Far Eastern University Nicanor Reyes Medical Foundation

Pathology A Genetic Disorders

Jocelyn Q. Gacasan M.D.
Genetics
Study of a single or a few genes and their phenotypic effects.
Genomics
Study of all the genes in the genome and their interactions.
Proteomics
Measurement of all the proteins expressed in a cell or tissue.
GENETIC DISORDERS
More common than appreciated, there are many existing cases
of genetic disorders that are not being observed.
Lifetime frequency of 670 per 1,000
This includes classic genetic disorders, cancer, and cardiovascular
diseases.
Definition of terms
HEREDITARY
Derived from parents and transmitted through the germ line.
Genetically acquired and inherited from the parents.
FAMILIAL
It runs in the family.
CONGENITAL
Present at the time of birth.
It does not necessarily mean it is hereditary.
Congenital Syphilis
Hereditary diseases on the other hand, do not also mean it is
congenital, because there are hereditary diseases that manifest
when an affected individual reaches adulthood.
Huntingtons disease usually manifests at 20 y/o.
MUTATIONS
A permanent change in the DNA make up of an individual.
Germ Cells may give rise to the inherited diseases.
Somatic Cells do not give rise or do not cause hereditary
diseases but they are important in the genesis of cancers and
some congenital malformations.
TYPES OF MUTATIONS
1.) Point mutations with coding sequences

A single nucleotide base is substituted by a different base.

Missense Mutation alters the genetic code and protein output.
Conservative Missense replaced AA is biochemically the
same as the previous amino acid.
Non-conservative Missene replaced with biochemically
different AA.
Nonsense Mutation produces a stop codon and terminates the
sequence (UAG, UGA, UAA).
In sickle cell anemia, thymine is replaced with adenosine. The previous
triplet: CTT, which codes for glycine, is replaced with CAT which now
codes for valine. The RBC phenotypically manifests a sickle shape rather
than biconcave disc shape.

2.) Mutations within non-coding sequences

Does not involve mutations of the exons.
Mutations here involve regulatory sequences that may interfere
with binding of transcription factors.
Involves promoters and enhancers.
Defective splicing, no mature mRNA, and translation does not
occur.
Example is Thalassemia.
3.) Frameshift Mutation

Involves deletion or insertion of one or two amino acids.

Insertion or deletion in the DNA sequence may disrupt the
reading frame, it may displace it forward (insertion) or displace it
back (deletion).
However, if 3 base pairs are inserted, there will be no frameshift,
but the amino acid that is translated is different.
Example is the deletion of a base pair in ABO alleles.
4.) Trinucleotide Repeats
Amplification of sequences in 3 nucleotides.
Commonly affects cytosine and guanine.
Dynamic, it continues to amplify through generations.
In fragile X syndrome, FMNR1 gene have 250-4,000 CGG repeats
In a normal population, the amount of repeats is only small,
averaging to about 29 repeats.

Page 1 of 10

TYPES OF GENETIC DISORDERS

1.) Single Gene Mutation Disorders (Mendelian Disorders)
With large effects.
Highly Penetrant
Follows the Mendelian pattern of inheritance.
2.) Chromosomal Disorders
Arise from structural or numerical alteration in the autosomes or
sex chromosomes.
Uncommon and highly penetrant.
Ex: Monogenic disorders
Visible with karyotyping.
3.) Complex Multigenic Disorders
Most common form
Polymorphisms
Multifactorial: interaction of genes and environmental factors.
4.) Single Gene Disorders with Non-classic inheritance
VARIABLE EXPRESSIVITY
A trait seen in all carriers of the disease, but expresses the
mutation differently.
Same genotype, different degrees of phenotype.
Ex: Neurofibromatosis
Some manifests macule type of lesions (brown spots)
Some manifests with tumors.
PENETRANCE
Expressed mathematically in terms of percent.
50% penetrance means 50% of those who carry the gene express
the trait or the phenotype.

CO-DOMINANCE
Both of the alleles of the gene pair, dominant and recessive,
contribute to the phenotype.
Ex: Blood group antigens
PLEIOTROPISM
A single mutant gene leads to multiple end effects
GENETIC HETEROGENEITY
Mutations at the several loci may produce the same trait
A.) MENDELIAN PATTERN OF DISORDERS
Result of expressed mutation of single genes of large effect.
More than 4,500 mendelian disorders
Each person is a carrier of at least 5-8 recessive mutant genes.
80-85% are familial, 15-20% are new mutations (de novo).
Transmission patterns
1. Autosomal Dominant
2. Autosomal Recessive
3. X-linked
1.) Autosomal Dominant
Manifested both in homozygous and heterozygous states
Some without affected parents, results from de novo mutation.
Both male and female can transmit the disease.
An affected one marrying a normal one, 1 out of 2 children may
manifest the disorder (50%)
De novo or new mutations may arise in germ cells of older father
Reduced Penetrance and Variable Expressivity.
Onset may be delayed.

