Mosaicism Flashcards
Mosaicism definition
Presence of >=2 genetically distinct cell populations in a single individual
Types of mosaicism
Chromosomal: generalized, tissue-specific
Single Gene
Generalized mosaicism
occurs in postzygotic divisions (may begin as a normal or abnormal karyotype if it is chromosomal) represented in all tissues examples: - X inactivation - mosaic Down syndrome
X inactivation
occurs in all females and males with more than 1 X
random event, but inactivation carried through all mitoses
become Barr bodies
Mosaic down syndrome
conceptus could begin as a trisomy, then lose one #21 in a cell in first several divisions
or could begin as normal, then nondisjunction in later mitotic divisions
may be underdiagnosed since they present with few clinical symptoms
Tissue-specific mosaicism types
Somatic
Germline (type of somatic)
Confined placental mosaicism
Germline mosaicism
e. g. osteogenesis imperfecta
- extreme bowing of legs, soft bones, small chest, many fractures, lethal
- usually new dominant
Recurrent risk of germline mosaicism
expect equal to mutation rate (since new dominant) BUT is actually 6%
sperm analysis shows 2 populations
father doesn’t have clinical symptoms –> gonadal/germline mutation
Confined placental mosaicism
most likely to be seen in placenta with no mosaicism at level of embryo
2% of viable pregnancies
Confined placental mosaicism pathophysiology
Occurs at/after third post-zygotic division
Blastocyst stage: blastocyst wall gives rise to chorion, inner cell mass gives rise to embryo (3 cells), yolk sac, allantois, part of amnion
Cells other than the 3 that makes the embryo –> mosaic
Reason: unclear, but fetus may push teh abnormal cells out onto placenta during development?
Can arise in diploid conception: begins as 46 N then disomy –> trisomy
Can arise in viable dividing chromosomall abnormal zygote: arises as 47 zygote then trisomy rescue
Confined placental mosaicism outcome
associated with spectrum of fetal manifestations
- N, IUGR, occasional overgrowth, fetal death
poor fetal outcome:
- suboptimal placental function
- particular chromosome involved
- proportions of normal to abnormal cells
- 16-21% of pregnancies with CPM have prenatal/perinatal complications
CPM trisomy 16
most common aneuploidy observed in early pregnancy losses, but generally lethal in non-mosaic state
Commonly associated with unexplained growth retardation
Uniparental disomy
inheriting all/part of a pair of chromosomes from one parent
Uniparental disomy etiology
1) Trisomy rescue
- if corrected in embryoblast lineage, have euploid fetus with trisomic placenta
2) Monosomic rescue
3) Gametic complementation
With correction, may end up with two chromosomes from maternal + paternal origin (NORMAL) or two from one parent (UPD)
Heterodisomy
2 different homologous chromosomes from 1 parent (e.g. from maternal grandmother and grandfather)
nondisjunction in Meiosis I
