Genetics

Chromosomal Abnormalities
 Background
• Human cells contain a multiple of 23 chromosomes (n =
23).
• Haploid cell (n) has 23 chromosomes (typically in the
ovum or sperm).
• Diploid cell has a normal diploid number of 46 (2n)
chromosomes
• Abnormal cells that do not contain a multiple of haploid
number of chromosomes are termed aneuploid cells.
• Aneuploidy is the most common and clinically
significant type of human chromosome abnormality,
occurring in at least 3-4% of all clinically recognized
pregnancies.
• The most common numerical abnormalities in
live born children include:
– Trisomy 21 (Down syndrome), trisomy 18
(Edwards syndrome), trisomy 13 (Patau syndrome)
– Sex chromosomal aneuploidies: Turner syndrome
(usually 45,X), Klinefelter syndrome (47,XXY),
47,XXX, and 47,XYY.
• Chromosomal disorders: Chromosome
deletions, duplications, and inversions that
affect whole chromosomes, or large portions
of a chromosome.
 Chromosomal Disorders
• The most common cause of aneuploidy is
nondisjunction, the failure of chromosomes
to disjoin normally during meiosis I or II or
during mitosis.
• After meiotic nondisjunction, the resulting
gamete either lacks a chromosome or has 2
copies instead of 1 normal copy, resulting in a
monosomic or trisomic zygote, respectively.
• Translocations: common type of chromosomal
anomaly, in which a piece of one chromosome
breaks off and becomes attached to a
different, nonhomologous chromosome.
• Mosaicism: when only a portion of cells carry
the chromosomal defect and rest of cells are
normal.
• Chromosomal disorders are typically identified
by chromosomal analysis (karyotyping)
• Genomic disorders are a group of diseases caused by
rearrangements of the genome including deletions
(loss of a copy of DNA), duplications (addition of a
new copy of DNA), and inversions (altered
organization of DNA).
• DiGeorge syndrome {deletions of genes located on
chromosome 22q11}
• Genomic disorders are often identified by fluorescent
in situ hybridization (FISH) or by array comparative
genome hybridization (aCGH) technologies
 MENDELIAN INHERITANCE

• Human genome: 46 chromosomes (22 pair of

autosomes and one pair of sex chromosome)
• There are 3 classic forms of genetic
inheritance:
• Autosomal dominant
• Autosomal recessive
• X-linked
Symbols in family pedigree
 Autosomal Dominant Inheritance
• Determined by the presence of one abnormal
gene on one of the autosomes (chromosomes
1 to 22)
• Change in 1 of the paired genes has an effect
on the phenotype; (physical manifestations,
behavioral characteristics ), or differences
detectable only through laboratory tests, even
though the other copy of the gene is
functioning correctly.
 Autosomal Dominant Inheritance

• Males and females are equally affected.

• 50% chance of transmission from parent to
offspring
• Vertical transmission, all generations.
• Parent to child transmission is a characteristic of
autosomal dominant inheritance
• Male to male transmission essentially confirms
autosomal dominant inheritance and exclude X
linked disorder.
Autosomal Dominant Inheritance
 Autosomal Dominant Inheritance

• Many patients with an autosomal dominant disorder

have no history of affected family member :
– new mutation occurred in the DNA of the egg or sperm
that formed that individual.
– Incomplete penetrance, meaning that not all individuals
who carry the mutation have phenotypic manifestations
(skipped generation, in which an unaffected individual
links two affected persons)
– variable expression ,individuals with the same
autosomal dominant mutation can manifest the disorder
to different degrees.
 Autosomal Recessive Inheritance

• Involves mutations in both copies of a gene.

• Examples of autosomal recessive diseases are cystic
fibrosis and sickle cell disease.
• Characteristics of autosomal recessive traits include
horizontal transmission, the observation of multiple
affected members of a kindred in the same generation,
but no affected family members in other generations;
• recurrence risk of 25% for parents with a previous
affected child
• males and females being equally affected
Autosomal Recessive
Autosomal Recessive Inheritance
 X-Linked Inheritance
• Males are more commonly and more severely
affected than females.
• Female carriers are generally unaffected, or if
affected, they are affected more mildly than
males.

• Male-to-male transmission excludes X-linkage

(seen with autosomal dominant and rare
disorders of Y-linked inheritance)
X-linked inheritance
• Female carriers have a
25% risk for having an
affected son, 25% risk
for a carrier daughter,
and 50% chance of
having child that does
not inherit the mutated
X-linked gene.
X-linked inheritance
• Affected males will have
only carrier daughters
(all) and have no chance
of having an affected
son because they will
pass the Y chromosome
to their sons.
X-Linked Recessive Inheritance
 Mitochondrial Inheritance