AUTOSOMAL AND SEX-LINKED

Autosomal: Located in the autosomes (22 autosomes)
Sex-linked: Located in the X and Y chromosomes
RECESSIVE
Expressed only when the individual is homozygous.
The individual must have the 2 recessive genes on both
chromosomes to be affected with the disease.
DOMINANT
Expressed in homozygous or heterozygous forms.
The individual only needs 1 dominant gene to manifest the
disease. The dominant gene in heterozygous form masks the
expression of the recessive gene.

Homozygous Dominant
Heterozygous Dominant
Homozygous Recessive

Page 2 of 10

Alleles Present
Dominant,
Dominant
Dominant,
Recessive
Recessive,
Recessive

Allele Expressed
Dominant
Dominant
Recessive

The biochemical mechanism of autosomal disorders depend

upon the nature of the mutation and the type of protein affected
Many autosomal dominant disorders arise from deleterious
mutations and result to mutations of:
Those involved in regulation of complex metabolic
pathways that are subject to negative feedback inhibition - Ex: Familial Hypercholesterolemia
Key Structural Proteins
- The product of the mutant allele can interfere with the
assembly of normal and functional multimeric proteins.
- Ex: Osteogenesis imperfecta

 Autosomal dominant mutations usually affect:

Non enzyme Proteins
Regulatory Proteins
Complex Structural Proteins
Loss-of-function mutations
More common
Dominant negative impairs the function of normal alleles
Gain-of-function mutations
Results in an increase in a protein[s normal function.
Imparts a wholly new activity completely unrelated to the
affecter proteins normal function.
Ex: Huntingtons disease results from generation of the
huntingtin protein which is toxic to the neurons.

3.) Sex-linked Disorders

Affected Male:
zDo not transmit the disease to the sons
But all daughters are carriers.
Heterozygous Females are carriers.
Sons have 1:2 chances of being affected (50%)
Females have 1:2 chances of being a carrier

2.) Autosomal Recessive

Single largest category of the mendelian disorders.
Both alleles at a given gene locus are mutant.
More uniform clinical expression of the defect.
Complete Penetrance is common.
Early onset, rarely de novo, rarely detected.
Enzyme products are affected.

Parents do not manifest the disorder but they are carrier of the
recessive gene.
1 in 4 chances a child can manifest the disease (25%)
If the gene occurs at low frequency, it is likely a product of a
consanguineous marriage.

Page 3 of 10

There is no Y-linked disorder, although it is possible, because

males with mutations affecting the Y-linked genes are usually
infertile.
X-linked recessive is the most common cause of sex-linked
disorders, the Y chromosome is not homologous to X, and so
mutant genes on X have no corresponding gene to the Y
chromosome, hence males are said to be Hemizygous for Xlinked disorders.
Females do not manifest the disease because there is an extra
normal X chromosome. However, there are chances that the
normal X chromosome get silenced and the abnormal X
chromosome be fully expressed.
There are few X-linked dominant disorder like Vitamin-D
resistant rickets.

BIOCHEMICAL AND MOLECULAR BASIS OF MENDELIAN DISORDERS

1. Enzyme defects
2. Defects in membrane receptors and transports
3. Structural and Functional protein defects
4. Unusual reaction to drugs

D.) Adverse reaction to drugs

The manifestation of the disease unmasks only after exposure to
a certain drug.
Drug-induced injury to genetically susceptible individual.
Ex: G6PD Deficiency (Glucose-6 phosphate dehydrogenase)
Primaquine, an anti-malarial drug, causes hemolytic anemia

