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
Isodisomy
when both homologues are derived from 1 grandparent
nondisjunction in Meiosis II
UPD clinical effets
not yet well-determined
often difficult to differentiate effects from CPM from effects of UPD16 - see IUGR for both
recessive disorders more apparent
effects may depend on presence of imprinted genes
Imprinting
differential allelic expression depending on parent of origin
Need complete maternal and paternal sets of chromosomes for fetal development in mice
triploid gynogenic embryos
ovum + polar body + 1 sperm
small placental tissue
embryo with many malformations
lethal
Triploid androgenic embryos
ovum + 2 sperm = huge, molar placenta
large placenta with little or no embryo
lethal
Prader-Willi syndrome
paternal chromosome deleted or maternal UPD at 15q11-13
don’t feed well at birth
by 2-3y, develop hypothalamic problem - overeat and obese
Angelman syndrome
maternal chromosome deleted or paternal UPD at 15q11-13
Adult polycystic kidney disease
somatic gene mosaicism
autosomal dominant
renal cysts - loss of heterozygosity
cells from cyst are clonal (from one cell/event)
mosaic for cells with only germline mutation and cells with both that and inactivation mutation
non-mosaic for inherited mutation at first, then somatic mutation and mosaicism in specific organ - kidney
Neurofibromatosis
mosaicism may explain variable expression
segmental darkening of skin
Followup with CVS result of mosaicism
amniocentesis
detailed ultrasound
may want to do UPD studies, depending on chromosome (e.g. 15 for Prader-Willi, Angelman)
Careful followup of pregnancy
