Chromosomal Abnormalities Flashcards
Describe the events in meiosis that produce genetic variability among offspring
- Meiotic recombination (crossing over) in Prophase I
- Independent assortment
Differentiate between the reproductive consequences of nondisjunction events in meiosis I versus meiosis II
Meiosis I - all the gametes will be abnormal. Half of the gametes will have two homologous chromosomes of a single while half the gametes will lack those chromosomes completely.
Meiosis II - half the gametes will be normal and half will be abnormal. Of the abnormal gametes, half will an extra sister chromatid and half will lack that chromosome altogether.
Describe the relationship between meiotic recombination (crossovers) and chromosome nondisjunction
Crossing over that occurs too far from the centromere causes the spindle attachments and segregation during meiosis I to be less effective.
Crossing over too close to the centromere, or having too many chiasmata results in the homologs becoming entangled. Reduced or absent recombination increases the risk of nondisjunction.
Down Syndrome
Trisomy 21
- Hypotonia as a newborn
- Short stature
- Brachycephaly (a wide head)
- Flat occiput (flat back of the head)
- Short nect with loose skin on the nape
- Flat nasal bridge
- Low set, folded ears
- Brushfield spots around the iris (white or gray/brown spots due to aggregation of connective tissue)
- Epicanthal folds and upslanting palpebral fissures (the opening for the eye between the upper and lower eyelids)
- Furrowed, protruding tongue
- Short, broad hands often with a transverse palmar crease
- Incurved fifth digits (aka clinodactyly)
- Wide gap between the first and second toes
- Intellectual disability
- Congenital heart defects
- Duodenal atresia
- Tracheoesophageal fistula
Edwards Syndrome
Trisomy 18
- Prominent occiput
- Receding jaw
- Malformed and low set ears
- Short sternum
- Fists clench with 2nd and 5th digits overlapping 3rd and 4th digits
- Rocker-bottomed feet with prominent calcaneous bones
- Single palm creases with arch patterns on digits
- Hypoplastic nails
- Intellectual disability
- Failure to thrive
- Severe malformation of the heart
- Hypertonia
Patau Syndrome
Trisomy 13
Infants born with Patau generally do not survive past year 1
- Sloping forehead
- Microccephaly
- Wide, open sutures
- Micropthalmia
- Iris Coloboma (holes, defects in iris)
- Absence of the eyes
- Cleft lip
- Cleft palate
- Hands and feet may have polydactyly
- Rocker-bottomed feet
- Transverse palmar creases
- Fists clench with 2nd and 5th digits overlapping 3rd and 4th digits
- Growth retardation
- Severe intellectual disability
- Severe central nervous system malformations
- Arhinencephaly (absence of olfactory bulbs, tracts or nerves)
- Holoprosencephaly (failure of embryonic forebrain to develop into 2 hemispheres)
- Congenital heart defects
- Urogenital defects
Klinefelter Syndrome
(47,XXY)
Develop as males
- Phenotypes include tall stature, hypogonadism, under-developed secondary sexual characteristics, gynecomastia, usually infertile, some degree of language impairment
- Incidence is 1/1000 live male births, half of cases result from errors in paternal meiosis I due to failure of recombination in pseudoautosomal regions.
- About 15% of cases result from mosaicism, and the most common mosaic karyotype is 46,XY/47,XXY
47,XYY Syndrome
- Indistinguishable physically or mentally from normal males and are usually fertile
- Incidence is 1/1000 live male births, results from errors in paternal meiosis II, producing YY sperm.
- Increased risk of behavioral and educational problems, delayed speech and language skills
Turner Syndrome
45,X
Develop as females
- ≥99% of 45, X fetuses abort spontaneously
- Incidence is 1/4000 live female births, and most frequent karyotype is 45,X; 25% of individuals with Turner syndrome are mosaic.
- Phenotypes include short stature, webbed neck, edema of hands and feet, broad shield-like chest, renal and cardiovascular anomalies, and a failure in ovarian development
Incidence of Trisomy 21
~ 1/830 live births
Incidence of Trisomy 18
~ 1/7,500 live births
Incidence of Trisomy 13
~ 1/22,700 live births
Mosaicism
Defined as two or more chromosome complements present within a single individual
- commonly caused by nondisjunction in an early post-zygotic mitotic division
- effects on development vary with the timing of the nondisjunction event, the nature of the chromosomal abnormality, and the tissues affected
- germ line mosaicism can result from a mitotic nondisjunction event in a germ cell precursor
Mechanism of common chromosomal structural rearrangements
All chromosomal structural rearrangements require double strand breaks of the DNA and can be induced by a variety of DNA damaging agents such as ionizing radiation.