A.) Enzyme defects

Synthesis of an enzyme with reduced activity or reduced amount

of the normal enzyme.
Results to:
Accumulation of substrates
- Can be accompanied by accumulation of one or more
intermediate substrates which are toxic to the tissues.
Ex: Lysosomal storage diseases
Metabolic block with decreased end product
May cause loss of function
Ex: Albinism (Tyrosinase enzyme defect)
- If the end product involves a negative feedback process,
the deficiency of the end product may permit
overproduction of the intermediates which are toxic to
the tissues.
Ex: Lesch Nyhan disease
Failure to inactivate tissue damaging substrate.
Absence of a regulatory component.
Ex: 1-antitrypsin deficiency.
- Patients with this deficiency dont have 1-antitrypsin
which inactivates neutrophil elastase in the lungs.
Without the antitrypsin, elastic structures of the lungs
are destroyed leading to emphysema.
B.) Defects in membrane receptors and transport system
Defective transport may result to accumulation inside the cell
Ex: Familial Hypercholesterolemia
Decreased synthesis of LDL-Receptors may lead to defective
transport of LDL to the liver cells.
Ex: Cystic Fibrosis
Defective transport system of Cl ions in exocrine glands
C.) Alteration in structure, function, or quantity of non-enzyme proteins
Often have widespread effects
Defects in the structural proteins.
Ex: Sickle Cell Anemia
Defects in the structure of globin molecules
Ex: Osteogenesis imperfecta

Page 4 of 10

MARFAN SYNDROME
Structural protein defect
A disorder of connective tissues manifested principally by
changes in the skeleton, eyes, and cardiovascular system.
Approximately 70-85% of the cases are familial and autosomal
dominant, remainder of it is sporadic.
Inherited defect in the extracellular glycoprotein Fibrillin.
Fibrillin 1 (FBN1) 15q21 for Marfan Syndrome
Fibrillin 2 (FBN2) 5q23 for Congenital Contractual
Arachnodactyly
The fibrils provide a scaffold on which tropoelastin is deposited
to form elastic fibers.
Most of these are missense mutations that give rise to abnormal
fibrilin-1 fibers, there can inhibit polymerization of fibrillin fibers
(dominant negative effect).
The reduction of the fibrillin content results to weakening of the
connective tissue (haploinsufficiency).
Loss of microfibrils results to activation of TGF-.
Excessive TGF- activates metalloproteases causing degradation
of extracellular matrix.
In other Marfan syndrome individuals, there is no mutation of
FBN1 but there is a mutation of the gene that encodes for TGF-
receptors.
Morphological Changes in Marfan Syndrome
Skeletal and Eyes
Unusually tall with exceptionally long extremities and long,
tapering fingers and toes.
Double jointed, can extend the thumb to the back of the wrist.
Frontal Bossing, Kyphoscholiosis, Pectum Excavatum.
Bilateral Ectopia Lentis
Cardiovascular Lesion
Two most common lesions:
1. Mitral prolapse
2. Dilation of the ascending aorta due to cystic medionecrosis.
Loss of medial support results in the progressive dilation of the
aortic valve ring and the root of aorta resulting to aortic
incompetence.
Weakening of the tunica media can predispose to tunica intima
tear, which may initiate intramural hematoma and cleave the
layers of the media producing aortic dissection.

EHLER-DANLOS SYNDROME
EDS comprise a clinically and genetically heterogeneous group of
disorders that result from some defect in the synthesis or
structure of collagen fibers.
The mode of inheritance encompasses all the 3 mechanisms of
mendelian pattern.
The tissues rich in collagen have a lack in tensile strength.
The skin is extraordinarily hyperextensible
The joints are hypermobile.
The internal structures that contain collagen (e.g. arteries, eyes,
colon) can rupture, detach, or herniate.
6 variants of EDS:
EDS Type
Classic
(I, II)
Hypermobility
(III)
Vascular (IV)

Kyphoscoliosis
(VI)
Arthrochalasia
(VIIa, b)
Dermatosparaxis
(VII c)

Findings
Skin and Joint hypermobility,
atrophic scars, easy bruising
Joint hypermobility, pain,
dislocations
Thin skin, arterial or uterine
rupture, bruising, small joint
hyperextensibility
Hypotonia, joint laxity, congenital
scoliosis, ocular fragility
Severe joint hypermobility, skin
changes, scoliosis, bruising
Severe skin fragility, cutis laxa,
bruising

Inheritance
Autosomal
Dominant
Autosomal
Dominant
Autosomal
Dominant
Autosomal
Recessive
Autosomal
Dominant
Autosomal
Recessive

