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Genetic Disorders
Dr. Mohamed Hesham Sayed
Professor of Pediatrics
Rabigh Medical College
Objectives
• Identify the different types of genetic disorders
• Appreciate that malformations are a common and
significant health burden.
• Recognize the red flags that signify a potential
underlying genetic syndrome that need a genetic
referral.
• Define malformations, their types and causes;
recognize that they may be isolated or part of a
larger spectrum and appreciate their medical
implications.
Basic definitions
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Chromosomes, DNA and genes
Chromatides, and centromere
Arms of a chromosome (p and q)
Karyotype
Autosomes and sex chromosomes
Genotype and phenotype
Human Chromosomes
• The chromosome is that portion of the
chromatin material of the nucleus which
carries the genetic information.
• Chromosomes are composed of
deoxyribonucieic acid (DNA) on framework
of protein .
• Segments of DNA molecules comprise the
genes; the units of heredity.
• During cell division, the chromosome can be
seen to consist of 2 parallel strands;
the chromatids, held together at one point,
the centromere.
Chromosomes
Short arm and long arm
Karyotype
• It is the set of chromosomes of an individual.
• It is the systematized arrangement of the
chromosomes of a single cell.
• Chromosomes are arranged in groups A to G
according to their shape & size.
• In the human cell, there are 46 chromosomes or 23
pairs (diploid number); of these 23 pairs, 22 are
similar in both sexes and are called the autosomes.
The remaining pair is called sex chromosomes : XX in
the female cells and XY in the male cells .
• The genotype is the set of genes the individual
carries.
• The phenotype is the external appearance of an
individual as determined by his genotype.
Karyotype of a normal male
Karyotype of a normal female
Karyotype of a normal male
Karyotype of a female Down syndrome
Genetic Disorders
• Chromosomal abnormalities
• Single gene disorders
• Multifactorial (polygenic) inheritance
• Unusual patterns e.g. mitochondrial
inheritance
• Due to teratogens
Chromosomal Abnormalities
Chromosomal Abnormalities
• Chromosomal abnormalities are either
numerical or structural.
• They are a very common cause of early
spontaneous miscarriage.
• Usually, but not always, cause multiple
congenital anomalies and learning difficulties.
Chromosomal Abnormalities
• Numerical Aberrations (abnormalities)
o Polyploidy: Multiple of the haploid (> Diploid)
o Aneuploidy: Abnormal number
• Structural abnormalities
o Translocation
o Deletion
o Others
Numerical Aberration
• Autosomal
- Trisomies: 1 ch extra (e.g. trisomy 21-13-18)
- Monosomies: 1 ch is missing
• Sex chromosome
- Klinefilter syndrome (47, XXY male)
- Turner syndrome (45, XO female)
Numerical abnormalities
Trisomy i.e. 47 chromosomes
- Trisomy 21 (the extrachromosome is No 21)
- Klinefelter syndrome ( 47, XXY male)
Monosomy i.e. 45 chromosomes
- Monosomy 21
- Turner syndrome (the missing chromosome is
X in female : 45, X or 45 XO )
Trisomy 18, Edward Syndrome
Overlapping of the fingers in
Edwards' syndrome
Structural abnormalities
1) Translocation :
the transfer of a chromosome or a segment of it to a
non-homologous chromosome.
2) Deletion : loss of a portion of a chromosome.
3) Ring chromosome
4) Duplication : extra piece of a chromosome.
5) Inversion : fragmentation of a chromosome followed
by reconstitution with a section inverted.
6) Isochromosomes : division of chromosome at
centromere transversely instead of longitudinally
Structural abnormalities
Structural abnormalities
Structural abnormalities
Structural Abnormalities
Inversion
Deletion
Duplication
Structural Abnormalities
Isochromosome
Ring chromosome
Structural abnormalities
Robertsonian Translocation
Reciprocal Translocation
Reciprocal translocations
• An exchange of material between two different
chromosomes is called a reciprocal translocation.
When this exchange involves no loss or gain of
chromosomal material, the translocation is 'balanced'
and has no phenotypic effect.
• Balanced reciprocal translocations are relatively
common, occurring in 1 in 500 of the general
population.
Reciprocal translocations
•Finding a balanced translocation in one parent
indicates a recurrence risk for future pregnancies and
antenatal diagnosis by chorionic villus sampling or
amniocentesis should be offered as well as testing of
relatives.
Reciprocal Translocation
Reciprocal Translocation
Robertsonian Translocation
Robertsonian Translocation
When to suspect chromosomal
abnormalities?
