CHROMOSOME

DISORDERS

Dr Anjali
Lecturer
Division of Human Genetics
Dept of Anatomy
 Genetic disorders
• Chromosomal
• Single gene
• Multifactorial
 Genetic disorders
1. Chromosomal disorders
2. Single gene (Mendelian) disorders
a) Autosomal dominant
b) Autosomal recessive
c) X-linked dominant
d) X-linked recessive
3. Multifactorial disorders
 GENETIC CONDITIONS

Chromosomal disorders Genetic disorders

Karyotype Mutational / DNA analysis

 Objectives
• Importance
• Classification
• Numerical abnormalities
• Structural abnormalities
• Summary
 CA
• Chromosome abnormalities (CA)may be
either numerical or structural
• May involve autosomes or sex chromosomes
Numerical chromosomal abnormality:
Aneuploidy…. An abnormal chromosome number
due to an extra or missing chromosome which is
always associated with physical or mental
maldevelopment.
 Classification of Chromosomal disorders

Numerical disorders Structural disorders

Aneuploidy Polyploidy

Autosomes Sex chromosomes

Translocation Deletion Insertion Invertion Ring Iso

Reciprocal Robertsonian Pericentric Paracentric

 Chromosomal disorders
– 10% in spermatozoa
– 25% in mature oocytes
Proportion
– Spontaneous pregnancy loss (50%)
– Childhood disability (20%)
– Malignancy (30%)
– Still born infants (5%)
– At birth (0.5-1%)

Turnpenny P and Ellard S. Chromosome disorders. Chapter 18, Emery’s Elements of Medical Genetics, 12 th ed, 271-91.
Numerical chromsomal abnormalities (NCA):
Aneuploidy:
• Increase or decrease of entire chromosome
– Trisomy (presence of extra chromosome)
• Autosomal trisomy
– Trisomy 21 ….. Down syndrome
– Trisomy 18 ….. Edward syndrome
– Trisomy 13 ….. Patuas syndrome
 Down syndrome (DS)
• 1866
• Dr Langdon Down
• Chromosomal basis in
1959
• Incidence
– 1 in 650 to 700
• Risk factor
– Advanced maternal
age
• Etiology
Dr Langdon Down 1866
– Non-disjunction
– Anaphase lag
 Incidence of DS in relation to maternal age
Five year interval Single year interval

Maternal age Down syndrome Maternal age Down

(years) (years) syndrome
20 1 in 1500 36 1 in 300
25 1 in 1350 37 1 in 250
30 1 in 900 38 1 in 200
35 1 in 400 39 1 in 150
- - 40 1 in 100
- - 41 1 in 85
- - 42 1 in 65
- - 43 1 in 50
- - 44 1 in 40
- - 45 1 in 30
Cuckle H S, Wald N J, Thompson SG. Estimating a woman’s risk of having pregnancy associated with Down
syndrome using her age and serum alpha-fetoprotein level. Br. J Obstet gynaecol. 1987; 94: 387-402.
 DS – clinical features
• Upward sloping palpebral
fissures
• Small ears
• Protruding tongue
• Single palmar crease (simian
crease 50%)
• Congenital cardiac
anomalies (40-45%)
– A-V canal defects
– VSD
– PDA
 DS – clinical features

• Broad range of
intellectual ability
• Relatively well
developed social skills
• Happy and affectionate
• Average life expectancy
50 to 60 years
• May develop Alzheimer
disease
 DS - Chromosomal findings
• Autosomal aneuploidy
• Extra chromosome 21
• Pure trisomy (96%) –
numerical
• Maternal origin of Extra 21
(90%)
• Translocation (4%) –
structural
• Carrier parent
• Mosaicism (having 2 different
cell lines) (1%) – less affect
Karyotype: DS: Female
47,XX+21
Karyotype: Female: 45,XX,t(14;21)
 Edwards Syndrome
Congenital characteristic;
facial deformities, fingers curled over
one another in clenched fists
heart defects,
kidney abnormalities
low, small ears,microcephaly (small
head and BRAIN)
small MOUTH and cleft deformities
spina bifida, SYNDACTYLY
TALI PEDES (club foot)
 Edwards syndrome - an AUTOSOMAL
TRISOMY
•  Disorder that results
from a ERROR during
cell division in which
a GAMETE ends up
with two copies
of CHROMOSOME 18
instead of the normal
single copy .
• Incidence: About 1 in
5,000 live births
 Edwards syndrome

• Multiple and life threatening congenital

anomalies.
• When all cells carry the extra chromosome
18), the anomalies are so severe that the defect
often is lethal well before birth.
• Edwards syndrome may occur as a mosaic
trisomy disorder (some cells contain the
trisomy 18), which tends to produce milder
though nonetheless significant symptoms.
•
 Edwards syndrome

• A KARYOTYPE confirms the diagnosis.

