2. Terminology
• Aneuploidy : a chromosomal profile with fewer or greater than normal
diploid number .
• Exon: portion of DNA that codes for the final mRNA , then translated into
protein .
• Mosaic : an individual with abnormal genotypic or phenotypic variation from
cell to cell within same tissue .
• Homozygous : a genotype consisting of two identical alleles of a gene for a
particular trait.
• Heterozygous : a genotype consisting of two different alleles of a gene for
a particular trait .
6. Chromosomal Abnormalities:
2. Deletion.
Part of a chromosome is missing, or part of the DNA
code is missing.
1-Cri du chat syndrome (5)
MR,spasticity,high pitched cry,craniofacial abnormalities
2-Prader-willi syndrome (15) (paternal inheritance)
N.Hypotonia ,facial obesity,low IQ,short,genital hypoplasia .
3-Angelman syndrome (15) (maternal inheritance)
Hypertonia ,ataxic gait ,prominent jaw ,absent speech ,MR
( happy puppet syndrome ) .
7. Chromosomal Abnormalities
3.Inversion.
When a chromosome breaks and the piece of the chromosome turns upside
down and reattaches itself. Inversions may or may not cause birth defects
depending on their exact structure.
E.g: benign familial neonatal convulsions (BFNC) - fifth day fits
10. Single Gene Abnormalities
• Also known as Mendelian inheritance disorders.
• Mutation can be inherited or occur spontaneously .
• Result from point mutation ,deletion,insertion,inversion and triplet repeat
expansion .
1. Autosomal Dominant .
2. Autosomal Recessive .
3. X-linked Dominant.
4. X-linked Recessive .
11. Autosomal Dominant Diseases
Both sexes are equally affected .
The defect may be transferred from the either Parents .
offspring have a 50 % chance of inheriting the defect
If one of the parents is heterozygous and the other
normal .
Offspring of unaffected individual are not affected .
High new mutation rate .
Rare and generally less severe than AR.
12. Autosomal Dominant Diseases
• Can exhibit variable expressivity (range of phenotypes )
Example: TS can be asymptomatic with harmless kidney cysts or fatal in next
generation due to brain malformation .
• Can exhibit anticipation .
Occurrence of disease with progressively earlier age of onset in successive
generations (eg. in triplet repeat expansion disease )
13. Examples of AD
• Facioscapulohumeral muscular dystrophy .
• Gilles de la Tourette syndrome .
• HSMN e.g :Charcot-Marie-tooth syndrome .
• Huntington’s chorea .
• Myotonic dystrophy .
• NF I and II .
• TS.
• Von Hippel-Lindau disease .
21. Autosomal Recessive Diseases
• Both sexes are equally affected .
• Only manifests in homozygous state. Heterozygous will be
carrier
• If both parents are heterozygous :
1. Chance of being normal 25%
2. Chance of expressing the trait 25%
3. Chance of being a carrier of the trait 50%
• If only one parent is heterozygous and other homozygous
dominant :
1. 50% will be normal .
2. 50% carriers will be .
22. Autosomal Recessive Diseases
• Asymptomatic carrier produce affected children .
• Those with the disease do not usually have affected children
unless marry a carrier (increase risk of disease among
offspring of consanguineous marriages)
• Ethnic associations: in Jews (e.g: Tay-Sachs disease ,
Gaucher disease )
23. Examples of AR.
• Friedreich’s ataxia
• Ataxia telangictasia
• Limb-girdle muscular dystrophy
• Most of IEM (e.g. galactosaemia ,GSD,Homocystinuria ,PKU,Lipidosis and
MPS)
• SMA I (werding-Hoffman disease )
• Wilson’s disease
• Xeroderma pigmentosa
24.
25. X linked Recessive Inheritance
• Incidence is much higher in males but not inevitable .
• Affected cases are usually males carrying the gene
and homozygous females (rare ).
• Half the sons of carriers are affected and half of
daughters are carriers.
• No male to male transmission .transmitted via carrier
women .
• Affected males can have only normal sons and
carrier daughters .
• Most X-linked illnesses are recessive .
27. X linked Dominant Inheritance
• Affects both sexes , but females more than males .
• All children of affected homozygous females are affected .
• Females pass the trait to half their sons and half their daughters .
• All daughters of affected males are affected ,but none of their sons .
