1. Human Genetics
By
Dr Muhammad Saleem Laghari
MBBS(KEMU), MCPS,FCPS (paeds)
Gold Medalist FCPS-I
Assistant Professor

2. GENETIC DISORDERS
DEFINITION
The genetic transmission of a particular
disorder from parents to offsprings.
FAMILIAL
A condition occurring in certain families but
not necessarily genetically transmitted

3. GENETIC
COUNSELING
Genetic counseling is the communication of
information and advice about inherited
conditions.
A person giving genetic advice is called
Counselor.
A person seeking genetic advice is called
consultand.

4. Stages in communication
• History and pedigree construction.
• Examination.
• Diagnosis.
• Counseling follow up.

5. Counseling steps
• Accurate diagnosis is of paramount
importance
• Both parents should be counseled and
adequate time allowed in an appropriate
setting.
• It is inappropriate to counsel too soon after the
initial shock of serious diagnosis.

6. • Counseling needs to include all
aspects of the condition, and the
depth of explanation should match the
educational background of the couple.
• A geneticist must calculate the
recurrence risk for the consultands;
• risk of more than one in ten is
considered high and of less than one
in twenty low.

7. • Consultands often feel very guilty or
stigmatized, and it is important to recognize and
alley this.
• Where there is an increased risk and specially
where the disease is significant. The possibility
of prenatal diagnosis for the condition needs
to be considered if available.
• This often encourages a couple to undertake a
further pregnancy which otherwise they would
be reluctant to risk.
• Counseling must be non directive. The aim is
to deliver a balanced version of the facts
permitting parents to make their own decision.

8. Genetically transmitted diseases
1, CHROMOSOMAL DISORDERS
Autosomal
e.g, Trisomy 21 ,13 ,18 etc
Sex chromosomes
e.g, Turner Synd, Klinefelter Synd
2, SINGLE GENE DISORDERS
Autosomal recessive
Autosomal Dominant
Sex –Linked recessive
Sex Linked – Dominant
3, MULTIFACTORIAL inheritance

9. AUTOSOMOAL DOMINANT
A a a a
A a A a a a a a
e.g, Achondroplasia, H. Spherocytosis

10. AUTOSOMAL RECESSIVE
T t T t
T T T t t T t t
Thalassemia,Galactosemia

11. t t T t
t T t t t T t t

12. X - LINKED DOMINANT
X y x x
X x X x y x y x

13. X x x y
X x X y x x x y
Vit D resistant rickets

14. X – LINKED RECESSIVE
X Y X x
X X X x YX Y x

15. MULTIFACTORIAL INHERITANCE
• Combination of Genetic & Environmental
factors.
• General population incidence is 1%
• For 2nd child 2—5%
• For 3rd child 10 – 15 %
• Risk for sibs & offspring is Equal

16. Prevention of genetic diseases
There are several approaches for the
avoidance of genetic disease, such as
1.Primary prevention
2.Population screening (prospective
counseling).
3.Antenatal screening (prenatal diagnosis
and selective termination)
4.Neonatal screening.

17. Primary prevention(Premarrital)
• The populations in which a particular genetic
disease is common and for which there is a
simple diagnostic test for carriers.
• School children or young adults can be
screened and given appropriate advice about
the choice of marriage partners e.g.
thalassemia. Tay sachs disease.

18. Population screening
• Programs are designed to identify
conditions that occur frequently in HIGH
RISK population
• for example, screening of pregnant
women to identify neural tube
defects, screening for down syndrome in
women over the age of 35.

19. Neonatal screening
• Neonatal screening programs confined to
conditions that are amenable to
treatment and for which a reliable test
exists like screening newborn infants
• for congenital hypothyroidism and for
phenyl ketonuria

20. Antenatal screening
• It is possible now to identify certain serious
hereditary diseases during the pre-natal
period. A couple at risk of having a child with
such a serious genetic disorder, may be
screened and selective termination of
pregnancy is done if the fetus is affected.

