Staff Members of Genetics Unit / Pediatrics Department

Prof. Soheir Abou Elella

Prof. Maha Atef Tawfik
Ass. Prof. Wafaa Moustafa Abo El-fotoh
Ass. Prof. Naglaa Fathy Barsseem
Dr Ahmed Shawky
Dr. Zeinab Abou zouna
[Company name]
1/1/2022
 PEDIATRICS GENETICS

Preface (Pediatrics)
The Genetics contents of this module have been collected and scripted by the staff members
of Genetic Unit, Pediatric Department, Faculty of Medicine, Menoufia University. We are
willing to feed the 3rd year students with the essential and up to date scientific material in a
simplified manner. The module has been accustomed to meet the requisite of knowledgeable
practice of the undergraduate student. The module handled the basic concepts of genetics,
inheritance patterns, and common genetic disorders. In addition to shedding light on
preventive genetics. As an advice from the authors of this scientific material, our students
should pay attention to the educational lectures associated with this course in order to better
understand the material presented, as well as keep abreast of the new in this regard. Finally,
we wish them continued success.

Wafaa Moustafa Abo El-fotoh

Ass. Professor of Pediatrics
Module Coordinator

- INTRODUCTION TO GENTICS
- CHROMOSOMAL ABERRATIONS
- CHROMOSOMAL DISORDERS
- CHROMOSOMAL ANALYSIS
- FAMILY PEDIGREE
- PATTERN OF SINGLE GENE INHERITANCE
- PREVENTIVE GENETICS
• GENETIC COUNSELING
• PRENATAL DIAGNOSIS
• NEONATAL SCRENING

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 PEDIATRICS GENETICS

G
enetics: is the study of heredity or genes.
Hereditary: is the transmission of characteristics from one generation to
the next.
 Deoxyribonucleic acid (DNA):
- DNA is the hereditary material in human.
- The genetic information is stored in DNA.
- DNA is a long linear polymer made of simpler units called nucleotides.
- Nucleotides composed of nitrogenous base, sugar molecule and phosphate
group.
- All nucleotides will make the structure of DNA double helix

- Two types of DNA present in the cell either nucular or mithochondrial DNA

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 Genes
- The basic unit of inheritance.
- A section of DNA that take a specific location on a chromosome and codes
for a protein product.
- Carry instructions to make proteins and each gene codes for one protein.
- Vary in size: hundred bases > 2 million bases and there are about 20,000 to
25,000 genes.
- Two copies of each gene: one inherited from each parent.
- > 99 % same in all people and <1% slightly different person’s unique
physical features.
- Composed of Exon: protein coding sequence, Intron: intervening sequence
and Control elements.
 Gene regulation:
- The process of turning genes on and off, so cells look and act different
- Occurs at the level of transcription.
 Gene expression: the process from gene to protein production, it involves 3 steps
- DNA replication: the process of producing two
identical copies from one original DNA.
- Transcription: mRNA carries the information
from the DNA out of the nucleus into the
cytoplasm.
- Translation: the ribosome reads the sequence of
mRNA bases then tRNA assembles one amino
acid at a time that continues until a stop codon.
 Proteins:
- Made up of amino acids
- Attached to one another with peptide bonds in long polypeptide chains
- Genetic Code: Each sequence of three bases, called a codon, usually codes
for one particular amino acid
- Stop codon: a sequence of 3 bases not code for AA
- Changes to the genetic code can mean that a particular protein is not
produced properly, produced in the wrong amounts or not produced at all.

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 Chromosomes
- DNA is packaged in the cells in the form of chromosomes that allows the
very long DNA molecules to fit into the cell.
- Each chromosome is Made of DNA double helix molecule and associated
histone proteins.
- Chromosomes are visible under a microscope during cell division.
- All somatic cells contain 46 chromosomes (Diploid number, 2n).
- All germ cells contain 23 chromosomes (Haploid number, n).
- The chromosome consists of two chromatids (sister chromatids), are joined
at a constriction known as the centromere.

- Chromosomes are classified according to size (A-G groups) and site of

centromere (3 types).

