 34

What are the 4 types of genetic abnormalities that can disrupt the **UBE3A** gene in Angelman syndrome?

Answer 34

* **Deletion** of maternal chromosome 15 (65-75%) * **Paternal UPD** for chromosome 15 (3-7%) * **Imprinting** defect (3%) * UBE3A gene **mutation** (5-11%)