21. Current method of prenatal
diagnosis
First trimester
Chorionic villous sampling
Second trimester
1. Amniocentesis
i) cells DNA Analysis.
2.Fetal blood sampling.
3. Biopsy of fetal skin and liver
i) DNA Analysis
4. Ultrasound examination of fetus.
5. Fetoscopy.
6. Radiography.

22. Amniocentesis
• Usually under taken at 15-16 week of
gestation, 10-30 ml of amniotic fluid is
withdrawn into a syringe under
ultrasonographic guidance.
• Fetal loss from amniocentesis is less than
0.5%.
• Results can be provided within 14-21 days
of the amniocentesis.

23. Amniotic fluid
• Alpha feto protein level: (AFP) the level of this
constituent of amniotic fluid increases between
14-18 week of gestation and falls steadily
therefore. The level of AFP is raised in the
following conditions:
1. Anencephaly 2. meningomyelocele.
3. Encephalocele4. omphalocele
5. Congenital nephrotic syndrome.
6. total abortion.
7. Intestinal atresia 8. Rh Isoimmunization

24. Cells in the amniotic fluids
• Obtained by amniocentesis can be used
for chromosomal analysis, biochemical
assay, or DNA analysis. Two or three
weeks are needed for the cells to multiply
to a number adequate for testing.

25. Fetal blood sampling
• Fetal blood sampling is being used for
prenatal diagnosis at about 20 weeks of
gestation for diseases like thalassemia, von
willebrand,s disease, sickle cell
anemia, red cell enzymes defect and
disorder of white cell function such as
chronic granulomatous disease. This
procedure is associated with 2-5% fetal
mortality and an increased maternal
morbidity due to infection and hemorrhage.

26. Ultrasound
• Ultrasound is used to determine
gestational age, to rule out multiple
pregnancies, to determine the sex of the
fetus and to diagnose major congenital
malformations.
Fetoscopy
Direct inspection of the fetus is possible but
the risk to the fetus is about 5%. IT IS
USED FOR OBTAINING SKIN BIOPSY.

27. Chronic villus sampling (CVS)
• CVS is performed at 9-11 weeks of
pregnancy, tissue is obtained by inserting
a sampling device either trans-abdominal
or trans-cervically under ultra sound
guidance and tissue obtained. The fetal
loss after CVS is about the same as for
amniocentesis.

28. • The real advantage of CVS is early result.
Each biopsy yields 10-15 mg of tissue which
can be used for fetal sexing, total
karyotyping, biochemical studies and DNA
analysis. Fetal chromosome analysis is
possible in 24 hrs as the cells need not to be
cultured before analysis. DNA analysis and
biochemical tests can be completed in 1-2
weeks.

29. DOWN SYNDROME

30. • Background: In 1866, Down described clinical
characteristics of the syndrome that now bears
his name.
• Down syndrome is by far the most common
and best known chromosome disorder in
humans.
• Mental retardation, dysmorphic facial
features, and other distinctive phenotypic traits
characterize the syndrome
• The cause of Down syndrome is full trisomy 21
in 95% of cases. Mosaicism (1%) and
translocations (4%) account for the remainder
of cases.

31. CLINICAL FEATURES
• Skull: Brachycephaly, microcephaly, flat
occiput, large fontanels with late closure,
• Eyes: Up-slanting palpebral fissures, bilateral
epicanthal folds, Brushfield spots (speckled
iris), refractive errors (50%), strabismus
(44%), nystagmus (20%),
• Nose: Hypoplastic nasal bone and flat nasal
bridge
• Mouth and teeth: An open mouth with tongue
protrusion, a fissured and furrowed tongue, tooth
agenesis, malformed teeth, delayed tooth
eruption, microdontia (35-50%)

32. • Ears: small with an over-folded helix. Chronic otitis
media and hearing loss
• Neck: Atlantoaxial instability (14%) can cause spinal
cord compression.
• Congenital heart defects: Congenital heart defects
(40-50%); endocardial cushion defect
(43%), ventricular septal defect (32%), secundum
atrial septal defect (10%),
• Gastrointestinal system (12%): Diastasis
recti, umbilical hernia. Duodenal Artesia or
stenosis, Hirsch sprung disease (less than 1%), TE
fistula, Meckel diverticulum, imperforate anus,.
• Genitourinary tract: Renal
malformations, hypospadias, micropenis, and
cryptorchidism occur.