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 Types of cell divisions:

Mitosis
- Division of somatic cells
- Products two daughter cells from one parent cell
- The number of chromosomes does not change
- DNA duplicates before entering the mitosis
- Takes 1-2 hours
Meiosis
- Only in gamete formation
- One diploidic parent cell produces four haploid gametosytes
- Mature gametocytes have 23 chromosomes (n)
- Crossing over: chromatids change parts between homologous chromatids
during the meiosis and this causes redistribution of the heredity material.

 Important Genetic terminologies:

 Phenotype: is the observable physical or biochemical characteristics of an
individual organism.
 Genotype: is the genetic make-up of an individual organism /The genetic
information written in DNA.
 Locus:position of gene on chromosome.

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 Allele: different versions of the same gene (e.g. gene of eye color may have brown
and green, blue, grey or dark alleles.
 Dysmorphism: individuals’ physical features that are not usually found in other
individuals with the same age or ethnic background.
 Syndromes: Multiple anomalies in one or more tissues or structures thought to be
pathologically related due to a specific etiologic mechanism as DS.
 Congenital anomalies: a wide range of abnormalities of body structure or function
that are present at birth and are of prenatal origin. It can be
- Minor anomaly: Abnormality that pose no significant health problem
and tend to have limited social or cosmetic consequences (e.g. Single
palmar crease and clinodactyly).
- Major anomaly: Abnormality that has medical, surgical, or cosmetic
significance so increases the risk of disability, morbidity or mortality.

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Etiology: may occurs spontaneously or due to environmental agents as chemicals,

radiation, and UV light.
Impact: may cause problems in growth & development and function of the
body’s systems.
Timing: during the formation of eggs and sperm, early fetal development or any
cell after birth.
 Types
1- Changes in chromosome number (numerical aberrations)
- Euploidy: when a cell has a multiple of 23 chromosomes, it is said to be
Euploid.
- Polyploidy: All the chromosomes are present in ≥ 3 copies and usually not
compatible with life.
- Aneuploidy: A change in the chromosome number does not involve entire
set and involve trisomy (2n+1), monosomy (2n-1) or nullisomy (2n-2).
- Mosaicism: when an individual has two or more cell populations with a
different chromosomal makeup.
2- Changes in chromosome size and structure (structural aberrations)
- Translocation: occurs when a piece of one chromosome breaks off and
attaches to another chromosome. May be reciprocal or Robertsonian,
balanced or unbalanced translocation.

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- Deletions: occur when a chromosome breaks and some genetic material is

lost.
- Duplications: occur when part of a chromosome is copied (duplicated) too
many times.
- Inversion: breakage of a chromosome in two places then the resulting piece
of DNA is reversed and re-inserted into the chromosome, either pericentric
or paracentric inversion.
- Isochromosome: is a chromosome with two identical arms.
- Dicentric chromosome is one which contain two centromeres.
- Ring chromosomes: occur when a chromosome breaks in two places and
the ends fuse together to form a circular structure.

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Incidence: Estimated in 0.7% of live births, in ≈ 2% of all pregnancies in woman

over 35yrs, and in 50% of all spontaneous 1st trimester abortion.

Down Syndrome
Occurrence: more with advanced maternal age: 1 / 20 by age 45 years and it
increases the risk of spontaneous abortion. Males affection equals females.
 Cytogenetic types:
Nondisjunction Type: the chromosome 21 pair
fail to separate during the formation of an egg (or
sperm); this is called "nondisjunction." When the
egg with 2 copies of chromosome 21 unites with
a normal sperm with one copy of chromosome 21
to form an embryo, the resulting embryo has 3
copies of chromosome 21 instead of the normal
two. The extra chromosome is then copied in
every cell of the baby's body, causing the features
of Down syndrome. The risk increases with
advanced maternal age. Most often type (94%).
Not familial with low recurrence (<1-2%).
Translocation type: 3-4% of cases have cells
that contain 46 chromosomes; however, there is
extra chromosome 21 material attached
(translocated) onto another chromosome. It is
called familial type with increased recurrence
risk (2-3% if translocated father or 10-15% if
translocated mother). This is because one of the
two parents may be a carrier of a balanced
translocation.
Mosaic type: In about 1-2% of cases, only some of the cells in a person's body
have an extra chromosome 21 and some cells have normal number. Not familial
with low recurrence risk and usually less severe features.

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Clinical phenotype
Dysmorphic features
- Upward slanting palpebral fissures
- Epicanthus and Burchfield spots of iris
- Small dysplastic pinnae and low set ears.
- Mid face hypoplasia, micrognathia, and protruded tongue.

