Genetics – Chromosomal Disorders

Chromosomal Terminology
Types of Chromosomes:

1. Metacentric: centromere in the centre, such that both sections are of equal length.
Chromosomes 1 and 3.
2. Submetacentric: centromere slightly off-centre leading to a slight asymmetry in the length
of the two sections.
3. Acrocentric: centromere is severely off-centre (near apex). Chromosomes 13,15, 21, and 22.
4. Telocentric: centromere at very end of the chromosome.

Banding Nomenclature

Chromosomal Abnormalities
Main types of chromosomal abnormalities:

1. Numerical – aneuploidy (monosomy or trisomy).

2. Structural – duplication, deletion, inversion, ring chromosome (1 chromosome) &
translocations (2 chromosomes)

Numerical:

Aneuploidy is due to nondisjunction:

Failure of homologous chromosomes to separate and segregate normally in either mitosis

or meiosis. Mitotic nondisjunction produces two cell lineages from a single zygote known as
mosaicism. Mosaics are less symptomatic than the non-mosaics. Meiotic nondisjunction however,
produces imbalanced germ cells, which if fertilised would produce aneuploid zygotes. If the
nondisjunction occurs in the first meiotic division, gametes either both parental chromosomes
which failed to separate, or neither. If nondisjunction occurs in the second meiotic division, gametes
contain two identical copies of the same chromosome, or neither.
Structural:
1. Balanced – no net gain or loss of genetic material. Heterozygotes can pass on trait.
2. Unbalanced – net gain or loss of genetic material. Sufferers have developmental delay or
congenital malformations.

Reciprocal Translocations:
Two chromosomes exchange genetic material during crossing over.

Robertsonian Translocations:
Acrocentric chromosomes combine and act like one chromosome. Daughter cells can be the
(combined chromosome + the matching chromosome of one of its components) and the (remaining
chromosome) OR the (combined chromosome) and the (two normal chromosomes).

Syndromes:

1. Down Syndrome = trisomy 21 (95%) or Robertsonian translocation (5%)

developmental delay, variable intellectual disability, characteristic facial features, congenital
heart defects, premature ageing, risk of leukaemia.

2. Edwards Syndrome = trisomy 18

rocker-bottom feet, death usually within 1 year

3. Patau Syndrome = trisomy 13

polydactyly, death usually within 1 year

4. Turner Syndrome = monosomy X

short stature, low set eyes

5. Klinefelter Syndrome = 47 XXY

6. Triple X syndrome = 47 XXX

Embryos with aneuploidy of other chromosomes are not viable

Scenarios in which Cytogenetic Testing is Required
Prenatal Testing required if:
1. Abnormal ultrasound
2. Advanced maternal age/biochemical test
3. Previous birth of child with trisomy
4. Infertility, recurrent spontaneous abortion
5. Carrier of heritable chromosome abnormality

Postnatal Testing required if:

1. Dysmorphic features, congenital malformations
2. Developmental delay
3. Clinical features of specific chromosomal syndrome, e.g. Turners, Downs, Edwards etc.

Uses of Different Tests in Diagnosis of Chromosomal Disorders

G band karyotyping or FISH for recognized syndromes:

Down, Edwards, Patau, Turner etc.

G band karyotyping to detect balanced translocations:

Cases of recurrent spontaneous abortions etc.

FISH for suspected cases of recognized microdeletion syndromes:

1. Prader Willi/Angelman (15q11)
Deletion at chromosome 15q can result in either:
 Prader Willi (Paternal Deletion) with only maternal DNA present.
Facial dysmorphism, obesity, short stature, mental handicap
 Angelman (Maternal Deletion) Syndrome with only paternal DNA present.
Seizures and jerky movements, severe mental handicap

Array CGH for unexplained cases of developmental delay or congenital malformations:

1. More sensitive and expensive than G-band karyotyping
2. Same resolution as FISH, but is a genome-wide detection method
3. Should be applied to all cases of unexplained developmental delay/intellectual disability,
autism spectrum disorders, or multiple congenital anomalies.

NB: Imprinting = differential expression of the same chromosomal region, depending on whether
the region was inherited from mother versus father.