• Abnormal features
* coarse facies * Mongoloid eye
* Low set ears
* Micrognathia/cleft lip & palate
* Simian crease * Clinodactyly
• Mental retardation Do chromosomal analysis
• Ambiguous genitalia Do chromosomal analysis
• Delayed puberty:
Klinefelter syndrome and Turner syndrome
Coarse Features
Cardiofaciocutaneous Syndrome
Antimongoloid slant
Low set Ears
Low set Ears
Micrognathia
Ambiguous Genitalia
Ambiguous Genitalia
Clinodactyly
Clinodactyly
Down Syndrome
(Mongolism) Trisomy 21
Down Syndrome
Incidence :
• The most common chromosomal aberration
• Incidence 1/700 live birth & 10 % of M.R.
Definition : It is trisomy 21 i.e. the cell contain an extra
chromosome, number 21 i.e. the cell contains three
21 chromosomes instead of two .
Genetic types (Cytogenetics)
(1) Non-disjunction : “ 95 % of cases”
• It is due to failure of disjunction of the 2
chromosomes of the pair No 21 during division, the
extra 21 chromosome is separate and so total no. in
cell is 47.
• Incidence is higher with increasing maternal age & so
it is age-dependent
Cytogenetics
Non-disjunction
Genetic types (Cytogenetics)
(2) Translocation : “ 4 % of cases”
• The extra 21 chromosome is translocated (attached)
to another chromosome e.g. (15/21) so total no. of
chromosomes is 46 but the genetic material is that
of 47 chromosomes .
• Incidence is usually in young mothers & risk of
recurrence is high & mother is called translocation
carrier
Translocation
Types of translocation
Down syndrome
Translocation carrier
Down syndrome
Translocation carrier
• One parent contains a 14/21 translocation
and has only 45 chromosomes, and is a
phenotypically normal carrier.
• 1/4 of the individual's gametes will have
almost 2 copies of chromosome 21.
• The resulting zygote has 46 chromosomes, but
almost 3 copies of chromosome 21, and
exhibits Down syndrome.
Translocation carrier
Recurrence Risk ??
Translocation carrier
Recurrence Risk ??
Figure 8.4 Translocation Down's syndrome. There is a translocation between
chromosomes 21 and 14 inherited from a parent
Genetic types (Cytogenetics)
(3) Mosaicism : “ 1 % of cases”
• Some cells are normal (46 chromosomes) & others
are trisomic (47 chromosomes)
• Clinical feature are less evident & M.R. is mild .
Down syndrome-Prenatal diagnosis
• Triple test ( low estriol, low maternal serum alphafetoprotein and elevated HCG) is often associated
with chromosomal syndromes; 15-18 weeks
• Quad screen (quad test): Triple test + inhibin A (↑ )
• Ultrasonography: nuchal thickening; 11-14 weeks
• Amniocentesis: chromosomal analysis; 15-18 weeks
• Chorionic villous sampling: chromosomal analysis;
10-12 weeks
Normal nuchal thickening
Abnormal nuchal thickening
Chorionic villous sampling
Amniocentesis
Clinical Features
Diagnosis depends on
abnormal features
IN THE PRESENCE OF
mental retardation
& delayed motor development
(due to hypotonia)
Clinical Features
1) Mental retardation
• Moderate - severe range except in mosaic
• Manifested by delayed smiling, laughing &
recognition of mother .
2) Delayed motor development (Hypotonia)
• Delayed head support, sitting & standing
Clinical Features
3) Characteristic physical features
(in the absence of mental retardation, they should
NEVER be considered diagnostic)
Head
• Flat occiput
• Upward slanting of palpebral fissure
• Epicanthal folds
• Flat nasal bridge
• Malformed ears
• Protruded tongue
Clinical Features
Hands
• Simian crease (transverse palmar crease)
• Clinodactly (incurved little finger)
• Short broad hand
Feet
• Big space between the first and second toes
Down syndrome, child
Baby demonstrates the typical
features of Down syndrome
Brushfield spots
Brushfield spots
Brachycephaly
Simian Crease, Trisomy 21
Simian Crease, Trisomy 21
Short broad hand
Gap between first and second toes
Gap between first and second toes
Down Syndrome
Down Syndrome
Clinical Features
Associated congenital anomalies
1 - Congenital heart disease: (40% of cases)
Common atrioventricular canal or VSD
2 - GIT anomalies: Duodenal atresia
3 - Renal anomalies
Complications
1 - Recurrent chest infections: due to hypotonia and
CHD
2 - Leukemia : 20 times commoner in trisomy 21.