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Body system affection:

Cardiac: Congenital heart defects (50%), particularly septal defects (VSD)
CNS: Microcephaly, mental retardation, generalized hypotonia and premature
Alzheimer.
Endocrine: Hypothyroidism, obesity, and insulin resistance.
Gastrointestinal: Duodenal/esophageal/anal atresia, TE fistula, Hirschsprung
disease, chronic constipation and poor feeding, vomiting, aspiration.
Orthopedics: Short fingers, curved 5th finger, transverse palmer crease, wide
gap between 1st and 2nd toes, lax joints including dysplastic hips, vertebral
anomalies including atlantoaxial instability
Blood and skin disorders: 1% lifetime risk of leukemia
Other problems: Visual and hearing difficulties, dental problems, speech
problems, and sleep apnea.

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Turner syndrome
 Genotype: 45X (most common) /Mosaic (45X/46XX)
 Clinical phenotype:
✓ Intrauterine: may be presented with polyhydramnios and lung hypoplasia.
✓ Neonatal: may be presented with lymphedema of hands and feet, low posterior
hair line and cystic hygroma.
✓ Childhood: Intelligence usually normal, may have mild learning disabilities,
short stature, short webbed neck, low posterior hair line, wide carrying angle at
elbows, broad chest, widely spaced nipples, renal anomalies, coarctation of the
aorta, bicuspid aortic valve.
✓ Adolescence: Gonadal dysgenesis lead to infertility, primary amenorrhea, lack
of development of secondary sexual characteristics: absence of breast development
and failure to menstruate and increased risk of hypertension.
 Prognosis: Normal life expectancy if no complications / Infertile.
 Management: Early screening for cardiac disease, growth hormone therapy for
short stature and estrogen replacement at time of puberty.

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Klinefelter syndrome
 Genotype: 47 XXY (most common)
 Incidence: 1:1000 live male births
 Clinical phenotype:
- Klinefelter males are usually slow to learn but are not mentally retarded.
- Tall and eunuchoid build and minimal facial hair.
- Micropenis, small dysgenetic testes, cryptorchidism (undescended testes),
hypospadias, and lack of secondary sexual characters.
- Diagnosis is rarely made before puberty
 Treatment: Testosterone in adolescence

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Edward syndrome (trisomy 18

 Clinical phenotype: Polyhydramnios, growth retardation, CHD, low-set
malformed auricles, clenched hand with overlapping fingers, and rocker
bottom feet/ sandal gap
 Prognosis: 30% of babies with trisomy 18 die in the first month of life. Only
10% of these children survive their first year of life

Patau syndrome (trisomy 13)

 Clinical phenotype: Holoprosencephaly, cutis aplasia, microcephaly,
microphthalmia, cleft lip +/- palate, polydactyly, and congenital heart
defects.
 Prognosis: most of babies with trisomy 13 die in the first months of life.

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Karyotyping for Chromosomal Abnormalities

 Definition: is the process by which a karyotype is prepared from photographs of
chromosomes through paring metaphase chromosome in one complete set.
 Importance: to detect numerical or gross structural chromosomal abnormalities.
 Main steps:
- Cell growth and multiplication: culture of
cells derived from a blood specimen during
which there is a period of cell growth and
multiplication.
- Cell arrest: dividing cells are arrested in
metaphase by addition of colchicine, which
stop the mitotic spindle.
- Addition of hypotonic solution: it causes the
cell nuclei to swell and the cells to burst.
- Addition of fixative solution: to fix the cells
then it dropped on a glass slide.
- Staining: various stains used to generate
characteristic banding patterns for different
chromosomes. In G-banding, the metaphase chromosomes are first treated briefly
with trypsin, an enzyme that degrades proteins, before the chromosomes are stained
with Giemsa stain.
- Karyogram: individual chromosomes are arranged into a standardized format
known as a karyotype, or more precisely, a Karyogram to be better visualized under
high resolution light microscope.
Clinical Indications for Chromosomal Analysis
- Mental retardation, growth retardation and developmental delay.
- Dysmorphic features and multiple congenital anomalies.
- Female with short stature.
- Ambiguous genetalia and intersex disorders.
- Recurrent abortions and fertility problems.
- Family history of translocations or chromosomal disorders.