Duplications, deletions, inversions, insertions and translocations all appear to have breakpoints in regions of chromosomes in which repeated sequences are prevalent.
Structural rearrangements can be inherited and can also lead to further rearrangement during meiosis
Acrocentric chromosomes
13, 14, 15, 21, 22, Y
p (short) arm is so short that it is hard to observe, but still present
p arm contains genetic material including repeated sequences such as nucleolar organizing regions, and can be translocated without significant harm, as in a balanced Robertsonian translocation
Types of chromosomal structural abnormalities
Balanced; unbalanced
Balanced structural abnormalities
normal complement of chromosomal material
- Inversions
- Reciprocal translocations
- Robertsonian translocations
Chromosomal inversion
One chromosome undergoes two double strand breaks and the intervening sequence is inverted prior to the rejoining of the broken ends
- *Paracentric** inversions exclude the centromere.
- *Pericentric** inversions include the centromere.
Chromosomes with inversions can have normal gene complements and often produce no phenotypes in carriers of the rearrangement
However, inversions may lead to the production of abnormal gametes during meiosis
Paracentric inversion
Excludes the centromere
If a crossover occurs within the inverted region of a paracentric inversion, both dicentric (two centromeres) bridges and acentric chromosomes can be generated, leading to chromosome breakage or loss
Observed risk of producing live offspring with unbalanced chromosomal complement is ~0; gametes are often not compatible with life
Pericentric inversion
Spans the centromere
Crossovers within the inverted region can produce duplications and deletions due to looping during crossover
Sample karyotype: 46, XX inv(9)(p13q13)
Female with an inversion of the sequences between band 13 on the short arm and band 13 on the long arm of chromosome 9
Reciprocal translocation
Results from the breakage and rejoining of nonhomologous chromosomes, with a reciprocal exchange of the broken segments
When the chromosomes of a carrier of a balanced reciprocal translocation pair at meiosis, a quadrivalent figure is formed
At anaphase, these chromosomes may segregate in one of three ways:
Alternate segregation: produces gametes that have either the normal chromosome complement or two reciprocal chromosomes, both of which are balanced
Usual form of segregation
Adjacent-1 segregation – unbalanced gametes
Adjacent-2 segregation – unbalanced gametes
The risks to offspring depend on the specific translocation, but the general empirical risk is 5-10% lethality
Robertsonian translocation
Fusion of two acrocentric chromosomes within their centromeric regions, resulting in the loss of both short arms (containing rDNA repeats).
Result in the reduction of chromosome number
Still considered balanced rearrangements because the loss of some rDNA repeats is not deleterious
Carriers of Robertsonian translocations are phenotypically normal, but these rearrangements lead to unbalanced karyotypes for their offspring, resulting in monosomies and trisomies
The most common example is a translocation involving chromosomes 14 and 21, karyotype 45, XX or XY der(14q;21q)
Unbalanced structural abnormalities
abnormal chromosomal content
- Deletions
- Duplications
- Isochromosomes
- Marker (ring) chromosomes
Chromosomal deletion
Loss of genetic information that can arise by simple chromosome breakage and rejoining, unequal crossing over between misaligned homologous chromosomes or sister chromatids, or by abnormal segregation of a balanced translocation or inversion.
Terminal deletion
Interstitial deletion
The clinical consequences of deletions reflect haploinsufficiency, where the contribution of the remaining normal allele is unable to prevent disease
Severity of the phenotype depends on the size of the deletion and the number of genes affected
Sample karyotype for a deletion: 46, XY del (5)(p15)
Describes a deletion of chromosome 5 in the region denoted p one-five (Cri-du-chat syndrome)
Chromosomal duplication
gain of genetic information, which is generally less harmful than deletion, but can lead to abnormalities (i.e. partial trisomy 21).
Duplications can also result from unequal crossing-over or by abnormal segregation during meiosis in a carrier of a translocation or inversion
Isochromosomes
Refers to a chromosome in which one arm is missing and the other arm is duplicated in a mirror-like fashion
Two models for the formation of this rearrangement:
1) mis-division through the CEN in meiosis II
2) exchange between one arm of a chromosome and its homolog at the proximal edge of the arm, adjacent to the centromere
- most common isochromosome is one involving the long arm of the X chromosome
- small percentage of Down syndrome patients have this rearrangement (sometimes written as 21q21q translocation)
- 100% of the viable offspring of a carrier of isochromosome 21 are abnormal
Ring chromosome
Chromosome fragment that circularizes and acquires kinetochore activity for stable transmission to daughter cells
Also called a marker chromosome
Sample karyotype: 46, XY r(13)(p11q34)
Male with a supernumary ring chromosome derived from the p11 to q34 region of chromosome 13
Two most common leukemia translocations
t(9;22) for chronic lymphocytic leukemias (CML)
t(15;17) for acute myeloid leukemia (AML)
Wolf-Hirschhorn syndrome
del(4p16.3)
facial clefting
prominent ears
microcephaly, intellectual disabilities
Cri du chat syndrome
del(5p15.2)
microcephaly
characteristic cry
seizures, intellectual disabilities
Williams syndrome
del(7q11.2)
The majority of cases are due to random events at fertilization. If someone with Williams syndrome has a child, there is a 50% chance it will be passed to that child.