Genetic counseling
• Parents need information about
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short-and long-term implications of the diagnosis.
how and why the condition has arisen,
risk of recurrence
antenatal diagnosis for future pregnancies.
• > 85% of infants with trisomy 21 survive to 1 yr of age.
• Severe CHD is a major cause of early mortality.
• At least 50% of affected individuals live > 50 years.
Investigations
1) Karyotyping = chromosomal study
• To establish diagnosis
• To determine genetic type for genetic counselling & prognosis
2) Chest X - ray & echocardiography
for suspected congenital heart disease.
3) Others : hearing and vision testing and checking thyroid
profile due to increased risk of hypothyroidism
Management
• Supportive care :
1- Proper nutrition & medical care to diagnose and
manage possible complications.
2- Special social & educational care in specialized
institutes like speech therapy aiming to make the
child as independent as possible
Klinefelter syndrome
Cytogenetics 47,XXY, MALE
Incidence: 1/1000
Features
• Hypogonadism with small testes
• Gynecomastia
• Tall stature (tall legs)
• Infertility (most common presentation)
• A common but not a serious disease, which may
benefit from testosterone therapy
Klinefelter syndrome
Turner syndrome
Cytogenetics: 45, XO, FEMALE
Incidence: 1/5000
Features
• Lymphedema of hands and feet in newborn
• Short stature
• Webbing of neck
• Wide carrying angle
• Gonadal dysgenesis (1ry amenorrhea)
• Renal anomalies and cardiac anomalies
Turner syndrome
(Gonadal Dysgenesis)
At Birth .. Edema of dorsum of hand & feet
.. Webbing of neck.
Childhood period
- Short stature
- Head .. Low posterior hairline
- Neck .. Webbing of the neck
- Chest .. Broad chest & wide spaced nipples
- Limbs .. Cubitus valgus
Turner syndrome
Adolescence
- Failure of development of 2ry sex characters
- 1ry amenorrhea (streaked ovary)
- Normal mentality, Some learning disability
Associated anomalies & complications:
1- Cardiac anomalies: Bicuspid aortic valve –
AS - coarctation of aorta
2- Renal anomalies: Horseshoe kidney
3- Ear: Recurrent OM – SNH loss
Turner syndrome - Treatment
• Growth hormone therapy
• Oestrogen replacement for development of
secondary sexual characteristics at the time
of puberty (but infertility persists).
Turner Syndrome
Turner Syndrome, webbed neck
Turner Syndrome, webbed neck
Turner Syndrome, Lymphedema
Single gene disorders
Single gene disorders
• Every trait is represented by 2 genes, one from the
father and the other from the mother . When the 2
genes for any given trait are similar, the person is
homozygous for this trait . If the 2 genes are
different, the person is heterozygous.
• A dominant gene expresses itself whether
homozygous or heterozygous while recessive gene
expresses itself only when homozygous .
• Family pedigree means summarizing genetic data
that is collected by observing the patterns of
transmission of traits within the family
Autosomal dominant inheritance
Characteristics :
1 - Every affected person has an affected parent.
2 - Unaffected persons are normal, do not transmit the
trait, no carrier state
3 - The trait appears in every generation, no skipping
4 - The trait is transmitted by an affected person to 1/2 of
his children at least.
5 - Transmission of trait is not influenced by sex or
consanguinity; male to male transmission occurs
Autosomal dominant pedigree
Autosomal dominant inheritance
Examples : mostly structural abnormalities
1) Achondroplasia, Osteogenesis imperfecta
2) Neurofibromatosis
3) Congenital spherocytosis, Von willebrand disease
4) Fascioscapulohumoral muscle dystrophy
Autosomal dominant inheritance
Complicating factors include the following.
Variation in expression
Within a family, some affected individuals may
manifest the disorder mildly and others more
severely.
Non-penetrance
Refers to the lack of clinical signs and symptoms in
an individual who must have inherited the
abnormal gene.
Non-penetrance
Example of non-penetrance. I1 and III2 have otosclerosis.
II2 has normal hearing but must have the gene. The gene is non-penetrant in II2.
Autosomal dominant inheritance
No family history of the disorder
• A new mutation in one of the gametes.
• The most common reason for absence of a family history
in dominant disorders, e.g. >80% of individuals with
achondroplasia have normal parents.
Homozygosity
In the rare situation where both parents are affected by
the same autosomal dominant disorder, there is a 1 in 4
risk that a child will be homozygous for the mutant gene.