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 Degrees of relationship
First degree: Parents, children, brothers and sisters
Second degree: Grandparents, grandchildren, uncles, aunts, nieces, and nephews.
Third degree: first degree cousins.
 Symbols’ used in family pedigree

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 Definition: Its the manner in which a particular genetic trait or disorder is passed
from one generation to the next and help to predict the recurrence risk for relatives.
 Pattern of inheritance
- Single Gene Inheritance: Autosomal, X-linked, Y- linked and Co-dominant
- Maternal (mitochondrial) inheritance
- Multifactorial inheritance
- Nontraditional inheritance
AUTOSOMAL DOMINANT INHERITANCE
- A trait or disorder that is determined by a gene on an autosome
- Dominant: Traits that are manifest in individuals with just one copy of the allele.
 Characteristics:
- Affected mothers and fathers transmit the phenotype to both sons and
daughters (Males and females are equally affected).
- Each child of an affected parent has a 50% chance of inheriting the disease.
- The phenotype appears in every generation “vertical pattern”, exception (fresh
mutation and non-penetrant disease).
 Examples: Achondroplasia, Huntington disease, neurofibromatosis type 1,
myotonic muscular dystrophy.

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AUTOSOMAL RECESSIVE INHERITANCE

- Due to a recessive gene on an autosome
- A recessive allele is only visible when paired with another recessive allele.
 Characteristics:
- Affected mothers and fathers transmit the phenotype to both sons and
daughters (Males and females are equally affected).
- The parents of an affected individual may not express the disease.
- Phenotype may skip a generation “Horizontal Pattern”
- Recurrence risk is 25%.
 Examples: Cystic Fibrosis, phenylketonuria, galactosemia, albinism, sickle-cell
anemia.

X-LINKED RECESSIVE INHERITANCE

- Due to a recessive allele on the X-chromosome.

 Characteristics:
- If male inherited the affected gene from the mother, it will be affected (Males
more likely to be affected than females).
- The presence of one normal X chromosome masks the effects of the X
chromosome with the abnormal gene. So, almost all of the daughters of an
affected man appear normal, but they are all carriers of the abnormal gene.
 Examples: Color Blindness, hemophilia, G6PD, Duchenne muscular dystrophy.

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X-LINKED DOMINANT INHERITANCE

- Due to a dominant allele on the X chromosome
 Characteristics:
- The presence of the defective gene appears in females even if there is also a
normal X chromosome present.
- Since males pass the Y chromosome to their sons, affected males will not
have affected sons, but all of their daughters will be affected.
- Affected heterozygous females produce 50% normal and 50% affected
offspring
 Examples: Hypophosphatemic rickets and Fragile X Syndrome.

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Y-LINKED INHERITANCE
- Due to an allele on the Y-chromosome
- If a male is affected, all of his male children
are affected
- Hypertrichosis Pinnae is an example

CO-DOMINANT INHERITANCE
- Two different versions (alleles) of a gene can be expressed.
- Each version makes a slightly different protein
- ABO blood group is an example.

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MITOCHONDRIAL DNA-LINKED DISORDERS

- Due to a mutation in mitochondrial

DNA.
- This type of inheritance, also
known as maternal inheritance,
because only females (not males)
can pass on mitochondrial
mutations to their children (males
and females).
- Leber hereditary optic neuropathy
(LHON) is an example.

MULTIFACTORIAL INHERITANCE

- The most common cause of genetic disorders

- Due to the combined effects of multiple genes
and environmental factors
- Empiric risks are used to predict the recurrence
risk
- Examples include cleft lip and palate,
congenital hip dislocation, schizophrenia,
diabetes and neural tube defects such as spine
bifida.

SEX-LIMITED TRAITS
- A trait that appears in only one sex is called sex-limited
- Due to anatomic difference e.g. uterine or testicular defects.
- Examples: Beard growth and breast size.
SEX-INFLUNCED TRAITS
- A trait that appears in both sexes, but expression of the phenotype influenced by
sex.
- For example, premature baldness is an autosomal dominant trait, but the condition
is rarely expressed in the female, and then usually only after menopause.

