Chromosomal
aberrations and
their influence on
the development
Anna Mac Gillavry Danylevska
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≈ 78 % of all conceptions are aborted; 15 – 20 % of diagnosed
pregnancies and not carried to term;
50 % of early stage abortions displays abnormal karyotype
Chromosomal aberrations:
autosomal x gonosomal
non-mosaic x mosaic
Numeric Structural
- trisomy Balanced:
- monosomy - inversion
- polyploidy - translocation
- uniparental disomy (UPD) - insertion
Unbalanced:
- duplications
- deletions
- dicentric chromosome
- acentric chromosome
- isochromosome
- ring chromosome
- marker chromosome
- complex rearrangements
Chromosomal aberrations:
1. Numeric
- autosomal aneuploidies – 0,2 % live births,
up to 30 % in spontaneous abortions;
constitute more than 90 % of all aberrations in oocytes
and less than 50 % in sperms
Trisomy – all of the autosomes except for 1 a 11 (!!!) in liveborns
which are the most common ones???
frequency of the occurrence at the conception is the same for all autosomes
Unisomy, nullisomy – incompatible with life
Uniparental disomy
Nondisjunction I
Nondisjunction II
Premature separation
of sister chromatids
- polyploidy – triploidy (diandry/digyny): app. 1 % of all conceptions,
17-18 % of chromosomal aberrations in miscarriages; 50 described cases
of live births (10 month the longest)
- tetraploidy: 6 -7 % chromosomal aberrations in miscarriages;
8 described cases of live births (22 months the longest)
- partial autosomal aneuploidies – presence of a supranumerary
isochromosome [47,XX or XY,+i(5)(p10)] or marker (0,7 % live births;
40 % of all markers are comprised of 2 copies of a short arm of
chromosome 15 with different amount of material from the long arm)
[47,XX or XY,+21]
- constitutes 95 % of Down syndrome cases (remaining 5 % - mosaics or
Robertsonian translocation); 1,2:1 males:females
- hypotonicity
- up to 50 % of patients with congenital cardiovascular defect!
atrioventricular canal defect, ASD, persisting ductus arteriosus
- duodenal atresia, pancreas annulare, megacolon, cataract
- 10 to 20 times higher leukemia incidence
[47,XX or XY,+21]
[47,XX or XY,+21]
[47,XX or XY,+21]
[47,XX or XY,+18]
- 1:3-4 males:females
- hypotonicity with following hypertonicity
- VSD, ASD, persisting ductus arteriosus
- hernia, one umbilical artery, cryptorchidism, short sternum, congenital
vertical talus, micrognathia, narrow bifrontal diameter…
- median survival is app. 5 days, only 10 % of patients reaches 1 year
[47,XX or XY,+18]
[47,XX nebo XY,+13]
- holoprosencephaly
- hernia, one umbilical artery, cryptorchidism, uterus bicornus, polycystic
kidney
- congenital heart defects in 80 % patients
- median survival is 2,5 days, only 5 % of patients reaches 6 months of age
[47,XX or XY,+13]
Chromosomal aberrations:
2. Structural
- 75 % of structural aberrations are of paternal origin!!!
(exceptions: de novo non-homologous Robertsonian translocation and
terminal deletion of the short arm of the chromosome 1)
- rare in mosaic form
- limitations of the classic cytogenetics (G-band+microscope) – maximum
resolution is 2-5 Mb, there for implementation of a molecular cytogenetic
methods (FISH, CGH)
- [46,XX or XY,del(5)(p15.3)] [46,XX or XY,del(13)(q21.3q33)]
- terminal vs. interstitial
- resulting in monosomy; the phenotype depends on the size of the
deletion and the quality of the material; (loss of the material of the short
arms of acrocentric chromosomes or heterochromatin does not affect
the phenotype)
Deletions
- Cri du chat – 5p – cat like cry, growth and mental retardation,
microcephaly
- Angelman syndrome – maternal deletion of 15q11-15q13 (or UPD!!!) –
mental and growth retardation, inappropriate laughter, seizures
- Prader-Willi – paternal deletion of 15q11-15q13 (or UPD!!!) – mental and
growth retardation, obesity – hyperphagia, hypogonadism
- DiGeorge/velocardiofacial syndrome – 22q11.2 – learning disabilities,
cleft palate, velopharyngeal incompetence, conotruncal heart defects
- Ichtyosis (X-linked) – Xp22.3 – typically not apparent using traditional
cytogenetics
Deletions
- [46,XX or XY,dup(15)(q24q26.3)]
- direct vs. inverted
- „pure duplication“ vs. in combination with other rearrangement:
isochomosome, dicentric chromosome, marker…
- results in partial trisomy
Duplications
- [46,XX or XY,inv(2)(p21q31)] vs. [46,XX or XY,inv(3)(q21q27)]
- pericentric vs. paracentric
- in 85-90 % of parents of patients with inversions inversion is found upon
cytogenetic examination, there for inversions are inherited
- common underlying cause of infertility
Inversions
All of the most common chromosomal
syndromes and most of the less common
have ear anomalies in their
characteristics!!!(Langman’s medical embryology, T. W. Sadler, 12th edition, p. 328)