33. • Skeleton: Short and broad
hands, clinodactyly, increased space between the
great toe and the second toe
• Endocrine system: Hypothyroidism (16-
20%), diabetes, and decreased fertility.
• Hematological system: 10- to 15-fold increased risk
of developing leukemia. Neonatal Leukemoid
reactions (ie, pseudo leukemia). Risk of hepatitis B
carrier status is increased.
• Immunodeficiency: 12-fold increased risk of
developing infectious diseases, especially
pneumonia, secondary to impaired cellular immunity.
• Skin: Xerosis, localized hyperkeratosis
lesions, alopecia areata (up to 10%), vitiligo, folliculitis,
• Dermatoglyphics: Distal axial triradius in the
palms, transverse palmar creases(simian crease).

34. • Premature aging: Decrease in skin &
Muscle tone, early graying or loss of hair.
• Growth: Short stature and obesity occurs
during adolescence.
• CNS: Moderate-to-severe mental
retardation occurs, with an IQ range of 20-
70 (mean IQ is approximately 50).
Hypotonia. Seizure disorder (5-
10%),senile dementia of Alzheimer type
• Behavior: Genuine
warmth, cheerful, gentleness, patience, an
d tolerance are characteristics.

40. •

42. INVESTIGATIONS
• Clinical diagnosis should be confirmed
with cytogenetic studies.
• Karyotyping is essential for determination
of recurrence risk.
• In translocation Down
syndrome, karyotyping of the parents and
other relatives is required for proper
genetic counseling.
• Radiological investigations.

43. • BAER: Also known as brainstem auditory
evoked response (BAER), Speech
evaluation
• Ophthalmic examination: Pediatric
ophthalmic examination for vision
screening and detection of ophthalmologic
disorders.
• Developmental chart: modified Denver
Developmental Screening Test is available
for assessing developmental milestones.
• Growth charts

44. ANTENATAL SCREENING
First trimester
Chorionic villous sampling
Second trimester
1. Amniocentesis
i) fluids. ii) cells DNA Analysis.
2.Triple screen on Maternal blood
1) Alpha fetoprotein (Low)
2) Serum unconjugated oestriol (low)
3) HCG (High)
3. Quad screen. All above+ Inhibin level

45. • MORTALITY & MORBIDITY
• Approximately 75% of concepti with trisomy 21
die in embryonic or fetal life.
• Approximately 85% of infants survive to 1 year
• 50% can be expected to live longer than 50
years.
• The presence of congenital heart disease is the
most significant factor that determines survival.
• In addition, esophageal Artesia with or without
transesophageal (TE) fistula, Hirsch sprung
disease, duodenal Artesia, and leukemia
contribute to mortality

46. Reproduction
–Affected individuals rarely reproduce.
–15-30% of females with trisomy 21 are
fertile and they have a 50% risk of
having an affected child.
–Males are always INFERTILE.

47. Genetic counseling
MATERNAL AGE
In general 1 in 700
Mother age > 20 yr 1 in 2000
> 35 yr 1 in 50
> 40 yr 1 in 20

48. Genetic counseling
Trisomy 21:
–If the couple has a child with trisomy 21, the
recurrence risk is about 1%.
Translocation
–Generally in translocation, the risk of Down
syndrome in a subsequent pregnancy is
estimated at 2-3%.
–In a carrier parent with a 21q21q
translocation or isochromosome, the
recurrence risk is 100%.