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PREVENTION OF GENETIC DISEASES

Primary intervention: before condition occurs as in genetic counseling and

prenatal diagnosis.
Secondary intervention: soon after condition detection for early diagnosis and
treatment as in neonatal screening.
Tertiary intervention: to reduce long term effects including early detection of
complication and rehabilitation.
GENETIC COUNSELING
 Description:
- A health service that provides information and
support to people who have or may be at risk for
genetic disorders.
- During a consultation, a professional meet with an
individual or family to discuss genetic risks or to
diagnose, confirm, or rule out a genetic condition.
- An important part of the decision-making process
for genetic testing.
 Indications:
- A personal or family history of a genetic condition, birth defect,
chromosomal disorder, or hereditary cancer.
- A woman who is pregnant or plans to become pregnant at or after age 35 or
with history of recurrent miscarriages or a stillbirth.
- Abnormal test results that suggest a genetic or chromosomal condition.
- Prevalence of a particular genetic disorder on the basis of ethnic background.
- People related by blood who plan to have children together.
 Screening team/ settings
✓ Counselors: include genetics professionals and other
healthcare professionals as nurses, psychologists and
social workers trained in genetics.
✓ Settings: doctor’s office, hospital, genetics center,
other type of medical center

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 Counselling information/Ethics:
- Interpret and communicate complex medical information about the
condition.
- Help each person make informed, independent decisions (Nondirective
approach).
- Explaining alternatives to reduce the risk of genetic disorders
- Respect each person’s individual beliefs, traditions, and feelings.
- Addresses a patient’s specific questions and concerns
- Keep privacy of individual and family and offers support.

PRENATAL DIAGNOSIS
 Importance of prenatal diagnosis
- To detect changes in a fetus’s genes or
chromosomes before birth.
- To manage the remaining weeks, determine
outcome, decide whether to continue the
pregnancy.
- To plan for possible complications with the birth
process or problems that may occur in the
newborn infant.
- To find conditions that may affect future pregnancies.

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 Indications: population at risk of having abnormal baby as

1- Those at increased risk of genetic disorders as
- Women aged 35 or more or have recurrent abortions.
- Previous child with chromosomal abnormalities or multiple congenital
anomalies.
- Carriers for X- linked inherited disorders such as Duchenne muscle
dystrophy and Fragile-X syndrome or Parents who are carriers for
chromosomal abnormalities.
2- Inborn errors of metabolism
3- Neural tube defects: Anencephaly-encephalocele – spina bifida
 Types of prenatal screening tests
Non-invasive Biochemical markers in maternal serum or blood tests
screening tests Isolation of fetal cells from maternal circulation
Ultrasound
Invasive screening Chorionic villus sampling
tests Amniocentesis
Fetal blood sampling
Fetoscopy
Fetal tissue sampling

Non-invasive screening tests:

A. Biochemical markers: is routinely used to investigate women at risk of having a
Down syndrome or other genetic conditions.
Triple tests result in some genetic disorders
Condition AFP uE3 HCG
Open neural tube defect Increased Not applicable Not applicable
Down syndrome Decreased Decreased Increased
Turner syndrome Normal/ Decreased Decreased Increased
Edward syndrome Decreased Decreased Decreased
Some prenatal tests using biochemical markers
Triple test hCG, AFP, uE3
Quadruple test hCG, AFP, uE3, inhibin A
Combined test NT, hCG, PAPP-A
Integrated test NT, PAPP-A + hCG, AFP, uE3, inhibin A
AFP:alpha feto-protein, hCG: human chorionic gonadotrophin, uE3: unconjugated estriol,
PAPPA: pregnancy associated plasma protein-A, NT: nuchal translucency

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B. Isolation of Fetal cells from maternal circulation:

- Isolation of fetal nucleated cells enabling investigation of fetal chromosomes
in early pregnancy (FISH for numerical aberrations only).
- Isolation of fetal DNA to screen paternally inherited single-gene disorders
or mutated genes.
- It can screen for Duchenne muscle dystrophy, fetal RhD blood type, sickle
cell anemia and beta-thalassemia in heterozygous carriers.
C. Ultrasound
- Fetal abnormalities in the first trimester including
changes in the head circumferences; heart, nuchal fold
thickness, fetal and limbs size are indicators of
chromosomal anomalies and several disorders.
- The second trimester ultrasound findings assess the fetal
measurements and can assess fetal age.
Invasive screening tests:
A. Chorionic villus sampling
- Can be done at about 10-11 weeks, either transvaginal
or transabdominally.
- There is a small chance of maternal cell contamination
and a 1-4% risk of miscarriage, infection, placental
trauma, or feto-maternal hemorrhage.
B. Amniocentesis
- Can be done at 16- 18/20 weeks, transabdominally.
- Miscarriage, intrauterine infection, persistent amniotic
fluid leak, feto-maternal hemorrhage, fetal injuries are
less frequent complications.
C. Fetal blood sampling
- Blood is taken from the umbilical vein at the placental
insertion. Fetal loss rate is variable from 0-24%- 12%.
- Rapid assessment of fetal chromosomal anomalies,
haemoglobinopathies, coagulopathies, infection and
immunodeficiency later in pregnancy.

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D. Fetoscopy
- Permit direct access to fetus via percutaneous introduction
of small fiberoptic telescope in amniotic cavity.
- Blood from fetus to diagnose blood and metabolic diseases.
Also, fetal malformation visualization.
E. Fetal tissue sampling: Fetal biopsy for histological and
ultrastructure studies as for prenatal diagnosis of
epidermolysis bullosa lethalis. Fetal loss is as high as 1%.

NEWBORN SCREENING
✓ NS is a public health program designed to screen infants shortly after birth.
✓ Is designed to detect babies at risk before they have signs and symptoms.
✓ Screens for congenital and heritable disorders.
✓ Early detection and treatment results in prevention of irreversible
complications.
 Criteria for ideal screening program
a) Screened condition: should be an important, frequent, well known health
problem.
b) Screening test: should be inexpensive, simple, safe, reliable, precise and
validated.
c) Treatment: effective treatment/intervention exists. If untreated: baby may die
or develop severe retardation. Treatment should be at an early stage.
d) Staffing and facilities: adequate staffing and facilities for testing, diagnosis,
treatment, and program management.
e) Screening program: including test, diagnostic procedures,
treatment/intervention is clinically, socially and ethically acceptable, effective
in reducing mortality or morbidity, and should outweigh the physical and
psychological harm and cost versus benefit.
 Examples of screened disorders
A. Blood cell disorders: as sickle cell anemia and Beta-Thalassemia.

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B. Inborn errors of metabolism: as tyrosinemia, phenylketonuria,

homocystinuria, classical galactosemia, organic academia’s, carnitine uptake
defect and fatty acids oxidation defects.
C. Endocrine diseases: congenital hypothyroidism and congenital adrenal
hyperplasia
D. Other diseases: as cystic fibrosis and NB hearing screening for congenital
deafness.
 Screening samples
- Newborn screening tests are most
commonly done from whole blood samples
between 24 hours and 7 days after birth. The
baby should be fed at least once.
- Use either the lateral or medial plantar
surface of the heel for the puncture site.
 Advantage of filter paper
• Simple collection
• More analytes stable
• Simple transportation
• Storage easy/compact
• Whole blood matrix
• Safety/handling exposure.

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REFERNCES
• Nelson textbook of Pediatrics 21st edition.
• Introduction to Genetics: A Molecular Approach - 1st Edition - T A Br routledge.com
• Essential Medical Genetics, Includes Desktop Edition, 6th Edition | Wiley.wiley.com
• Medical Genetics - 6th Edition.elsevier.com
• MEDLINE Database | U.S National Library of Medicine
• National human genome research institute NIH, glossary of genetic terms.
• Atlas of genetic diagnosis and counselling
• Wiley Online Library. onlinelibrary.wiley.com
• Down syndrome. Genetics Home Reference Web site. June, 2012;
http://ghr.nlm.nih.gov/condition=down syndrome.
• Chromosome Abnormalities and Genetic Counseling: R.J. McKinlay Gardner :
9780195375336.bookdepository.com
• O'Connor, C. (2008) Karyotyping for chromosomal abnormalities. Nature Education
1(1):27.
• Spectral karyotyping | definition of Spectral karyotyping by Medical dictionary.
medical-dictionary.thefreedictionary.com
• Inheritance patterns | Genetic Alliance UK. geneticalliance.org.uk
• MedlinePlus Genetics. medlineplus.gov
• Wikipedia. en.wikipedia.org
• BioNinja. Genes and Loci | BioNinja

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