Examples :
Rett syndrome
X-linked lissencephaly
Double cortex syndrome
Incontinentia pigmenti type 1
28. Mitochondrial Disease
• Mitochondria are cellular organelles that are
intimately involved in intermediate metabolism .
• All mitochondrial DNA is derived from the
mother’s ovum (maternal inheritance ). But not
all diseases mitochondrion inherited in
matrilineal fashion .
• Inheritance is largely nonmendelian .
• Most mitochondrial diseases that affect Krebs
cycle and diseases of fatty acids oxidation are
inherited in mendelian fashion .
29. Mitochondrial Disease
• Examples of matrilineal inheritance (mitochondrial DNA)
Kearns-sayre syndrome
MERRF (myoclonic epilepsy with ragged red fibers) .
MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke
like episodes .
Leber optic atrophy .
• Examples of Nuclear inheritance
Pyruvate dehydrogenase deficiency
Respiratory chain abnormalities (e.g Leigh syndrome )
30. Trinucleotide repeats
• Are diseases associated with an increase number of oligonucleotides .
• The severity of disease type relates directly to number of repeats .
• Associated with the phenomenon of anticipatory inheritance .
• More sever in siblings than parents
31. Lysosomal diseases
• Lysosomes are subcellular vesicles that contain
enzymes responsible for the degradation of
catabolic products .
• Lysosomal storage diseases are a
heterogeneous group of rare inherited disorders
.
• characterized by the accumulation of
undigested or partially digested
macromolecules, which ultimately results in
cellular dysfunction and clinical abnormalities.
• Most of lysosomal diseases are recessive .
32.
33.
34.
35. Multifactorial
• Some birth defects do not follow a single gene or chromosomal abnormality
pattern.
• They may be due to several problems, or a combined effect of genes and
the environment.
• It is difficult to predict inheritance of abnormalities caused by multiple
factors.
• Example : neural tube defects .
36. Teratogenic
• Exposure to teratogen during the first trimester of pregnancy when organs
are forming. Some known teratogens include the following:
• Certain medications (always consult your doctor before taking any
medications during pregnancy)
• Alcohol
• Maternal diabetes
• High level of radiation exposure
• Lead
• Certain infections (such as rubella)
37. Types of GeneticTesting
• Diagnostic testing :
The aim of diagnostic testing is to confirm or exclude a diagnosis ,which can guide:
1- future management.
2- predict prognosis .
3- clarify the genetic risk to family members.
• Pre-symptomatic testing:
A pre-symptomatic/predictive test is an indication of future risk rather than current clinical
status.
• Carrier testing:
Carrier testing is undertaken when there is a family history (cascade testing) or when an
individual is part of an at risk population.
e.g: female carriers of the gene causing X-linked adrenoleukodystrophy
38. LaboratoryTechniques
• Cytogenetics (chromosome analysis)
1- karyotyping
Counting and visualizing appearance of chromosomes under a light microscope.
2- Array comparative genomic hybridization (aCGH)
- Has replaced karyotyping
- Arrays can detect copy number variants such as deletions and duplications across
the whole genome at high resolution
3- Fluorescence in situ hybridization (FISH)
For identifying deletion or duplication
39. LaboratoryTechniques
• Molecular genetics (DNA analysis)
• Small genetic changes (one or a few base pairs) can be detected using DNA
sequencing
• E.g: those detecting trinucleotide repeats (e.g. Huntingdon’s disease,
Friedreich’s ataxia, some spinocerebellar ataxias, fragile X).
• deletions and insertions of whole exons or genes that may be too small to be
detected by aCGH or FISH but too large to be reliably detected by sequencing.
Multiplex ligation dependent probe amplification (MLPA) technology addresses
these issues,
40. LaboratoryTechniques
• Panel testing:
multiple genes, generally around 10-200, is effective for clinically similar but genetically
heterogeneous disorders such as spastic paraplegia, ataxia, Joubert’s syndrome and
epilepsy .
• Whole-exome sequencing:
Exomes are selected and sequenced. This equates to less than 2% of the total
genome so is cheaper and faster than sequencing an entire genome.
This strategy is used because most disease-causing mutations are thought to occur in
the exome. whole exome is sequenced but only genes of clinical interest are analysed.
Analysis is quicker and cheaper. If an answer is not found on this analysis, the entire
exome is available for later testing.