• Mitochondrial Inheritance
• An individual’s mitochondrial genome is
entirely derived from the mother because
sperm contain few mitochondria, which are
typically shed upon fertilization
• A woman with a mitochondrial genetic
disorder can have affected offspring of either
sex, but an affected father cannot pass on the
disease to his offspring
• e.g mitochondrial myopathy
 Clinical cytogenetics
• Clinical cytogenetics is the study of chromosomes:
their structure, function, inheritance, and
abnormalities.
• chromosome abnormalities are very common
• Occur in approximately 1-2% of live births, 5% of
stillbirths, and ~50% of early fetal losses in the 1st
trimester of pregnancy.
• Chromosome abnormalities are more common among
persons with mental retardation and have a significant
role in the development of some neoplasms.
Risks of Chromosomal anomalies
– advanced maternal age
– multiple abnormalities on fetal ultrasound (prenatal testing)
– multiple congenital anomalies
– unexplained growth retardation in the fetus or postnatal
growth and development problems
– mental retardation
– ambiguous genitalia
– primary amenorrhea or infertility, recurrent miscarriages (≥3)
or prior history of stillbirths and neonatal deaths
– 1st-degree relative with a known or suspected structural
chromosome abnormality
– clinical findings consistent with certain chromosomal anomaly
– Certain malignancies, and chromosome breakage syndromes
(e.g Fanconi anemia).
 Chromosomal disorders
• Trisomy is characterized by the presence of 3
chromosomes, instead of the normal 2, of any particular
chromosome.
• The occurrence of trisomy 21 and other trisomies
increases with advanced maternal age >35yr
• Most individuals with trisomy exhibit a consistent and
specific phenotype depending on the chromosome
involved:
– trisomy 21 (Down syndrome)
– trisomy 18 (Edwards syndrome)
– trisomy 13 (Patau syndrome)
Trisomy 21 (Down Syndrome)
 Down Syndrome
• Trisomy 21 is the most common genetic cause
of moderate mental retardation.
• The incidence of Down syndrome in live births
is approximately 1 in 733
• The life expectancy for children with Down
syndrome is reduced (approximately 50-55 yr.)
Down Syndrome
 Down Syndrome
• Neuropsychatric : (autism, disruptive behaviour,
depression, alzheimer disease)
• Musculoskeletal : (atlantoaxial instability, hip dysplasia,
Slipped capital femoral epiphyses, joints dislocations
• Endocrine : (Congenital or acquired hypothyroidism,
DM, infertility, hyperthyroidism)
• Hematology: Transient lymphoproliferative syndrome,
acute lymphocytic leukemia, acute myelogenous
leukemia
• GI: Celiac disease, obesity
 Down Syndrome
• Affected individuals are more prone to congenital
heart defects (40-50%) , commonest atrioventricular
septal defects
• Developmental delay is universal
• Cognitive impairment does not uniformly affect all
areas of development.
• Social development is relatively spared
• Most males with Down syndrome are sterile, but
some females have been able to reproduce, with a
50% chance of having trisomy 21 pregnancies
 Down Syndrome
• Down syndrome patients are at risk for
leukemia (leukemias accounted for 60% of all
cancers in people with Down syndrome)
 Down Syndrome
• All women should be offered screening for
Down syndrome in their 2nd trimester by quad
screen : 4 maternal serum tests (free β-human
chorionic gonadotropin (β-hCG), unconjugated
estriol, inhibin, and α-fetoprotein).
• Screening during the 1st trimester by fetal
U/S of nuchal translucency thickness
Edward’s Syndrome
Trisomy 18 (Edward Syndrome)
Patau Syndrome
Patau Syndrome
 Turner syndrome
• Turner syndrome = 45X
• Maternal age is not a predisposing factor
• Turner syndrome occurs in approximately
1/5,000 female live births.
• In 75% of patients, the lost sex chromosome is
of paternal origin
• Most patients tend to be of normal intelligence,
but mental retardation is seen in 6%
Karyotype for female with Turner syndrome—45XO
Turner Syndrome
 Turner Syndrome
• Phenotypic females with 45,X/46,XY
mosaicism have a 15-30% risk of developing
gonadoblastoma.
• The AAP has recommended the use of FISH
analysis to look for Y-chromosome mosaicism
in all 45,X patients. If Y chromosome material
is identified, laparoscopic gonadectomy is
recommended
 Noonan Syndrome
• Noonan syndrome :autosomal dominant
disorder affect both sexes
• Features common to Turner syndrome include
short stature, low posterior hairline, shield
chest, congenital heart disease, and a short or
webbed neck
• Noonan syndrome has different pattern of
congenital heart disease typically involving
right-sided lesions.
 Klinefelter Syndrome
• Klinefelter syndrome pts are phenotypically male
• It is the most common cause of hypogonadism and
infertility in males and the most common sex
chromosome aneuploidy in humans
• 80% of Klinefelter syndrome have a male karyotype
with an extra X chromosome “47,XXY”
• Remaining 20% have multiple sex chromosome
aneuploidies (48,XXXY; 48,XXYY; 49,XXXXY),
mosaicism (46,XY/47,XXY).
• Each additional X chromosome reduces the IQ by 10-
15 points. The main effect is seen in language skills
and social domains.
 Klinefelter Syndrome
• phenotypically normal male
• Puberty occurs at the normal age, but the testes
remain small.
• Taller stature.
• Presentation usually in adulthood as infertility.
• Their intelligence shows variability and ranges from
above to below average.
• Persons with Klinefelter syndrome can show
behavioral problems, learning disabilities, and deficits
in language.
 Fragile X syndrome
• Fragile X accounts for 3% of males with mental retardation.
X linked dominant disorder
• The main clinical manifestations in affected males are
mental retardation, autistic behavior, macro-orchidism
(which may not be evident until puberty), and
characteristic facial features
• The facial features, which include a long face, large ears,
and a prominent square jaw, become more obvious with
age
• Females affected with fragile X show varying degrees of
mental retardation and/or learning disabilities.
Fragile X syndrome
 Prader Willi Syndrome
• Prader-Willi syndrome results from the loss of
paternal chromosome 15q11.2-13 locus.
• C/P: hypotonia as infant, developmental delay,
mental retardation, obesity, hypogonadism,
short hands and feet, bird{small} like head
• Dx; FISH
Prader Willi Syndrome
• Obesity
• Short stature
• Mental retardation
• Short hands and feet
• Hypogonadism
Thanks