FAMILIAL HYPERCHOLESTEROLEMIA
Receptor Disease
A mutation in the gene encoding the receptor for LDL
Chromosome 19 encodes for the LDL Receptors
Most frequent mendelian disorder, autosomal dominant.
Heterozygous have 50% normal LDL receptors.
Presence of Xanthomas
Elevated levels of cholesterol can induce premature
atherosclerosis.
5 Classes:

Page 5 of 10

LYSOSOMAL STORAGE DISEASES

Lysosomes are key component of the intracellular digestive tract,
they contain hydrolytic enzymes that have two special properties
First, they function in the acidic milieu of the lysosomes.
These enzymes constitute a special category of secretory
proteins that are destined not for the ECF but for the
intracellular organelles.
Lysosomes catalyze complex macromolecules via autophagy or
heterophagy.
Causes of lysosomal storage diseases:
Missing enzyme
- Called primary accumulation
Lack of Enzyme Activator or protein protector
Lack of Substrate Activator protein
Lack of transport protein
The lysosomal defects can lead to two pathologic consequences:

This leads to an incomplete digestion of the macromolecule

stuck inside the lysosome, also called primary
accumulation.
Impaired autophagy can give rise to secondary
accumulation of autophagic substrates such as
polyubiquinated proteins and old mitochondria.

LYSOSOMAL STORAGE DISEASES

1.) Tay-Sachs Disease
Accumulation of GM2 Ganglioside.
Hexosaminosidase A deficiency ( -subunit, chromosome 15)
Prominent CNS component
S/Sx appear at 6 months:
Motor and mental retardation, Blindness
Vegetative at 1-2 y/o, Death at 2-3 y/o
Cherry red spot on fundoscopy
Neurons present with cytoplasmic lipid vacuole, and appear as
whorled configurations on electron microscopy.

2.) Niemann-Pick Disease (Types A and B)

Lysosomal accumulation of sphingomyelin.
Spingomyelinase deficiency, typically autosomal recessive.
Evident at 6 months.
Type A secere infantile form with extensive neurologic
involvement.
Type B Have organomegaly but generally no central nervous
system involvement, usually survives into adulthood.
Cherry red spot is seen in 1/3 of cases.
Fine vacuolization of phagocytic cells.
Zebra bodies in electron microscopy.

3.) Gauchers Disease

A cluster of autosomal recessive disorder resulting from the
mutation of the glucocerebrosidase gene.
Accumulation of glucocerebroside in phagocytes.
Changes in Gaucher disease are also caused by activation of
macrophages and the consequent secretion of cytokines.
Three clinical subtypes:
Type I
- Chronic non-neuropathic form
- Most common, 99% of cases.
- Splenic and skeletal involvements dominate this type.
- Glucocerebrosides are limited to mononuclear phagocytes
- Has a predilection for Jewish of European stock.
Type II
- Acute neuropathic form
- Infantile cerebral pattern
- Hepatosplenomegaly, convulsions, mental retardation
- Progressive CNS Involvement
- Early death
Type III
- Intermediate between types I and II
The phagocytic cells have a crumpled-paper appearance.

Page 6 of 10

4.) Mucopolysaccharidoses (MPS)

Typically autosomal recessive, except Hunter syndrome
Due to deficiency of enzyme that degrades GAGs.
Present with severe somatic and neurologic changes
(retardation).
Some types of MPS:
MPS I (Hurler Syndrome)
Most severe form
L-iduronidase deficiency
Normal at birth
MPS II (Hunter Syndrome)
X-linked
L-iduronosulfate sulfatase deficiency
Coarse facial features
Clouding of the cornea, joint stiffness
Organomegaly, subendothelial deposits
Zebra bodies and Balloon cells

GLYCOGEN STORAGE DISEASES

Defects in the synthesis or catabolism of glycogen
Autosomal recessive
Can be divided into 3 major sub groups:
Hepatic Form von Gierkes disease
Glucose 6 Phosphatase deficiency
Hepatomegaly and Hypoglycemia
Myopathic Form McArdles disease
Muscle phosphorylase deficiency
Myopathy, muscle cramps after exercise
Failure of lactate to rise after exercises
Muscle weakness
Miscellaneous Form Pompes disease
Acid Maltase (-glucosidase) deficiency.
Storage in heart
Prominent cardiomegaly