Autosomal dominant inheritance
Autosomal recessive inheritance
Characteristics:
1- Affected persons are only homozygous(2 abnormal
genes)
2- Unaffected persons can be normal or carriers
(1 abnormal gene)
3- The parents of the affected child may be
consanguineous
(strong relation to consanguineous marriage)
4- Both parents of affected child have affected gene.
5- On the average1/4 of sibs (recurrence risk is 25%) of
affected child are also affected.
Males & females are equally affected.
6-The trait appears mainly in sibs of patient not
his parents or off springs.
Autosomal recessive inheritance
Autosomal recessive inheritance
Pedigree to show autosomal recessive inheritance.
Autosomal recessive inheritance
Autosomal recessive Inheritance
• Usually there is no previous family history
• The most likely place to find a second affected
child is a sibling of the first
Autosomal recessive inheritance
• Inbreeding increases the chance of observing an
autosomal recessive condition
• e.g. Cystic fibrosis, sickle cell disease,
Tay Sachs disease.
Autosomal recessive inheritance
Examples : mostly defective enzymatic activity
- Galactosemia, phenylketonuria
- Thalassemia and sickle cell anemia
- Albinism
- Werdnig - Hoffman's disease
Sex-linked recessive inheritance
Characteristics :
1- The trait is expressed by all males who carry the
gene, but females are affected only if they are
homozygous (only if father is affected & mother is
carrier) .
2- The trait is never transmitted from a father to his
son, no male to male transmission
3- Unaffected males give unaffected offspring (unless
marries a carrier female)
4- An affected male passes the gene through all his
daughters (carriers) to half their sons who become
diseased and half their daughters who become
carriers .
X-linked recessive inheritance
X-linked recessive inheritance
X-linked recessive inheritance
• Over 400 disorders
• Males are affected
• Females can be carriers but are usually healthy
• Each son of a female carrier has a 1 in 2 (50%) risk of
being affected
• Each daughter of a female carrier has a 1 in 2 (50%) risk
of being a carrier
• Daughters of affected males will all be carriers
• Sons of affected males will not be affected, since a man
passes a Y chromosome to his son.
X-linked recessive inheritance
X-linked recessive inheritance.
Sex-linked dominant inheritance
Characteristics :
1- Affected male transmits the trait to all his daughters
but none of his sons .
2- Heterozygous female transmit the trait to 1/2
children of either sex while homozygous female
transmit the trait to all children of either sex (in the
same way as autosomal dominant).
Examples :
1 - Vitamin D resistant rickets
2 - Pseudohypoparathyroidism
• The key for determining if a dominant trait is X-linked or autosomal is to look at
the offspring of the mating of an affected male and a normal female.
• If the affected male has an affected son, then the disease is not X-linked.
• All of his daughters must also be affected if the disease is X-linked.
• In Pedigree 5, both of these conditions are met.
X-linked dominant inheritance
• The trait is never passed from father to son.
• All daughters of an affected male and a normal female are
affected. All sons of an affected male and a normal female are
normal.
• Matings of affected females and normal males produce 1/2
the sons affected and 1/2 the daughters affected.
• Males are usually more severely affected than females. The
trait may be lethal in males.
• In the general population, females are more likely to be
affected than males, even if the disease is not lethal in males.
Exercises
?
?
A. Autosomal Dominant
B. Autosomal Recessive
C. Sex linked recessive
D. Sex linked Dominant
E. None of the Above
?
a. Mode of inheritance? Autosomal Dominant
b. Why?
All generations, no skipping, males and females
?
3. a. Mode of inheritance? X- linked Recessive
b. Why?
Only males affected,
unaffected parents (moms) pass it on…
?
?
a) A.R. – unaffected parents pass it on to offspring
– males and females affected
b) A.R. – consanguineous marriage
– female affected
– unaffected parents
Fragile X syndrome
•The prevalence of severe learning difficulties in males
due to fragile X syndrome is about 1 in 4000.
•This condition was initially diagnosed on the basis of
the appearance of a gap (fragile site) in the distal part
of the long arm of the X chromosome.
•Diagnosis is now achieved by molecular analysis of
the CGG (Cytosine-Guanine-Guanine) trinucleotide
repeat expansion in the relevant gene (FMR1)
Fragile X syndrome
Fragile X syndrome
Trinucleotide repeat expansion mutation
FMR1 (fragile X mental retardation 1) is a human gene that codes
for a protein called fragile X mental retardation protein, or FMRP
Trinucleotide repeat expansion mutation
Fragile X syndrome
•These unusual findings are explained by the nature of
the mutation, which occurs in 'pre-mutation' and 'full
mutation' forms.