Distinctive “elf-like” features. Includes wide mouth, full lips, short flat nose, full cheeks, and wide-spaced teeth.
Most patients show mild to moderate intellectual disability, though there is a wide range of mental capacity from severe intellectual disability to normal intelligence. Emotionally, a notable feature of children with Williams syndrome is their high sociability and empathy. Attention deficit hyperactivity disorder (ADHD) is common in children and adolescents.
Langer-Giedion syndrome
del(8q24.1)
Very rare disease that causes bone abnormalities and distinctive facial features
Tricho-rhino-pharangeal syndrome multiple exostoses (benign bone tumors)
WAGR syndrome
del(11p13)
- *Wilms tumor **- rare form of kidney cancer
- *Aniridia** - absence of iris
- *Genitourinary anomalies **- more in males
- *Intellectual disabilities** - depression, anxiety, attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD)
Beckwith-Wiedemann syndrome
dup(11p15.5) (paternal)
Classified as an overgrowth syndrome
overgrowth
omphalocele - opening in the wall of the abdomen
predisposition to Wilms, other tumors
Angelman syndrome
del(15q11-q13) (maternal)
primarily affects the nervous system
delayed development
intellectual disability
severe speech impairment
problems with movement and balance (ataxia)
recurrent seizures (epilepsy)
small head size (microcephaly)
Delayed development becomes noticeable by the age of 6 to 12 months, and other common signs and symptoms usually appear in early childhood
Prader-Willi syndrome
del(15q11-q13) (paternal)
hypotonia (weak muscle tone)
hypopigmentation (fair skin and light colored hair)
hypogenitalism
obesity (due to hyperphagia)
Contiguous gene syndrome
abnormal phenotypes caused by over-expression or loss of neighboring genes
Ex: Velocardiofacial Syndrome and DiGeorge Syndrome
Miller-Dieker syndrome
del(17p13.3)
People with lissencephaly have an abnormally smooth brain with fewer folds and grooves. These brain malformations cause:
severe intellectual disability
developmental delay
seizures, abnormal muscle stiffness (spasticity)
weak muscle tone (hypotonia)
feeding difficulties
Seizures usually begin before six months of age, and some occur from birth. Typically, the smoother the surface of the brain is, the more severe the associated symptoms are.
DiGeorge syndrome
del(22q11.2)
Poor development of several body systems
absent or hypoplastic thymus and parathyroid glands
congenital heart disease
poor immune system development
cleft palate
Velo-Cardio-Facial syndrome
del(22q11.2)
Comes from velum (palate) cardio (heart) and facial
cleft palate
heart defects
problems fighting infection
low calcium levels
differences in the way the kidneys are formed or work
a characteristic facial appearance
learning problems
speech and feeding problems
Charcot-Marie-Tooth Disease
- characterized by weakness of the foot and lower leg muscles, foot deformities known as hammertoes, and weakness and muscle atrophy of the hands late in the course of the disease
- several forms of CMT exist; all affect the normal function of peripheral nerves
- CMT type 1A is an autosomal dominant disorder caused by a duplication of 17p11.2, containing the gene for peripheral myelin protein-22 (PMP-22)
Mechanisms that lead to Down Syndrome
•meiosis I nondisjunction (maternal) (95% of Down patients)
e.g. 47,XY,+21
•Robertsonian translocation (4% of patients)
e.g. 46,XX,der(14;21)+21
•Isochromosome (21q21q translocation)
e.g. 46,XY,i(21)+21
•Mosaic Down syndrome
phenotype can be milder than typical trisomy 21, but patients exhibit wider variability in phenotypes due to variable portion of trisomy 21 cells in the embryo during development
•Partial trisomy 21
very rare, has only a portion of chromosome 21 duplicated
Uniparental Disomy
chromosomal sorting error in effect “rescues” the developing pregnancy from spontaneous abortion but may result in an abnormal phenotype if both remaining homologs are derived from the same parent
Two alleles from same parent, but affected phenotype due to silencing of gene in imprinted region