ALKAPTONURIA (Ochronosis)
Autosomal recessive
Deficiency of homogentisic acid oxidase.
Black color of urine (alkaptonuria)
Blue-black discoloration of collage (ochronosis)
Arthropathy due to deposition in joints.
B.) COMPLEX MULTIGENIC DISORDERS
Environmental influences and the mutant gene have additive
effects.
Dosage effect the greater the number of inherited deleterious
genes, the more severe the expression of the disease.
Multifactorial disorders:
Cleft lip or Cleft palate (or both)
Congenital Heart Disease
Coronary Heart Disease
Hypertension
Gout
Diabetes mellitus
Pyloric stenosis
C.) CHROMOSOMAL DISORDERS
Humans have either 46XY or 46XX.
Chromosomal result from either alteration in number or in
structure.
Karyotyping
Study of chromosomes.
Also called metaphase spread.
Chromosome pairs are arranged in order of decreasing length.
Total number of chromosomes + sex chromosome + description
of the abnormality:
Ex: 47, XY, +21 (Trisomy 21 male)
Nice to know but not included in the exam:
Each chromosome has 2 arms:
p = short arm, q = long arm.
Each arm is divided into region, bands, and sub-bands.
Disorders or mutations in a specific site of a chromosome is
named as:
[Chromosome number][arm][region][band].[sub-band]
Ex: Xp21.2, meaning there is a mutation in the short arm of the X
chromosome at region 1, band 1, sub-band 2.

Chromosomal Disorders
Chromosomal Number:
Euploidy exact multiple of the haploid
Aneuploidy not an exact multiple of 23
Monosomy (2n-1)
Trisomy (2n+1)

Page 7 of 10

Causes of Aneuploidy
Non-disjunction
When this occurs during gametogenesis, the gametes
formed have either an extra chromosome (n+1) or one less
chromosome (n-1)
Anaphase lag
One homologous chromosome in meiosis or one chromatid
in mitosis lags behind and is left out of the cell nucleus.
One cell is normal, and one is monosomy.
Monosomies involving an autosome generally cause loss of too
much genetic information to permit live birth or even
embryogenesis, but several autosomal trisomies do permit survival.

Structural aberrations
Inversion

Two breaks and inverted reincorporation

Paracentric involves only one arm of the chromosome.
Pericentric breaks are on the opposite sides of the centromere.
Isochromosome Formation

Loss of one arms followed by the duplication of the two

remaining arms.
The chromosome either only contains 2 short arms or 2 long
arms.
Translocation

A segment of one chromosome is transferred to another.

Balance reciprocal translocation single breaks in each of two
chromosome with exchange of material.
Centric fusion or Robertsonian fusion long arms of one is
transferred to the short arm resulting to one very long and one
very short arm.

Deletion

TRISOMY 18 (Edward Syndrome)

Most severe malformation
Meiotic non-disjunction
Rarely revives beyond one year

Loss of a portion of the chromosome.

Most deletions are interstitial but rarely terminal deletions may
occur.
Interstitial deletions occur when there are two breaks within a
chromosome arm, followed by loss of the chromosomal material
between the breaks and fusion of the broken ends.
Ring Chromosomes

Deletion of both the ends of the chromosome and fusion of the

damaged ends.
Cytogenetic Disorders involving Autosomes
1. Trisomy 21 Down Syndrome
2. Trisomy 18 Edwards Syndrome
3. Trisomy 13 Patau Syndrome
4. Chromosome 22q11.2 deletion syndrome

TRISOMY 13 (Patau Syndrome)

Also due to meiotic non-disjunction

TRISOMY 21 (Down Syndrome)

Most common chromosomal disorder
Major cause of mental retardation (80% have 25-50 IQ).
Due to meiotic non-disjunction.
Maternal age has a strong influence on the incidence.
Increased risks:
Coronary Heart Disease (40%)
Acute Leukemia
Alzheimers Disease
Abnormal Immunity

CHROMOSOME 22q11.2 DELETION SYNDROME

Spectrum of disorders
Result from a small deletion of band q11.2 in the long arm of
chromosome 22.
A fairly common syndrome occurring in 1 in 4,000 births.
Clinical features and manifestations:
Congenital Heart Defects
Facial Dysmorphism
Developmental delay
Variable T-cell deficiency with hypocalcemia

