Lecture 4: Chromosomal Mosaicism

Variation in chromosomal content in different tissues

Define MOSAICISM

presence of two or more genetically distinct cell populations within an individual that originated from a single zygote

What is CHROMOSOMAL MOSAICISM?

specifically is the presence of two or more cell lines with different chromosome complements in the same individual aka. different chromosome numbers or structures

****What are 4 key points about mosaicism?

• when do they arise

• What are the 2 things they can involve

• What do clinical effects depend on

• What influences the resulting phenotype?

1. Always arise post-zygotically (After fertilization - as early as first cell division to ANY TIME AFTER even adulthood)

2. Can involve CHROMOSOMES (eg. turner mosaic x/ xx) or Single Gene variants

3. Clinical effects depend on:

   1. which tissues are affected

   2. What proportion of cells carry the abnormality

4. Timing influences tissue distribution, cell number and resulting phenotype

What are 5 types of Mosaicism?

Any type of genetic change that affects some but not all cells

*****Error during Embryonic development (EARLY errors) results in what type of Mosaicism?

Somatic = mutations occur early in embryogenesis + affects somatic tissue

• can be wide spread (if very early on) or patchy (a little later on)

****What is a tell tale sign of mosaicism?

Skin

*****LATE errors results in what type of Mosaicism?

• hint 2

1. Germline (gonadal): occurs when a variant arises in the germ cell precursor = only a PORTION of a individuals sperm or egg have the variation

   1. Variant may or may not be passed onto offspring depending on if a variant gonad or normal one is passed on

2. Cancer: may arise from variants arising in a single cell at any time in life

Of the 3 scenarios which are due to Earlier Errors vs. later?

*Case:

LOW risk

• Since parents tested NORMAL ==> usually expect to be result of DeNovo mutations in the child

The parents have a second child + they also have a 22q11 del

• What is the suspected cause?

****Can you test for a suspected gonadal mosaicism?

NO not practical

• the easier tests using blood or saliva would not tell us anything about the genetic material of the gonads

********What is the PERCENT chance that the parents have a gonadal mosaicism?

< 1%

• empiric recurrence risk (RR) is an estimate of the likelihood that a genetic trait or multifactorial disorder will reappear in a family member, based strictly on real-world observational data rather than theoretical Mendelian inheritance rules

****What is an example of a disorder that can exist in both CONSITUTIONAL or MOSAIC form?

Trisomy 21

• mosaic may have milder phenotype than constitutional T21

***Can mosaic Trisomy 21 be detected by Karyotype? WHY?

Cannot predict based on karyotype alone (tissue distribution is not known)

• Because a karyotype only looks at one cell line at a time

****What are 2 examples of Disorders that exist in MOSAIC form ONLY?

1. Pallister Killian (Mosaic Tetrasomy 12p)

   1. Severe intellectual disability, congenital anomalies, pigmentary differences, coarse + distinctive facial features

2. Mosaic trisomy 8

   1. Intellectual disability, facial dimorphisms, deep palmar/plantar creases, growth deficiency, leukemia risk

*****

*****What are the 2 main Mechanisms by which Chromosomal mosaicism arises?

How does Non-Disjunction in Mitosis cause Mosaicism

POST ZYGOTIC Mitotic error

• Non-Disjunction → 1 daughter cell with extra and 1 with missing

• When ND occurs post zygotically there is also a NORMAL cell line = mosaicism; 2 different cells lines (eg. some norm + some monosomic or trisomic)

  • monosomic cell line may not survive

**What is the ONLY exception to the monosomic cell line not being viable?

SEX CHROMOSOMES

How does Trisomy rescue cause Mosaicism

MEIOTIC non-disjunction = results in a trisomic zygote

• Rescue only occurs in EARLY embryonic cell division (one extra chr is lost by chance eg. via anaphase lag)

• Creates a “rescued” Disomic line alongside the persisting trisomic line= mosaic trisomy

Mosaicism in the Prenatal Setting

• An abnormal cell line can be present in which 3 possible combination of locations?

1. In both the fetus and placenta

2. Only in the fetus, or

3. Only in the placenta

• Placenta is typically is a good representation of the DNA of the baby

• Complete fetal placental concordance

• Confined placental mosaicism

• Fetal placental mosaicism

• Non mosaic fetus mosaic placenta

• Fetal mosaicism non-mosaic placenta

• Fetal mosaicism

• Complete fetal placental discordance

****What is the DNA source for each? Placental or fetal?

Nuchal translucency = an increased amount of fluid accumulated under the skin at the back of the fetal neck → indicates abnormalities

An ANMIOCENTESIS (test fetal DNA) should be done as CVS = Placental cells

****Which of combinations is the Case study? CVS = Mosaic trisomy 16 + Amniocentesis = normal karyotype

Confined Placental mosaicism

Cancer as a form of SOMATIC MOSAICISM

***What are 3 ways Chromosomal Mosaicisms arise in Cancer?

Cancer as a form of Somatic Mosaicism: What are 3 examples of Chromosomal Mosaicism in HEMATOLOGICAL malignancies?

Cancer as a form of Somatic Mosaicism: What are 2 examples of Chromosomal Mosaicism in SOLID TUMORS?

*****What is LOSS OF CHR 7 associated with?

Loss of chromosome 7 = loss of key tumor suppressor genes (like EZH2, SAMD9, MLL3).

• This makes hematopoietic stem/progenitor cells unstable and prone to malignant transformation. = predisposition to cancer

***What is CHIMERISM?

****What are the 4 types of Chimerism?

1. Dispermic = extremely rare

****What are 4 possible explanations for the karyotype?