• Less than 10 percent of infants born with Edwards
syndrome survive the first year after birth;
• But require extensive, ongoing medical care and
developmental support.
• Survival beyond five years is extremely rare.
Edwards syndrome
 Screening
• Edwards syndrome and other autosomal trisomy
disorders can be diagnosed before birth, through
prenatal screening methods such as
AMNIOCENTESIS and CHORIONIC VILLI
SAMPLING (CVS). These methods retrieve cells
from the FETUS from which a Karyotype can be
analysed.
 Pataus syndrome
Characteristics ;
• Cleft lip and cleft palate
• Polydactyly, particularly
of all extremities,
• Extra toes seen here on
each foot.
• Incidence: 1 in 6000 live
births.
 Pataus syndrome

• The karyotype here demonstrates trisomy 13

(47, XX, +13) also known as Patau's syndrome.
• It is rare for babies to survive for very long if
liveborn because of the multitude of
anomalies that are usually present.
• This is a prominent bilateral cleft lip
associated with trisomy 13.
Pataus syndrome
Mitotic Nondisjunction
 Numerical Sex chromosomal
abnormality
– Sex chromosomal trisomy
– E.g: 47,XXY - Klinefelter syndrome
– Monosomy (absence of one homologous
chromosome)
• E.g: 45,X – Turner syndrome
 Turner syndrome (TS)
• 1938
• Henry Turner
• Absence of Barr body
• Only one X chromosome
• Chromosomal basis in 1959
• Incidence
– 1 in 5000 to 10000
• Risk factor
– advanced maternal age
• Etiology
– Non-disjunction
– Anaphase lag Henry Turner 1938
 TS - Clinical features
• Generalized edema
• Thick nuchal pad
• Webbed neck
• Low posterior hair line
• Increased carrying angle
• Broad shield shaped chest
• Short stature
• Normal intelligence
• Ovarian failure
• Loss of secondary sexual
characters
 TS – chromosomal findings
• Sex chromosomal
aneuploidy
• Loss of one of the X
chromosome
• Pure monosomy – 45,X
(50%)
• Mosaic status – 20%
(numerical)
• Structural variants –
30%
Karyotype: 45,X
• 1942
Klinefelter syndrome (KFS)
• Harry Klinefelter
• Extra X chromosome
• Barr body in male
• 1959
• Incidence
– 1 in 1000 male live births
• Risk factors
– No definite predisposing factors
• Etiology
– Non-disjunction
– Anaphase lag

Harry Klinefelter, 1942

 KFS – clinical features
• Manifest at puberty
• Mild learning difficulties
• Self obsessed behavior
• Taller
• Gynaecomastia
• Infertile
• Hypogonadism
• Increases incidence of
Osteoporosis
• Poorly developed
secondary sexual
characters
 KFS – chromosomal findings
• Sex chromosomal
aneuploidy
• Extra X chromosome
• Pure sex chromosomal
trisomy - 47,XXY (90%)
• Mosaicism – 10%
• No structural
alterations Karyotype: 47,XXY
Meiotic Nondisjunction
 STRUCTURAL
CHROMOSOMAL
ABNORMALITIES
 Chromosomal disorders

Numerical disorders Structural disorders

Aneuploidy Polyploidy

Translocation Deletion Insertion Inversion Ring Iso

Reciprocal Robertsonian Pericentric Paracentric

SCA
Chromosomal breakage and subsequent reunion
in a different configuration
• Balanced:
• No loss or gain
• Complete chromosomal complement
• Generally harmless
• Harmful when an appropriate functional
gene gets damaged
• Carrier parents may give rise to offspring
with unbalanced chromosomal complement
•Unbalanced
• Incorrect amount of chromosomal material
• Serious manifestations
 FEMALE KARYOTYPE WITH BALANCED
STRUCTURAL ABNORMALITY : 45,XX,t(21;14)
 MALE KARYOTYPE WITH BALANCED
STRUCTURAL ABNORMALITY : 47,XY,t(21;14)
Translocation
• Transfer of genetic material
one chromosome to other
• Types
– Reciprocal –
• Breakage and exchange of
chromatids between homologous
or non homologous chromosomes
– Robertsonian –
• Breakage occur close to
centromere, only for acrocentric’s
i.e.., either between D group and
G group or with in D group and G
group
Down syndrome with Robersonian translocation
DS : 47,XY,t(21;14)
 Carrier mother for 14; 21 translocation
Karyotype: 45,XX,t(21;14) and Father with Normal Karyotype
Deletion
– Loss of a part of chromosome
– Monosomy for that specific part
– Large deletion (2% of haploid)
• Lethal and incompatible
– Cri du chat syndrome (5p-)
– Wolf Hirshchhorn syndrome (4p-)
Deletion
– Microdeletions
• Compatible
• Contiguous gene sydnrome
– Angelman syndrome (15q-)
– Paderwilli syndrome (15q-)
– DiGeorge syndrome (22q-)
Inversion
• Two break rearrangement in single chromosome
• Inverted segment
• Types
• Pericentric: involves centromere
• Paracentric: involves segment
• Balanced rearrangements
• Commonly seen in 9
• Produce unbalanced gametes
• Serious effect
• Ring chromosome:
– Breakage at the ends of chromatids
– Reunion of broken ends
– Autosomal ring formation
– Serious Ring formation

– Generally in mosaic condition

Isochromosome
• Loss of one arm
• Duplication of the other
Reason
• Centromere divides
transversely
E.g.
• Iso formation of Xq arm in TS
Thank you