Page 8 of 10

Fluorescence in Situ Hybridization

Left: Trisomy, Right: Deletion

Cytogenetic Disorders Involving Sex Chromosomes.
More common than autosomal abnormalities.
Better tolerated.
Not usually recognized until puberty
Increase in number of X chromosome is associated with mental
retardation.
Lyon Hypothesis:
Only one X is functional in females affected.
The other X is seen as a Barr body
The inactivation of X is due to inactivation of XIST molecule
Regardless the number of X chromosome, the presence of Y
chromosome sets the sex to male.
KLINEFELTERS SYNDROME
47 XXY
Most common sex chromosomal disorder and cause of
hypogonadism in males.
Low IQ, Infertile, Gynecomatia
Increased FSH and Estradiol and decreased testosterone.
Due to maternal meiotic non-disjunction
TURNER SYNDROME
45 X
Most common sex chromosomal disorder in females
Edema, congenital heart disease, absence of secondary female
characteristics, normal IQ, and ammenorhea.
Auto antibory to thyroid (50%), glucose intolerant, obesity.
Webbing of the neck, cubitus valgus
HERMAPHRODITISM
Presence of both testis and ovaries
Extremely rare
50% is 46XX.

Page 9 of 10

PSEUDOHERMAPHRODITISM
Disagreement of gonadal and phenotypic sex
Male due to mutations in the gene for androgen receptor
Normal testes and ducts but ambiguous external genitalia
Female due to excessive exposure to androgens during
pregnancy
Normal internal genetalia, virilized external genetalia
Large clitoris.
D.) SINGLE GENE DISORDER WITH NON-CLASSIC INHERITANCE
Four categories:
1. Trinucleotide Repeats
2. Mutation in mitochondrial genes
3. Genomic imprinting
4. Gonadal Mosaicism
Trinucleotide Repeat Mutation
Long repeating sequences of 3 nucleotides involving G and C.
DNA becomes unstable
Particularly neurodegenerative disorders.
The proclivity to expand depends strongly on the sex of the
transmitting parent.
Fragile X expansion occurs during oogenesis
Huntington expansion occurs during spermatogenesis
FRAGILE X SYNDROME
Seen as discontinuity of staining or as a constriction in the long
arm of the X-chromosome, and is liable to chromatid breaks.
One of the most common causes of familial mental retardation
in males.
Reduction in FMR protein due to mutation of the FMR1 gene
Long face, large mandible, large everted ears, macro-orchidism.
Atypical pattern of transmission:
Carrier males transmit to daughters, grandchildren are
affected
Affected females 30-50% are affected
Phenotypic effects:
9% brothers with Mental Retardation
40% grandsons have Mental Retardation
Worsens each generation
Mutations in the mitochondrial genes (mtDNA)
Maternal inheritance, because the mitochondria we inherit is the
one in the egg cells cytoplasm.
Mothers transmit their mtDNA to all their offspring but only
daughters can pass the mtDNA.

LEBER HEREDITARY OPTIC NEUROPATHY

mtDNA encodes for enzymes involved in oxidative
phosphorylation, thus mutations affect primarily the CNS,
skeletal, and cardiac muscles, liver, and kidneys.
Progressive bilateral loss of central vision.
First noted between 15 and 35 years and leads to blindness;
cardiac conduction defects and minor neurologic manifestations
may be seen.
Genomic Imprinting
Imprinting selectively inactivates either the maternal or the
paternal allele.
Occurs in the ovum or sperm before fertilization.
Maternal imprinting silences maternal alleles
Paternal imprinting silences paternal alleles.

MOLECULAR DIAGNOSIS
PCR and Detection of DNA alterations
Sanger sequencing
Pyrosequencing
Single base primer extension
Restriction Fragment length analysis
Amplicon length analysis
Real-time PCR
Molecular Analysis of Genomic Alterations
Fluorescence in situ hybridization (FISH)
Multiplex Ligation-dependent probe amplification (MLPA)
Southern Blot
Cytogenomic Array Technology
Array based comparative genomic hybridization
SNP Genotyping Array
Polymorphic Markers and Molecular Diagnosis
Epigenetic Alterations
RNA Analysis
Next Generation Sequencing

PRADER-WILLI SYNDROME
Deletion primarily affects the paternally derived chromosome 15
Retardation, short stature, hypotonia, small hands and feet
Hypogonadism
ANGELMAN SYNDROME
Deletion primarily affects the maternally derived chromosome
15
Mentally retarded, ataxic gait, seizures.
Inappropriate smile or laughter (happy puppets)
Gonadal Mosaicism
Mutation occurs postzygotically during early embryonic
development.
Parents are phenotypically normal but diseases are seen in
multiple children.
Germ line mutation the gametes carry the mutation.

Page 10 of 10

Meri Ionos Sonaro daoruni gimi!

Only Jon Snow knows nothing!