•Norma copy of gene < 50 copies of CGG trinucleotide.
•Genes with premutation contain 55-199 copies.
•Genes with full mutation contain > 200 copies of CGG.
•This big number affects gene function, leading to
learning disabilities.
A child with fragile
X syndrome. At this
age, the main
physical feature is
often the prominent
ears.
Fragile X syndrome
Fragile X syndrome
Clinical findings in males in fragile X syndrome
• Moderate-severe learning difficulty (IQ 20-80, mean 50)
• Macrocephaly
• Macro-orchidism - postpubertal
• Characteristic facies - long face, large everted ears,
prominent mandible and broad forehead, most evident in
affected adults.
• Other features - mitral valve prolapse, joint laxity,
scoliosis, autism, hyperactivity
•Fragile X syndrome is the second most common genetic
cause of severe learning difficulties after Down's
syndrome.
Multifactorial (polygenic) inheritance
• It results from interaction between genetic
predisposition and environmental factors
• Such disorders are much common than single gene
disorders with much lower recurrence risk
• Examples are cleft lip, congenital heart disease,
spina bifida, pyloric stenosis; and in later life
diabetes, hypertension and asthma
Mitochondrial inheritance
• Mitochondria are cytoplasmic organelles that
function as major energy producers for the cell and
contain their own DNA (mt DNA).
•Sperm do not contain mitochondria, so a father with
a disorder due to a mitochondrial DNA mutation will
not have affected children.
• Mitochondrial DNA mutations show only maternal
transmission.
Mitochondrial inheritance
Common teratogens
• Maternal illness, DM, HTN, Epilepsy
• Maternal infections, TORCH
• Drugs and toxins
– Thalidomide, anticogulants, anticonvulsants,
psychiatric drugs
• Alcohol and smoking.
– Fetal alcohol syndrome
• Ionizing radiation
Dysmorphology
The term 'dysmorphology' literally means 'the
study of abnormal form' and refers to the
assessment of birth defects and unusual
physical features that have their origin during
embryogenesis.
Pathogenic mechanisms
Malformation
A primary structural defect occurring during the
development of a tissue or organ, e.g. spina
bifida and cleft lip and palate.
Deformation
Implies an abnormal intrauterine mechanical
force that distorts a normally formed structure,
e.g. clubfoot, congenital hip dislocation
Pathogenic mechanisms
Disruption
Involves destruction of a fetal part which
initially formed normally; e.g. amniotic
membrane rupture may lead to amniotic bands
which may cause limb reduction defects.
Dysplasia
Refers to abnormal cellular organization or
function of specific tissue types, e.g. skeletal
dysplasias and dysplastic kidney disease.
Disruption
Pathogenic mechanisms
Sequence
Refers to a pattern of multiple abnormalities occurring after
one initiating defect. Potter's syndrome (fetal compression
and pulmonary hypoplasia) is an example of a sequence in
which all abnormalities may be traced to one original
malformation, renal agenesis.
Association
A group of malformations that occur together more often
than expected by chance, but in different combinations
from case to case, e.g. VACTERL association (Vertebral
anomalies, Anal atresia, Cardiac defects, TracheoEsophageal fistula, Renal anomalies, Limb defects).
Pathogenic mechanisms
Syndrome
When a particular set of multiple anomalies
occurs repeatedly in a consistent pattern, this is
called a 'syndrome'.
Early diagnosis of single gene disorders
• Prenatal diagnosis
for thalassemia and Duchenne myopathy
• Presymptomatic diagnosis for some autosomal
disorders with onset in later life
• Carrier detection for x-linked disorders as
hemophilia and Duchenne myopathy by testing
factor VIII and creatine kinase in suspected females.
DNA markers are more accurate.
Genetic counselling
• It is providing information about hereditary disorders
i.e. its meaning, risk, and prevention or treatment if
any
• Components:
1) Correct diagnosis by history, examination and
investigations including DNA testing
2) Risk estimation
3) Communication with family
4) Discussion of options for prevention and treatment if
any
Genetic counseling, indications
1. Advanced maternal age
2. Consanguinity
3. Child with congenital anomalies or
dysmorphic
4. Maternal history of stillborn with congenital
anomaly
Gene therapy
• It is the artificial introduction of genes into disease
tissue in order to cure the diseases
• Steps  Integration of the introduced gene into the
chromosomal DNA of recipient cells by transferring
the gene into suitable cells and then inserting the
transfected cells into the patient
• One example is cystic fibrosis
Gene therapy
Thank You