Birth defects, also known as congenital disorders, are abnormalities present at birth that can affect structure or function. Around 2-3% of live births have a recognizable birth defect. Common causes include genetic factors present before conception (such as chromosome abnormalities like trisomy and monosomy caused by non-disjunction), environmental exposures during pregnancy that act as teratogens, and unknown causes (around 50% of cases). Chromosome abnormalities can result in extra or missing chromosomes and often cause multiple birth defects or developmental issues.

1. 1
Introduction to
birth defects
Before you begin this unit, please take the BIRTH DEFECTS
corresponding test at the end of the book to
assess your knowledge of the subject matter. You
should redo the test after you’ve worked through 1-1 What is a birth defect?
the unit, to evaluate what you have learned.
A birth defect is an abnormality of structure
or function in a person, which is present
Objectives from birth. The birth defect may be clinically
obvious at birth, or may only be diagnosed
sometime later in life. For example, a neural
When you have completed this unit you tube defect is a structural defect which is
should be able to: obvious at birth while haemophilia, which is
• Define a birth defect. also present at birth, is a functional defect that
may only become obvious and be diagnosed
• Understand the birth prevalence and
when the child is older. Birth defects often
population prevalence of birth defects. present as an abnormal appearance or failure
• List the causes of birth defects. to grow and develop normally.
• Understand chromosomal inheritance.
• Understand the inheritance of single A birth defect is a structural or functional
genes. abnormality which is present from birth.
• Define a multifactorial birth defect.
• Define a teratogen and know their Congenital disorder is another term that has
dangers. the same meaning and definition as birth
defect. Congenital means ‘present at birth’.
Malformations are the commonest form
of birth defect. Congenital malformations
develop during the first trimester and are
caused by failure of the embryo to develop
normally. This results in a birth defect of one
or more organs (e.g. heart, eye, brain).

2. 14 BIR TH DEFECTS
live births. It is therefore a measure of
Congenital malformations occur early in
how common a defect is among newborn
pregnancy when the embryo is still forming.
infants.
NOTE An individual with an abnormal appearance
is said to be ‘dysmorphic’. It is important to 1-4 How common are birth defects?
differentiate dysmorphic features from the normal At birth two to three percent of live newborn
range of features found in a family or community. infants can be recognised as having a birth
defect, i.e. the recognisable birth prevalence
1-2 Are all birth defects serious? for all defects is 20–30/1000 live births in the
No. Birth defects may be mild or serious. A first month of life.
mild defect causes no disability. However, a However, not all birth defects are diagnosed
person with a serious birth defect may die at or around birth, and by five years of age
soon after birth, or survive with a disability between four and eight percent of children
due to the direct effect of the birth defect (e.g. in different countries are considered to have
neural tube defect) or due to a secondary effect suffered the effects of a serious birth defect, i.e.
(e.g. joint damage resulting from bleeding a birth prevalence of 40–80/1000 live births.
in haemophilia). Some serious birth defects
can be treated and this may be life-saving or The birth prevalence of serious birth
prevent or reduce serious disability. defects varies from 40/1000 live births in
industrialised countries to as high as 80/1000
Birth defects can cause a wide range of in some developing countries.
disability, e.g. physical disability, intellectual
disability, blindness, deafness and epilepsy.
The birth prevalence of serious birth defects is
lower in industrial countries than in developing
Serious birth defects can cause death or disability. countries.
1-3 How is the frequency of NOTE Research done in rural Limpopo province,
birth defects measured? South Africa, by genetic trained nursing staff
examining newborn infants on day one of life
The frequency of birth defects (i.e. how recorded a birth prevalence of serious defects
common are individuals with a birth defect) of 15/1000 live births (1.5% of live births). Birth
is expressed as population prevalence and defects can be diagnosed at any age from the
birth prevalence: newborn period (birth to 28 days) through
to adulthood. Examples of birth defects that
1. The population prevalence is defined can present for the first time in adulthood
as the number of affected individuals include inherited cancers, Huntington disease
per 1000 or 10 000 or 100 000 people, and adult onset polycystic kidney disease.
depending on how common or rare the
disorder is, in a given population at a 1-5 If birth defects are so common why are
certain time, e.g. the population prevalence they not seen more frequently at clinics?
of Down syndrome in rural Limpopo was
7.5/10 000 children between 1994 and 1. Infants and children with serious birth
1997. Therefore the population prevalence defects are very likely to die when they are
is a measure of how common a birth defect young, especially if there are inadequate
is in the general population. medical services available for their care.
2. The birth prevalence is defined as the Therefore many infants do not live long
number of affected infants per 1000 live enough to be seen at clinics.
births, e.g. the birth prevalence of Down 2. Many birth defects are not recognised and
syndrome in rural Limpopo is 2.1/1000 diagnosed.

3. INTRODUCTION TO BIR TH DEFECTS 15
3. It is often not realised that many of the
Birth defects are an important cause of infant
conditions seen in clinics and hospital
and childhood death.
have a congenital origin, e.g. many forms
of intellectual disability, cerebral palsy,
deafness and blindness. Up to 50% of these
disorders may be due to birth defects. CAUSES OF BIRTH
Therefore both the birth prevalence and DEFECTS
population prevalence of birth defects in
developing countries may seem to be much
lower than it really is. 1-7 What are the causes of birth defects?
Birth defects are caused by:
NOTE Another reason why infants and children
with birth defects are not seen is that their 1. Problems that are present before
parents do not take them to hospital or clinic conception (about 40% of birth defects) –
because they feel that they will not receive • Chromosome abnormalities.
adequate attention or care, and the visit will be • Single gene defects.
an unjustified burden on their limited family
• Multifactorial disorders.
resources. Experience from Limpopo showed
that when genetic clinics were established, These are also known as genetic causes of
the population soon got to know and parents birth defects.
brought their children with birth defects. 2. Problems occurring after conception
(about 10% of birth defects) –
1-6 How many children die • Teratogens.
from birth defects? • Constraint.
These are non-genetic causes of birth
In South Africa about 1 million infants defects. Note that all birth defects are not
are born annually. Based on the available due to genetic causes.
evidence, about 72 000 infants are born each 3. Cause not yet known (about 50% of birth
year with a severe birth defect. Of these defects).
infants, about 25% will die in the first five
NOTE The percentages given above are
years of life.
for industrialised countries. Figures for
It is estimated that 9 million children are born developing countries are not available.
in the world each year with a serious birth
defect. Of these children, at least 8.4 million
The cause of about 50% of birth defects is not yet
(93%) are born in developing countries. A
minimum of 3.3 million children with a serious
known.
birth defect are estimated to die annually.
NOTE It is quoted as a general rule that in CHROMOSOMAL
industrialised countries 30% of children with
serious birth defects will die in infancy (the first INHERITANCE
year of life), 30% will live with disability even
if treatment is available, and 40% can largely
be cured (mainly by surgery). Similar figures 1-8 What are chromosomes?
for developing countries are not available, but
the number that die or are successfully treated Chromosomes are packages of DNA
will depend on the level of available health (deoxyribonucleic acid), the genetic material
care. Currently at least 3.3 million children found in all cells. A person’s genetic plan of
with a serious birth defect die annually. all their inherited characteristics is stored in
their chromosomes.

4. 16 BIR TH DEFECTS
1 2 3 4 5
6 7 8 9 10 11 12
13 14 15 16 17 18
19 20 21 22 X Y
Figure 1-1: Normal karyotype of a male (46,XY) with 23 pairs of chromosomes (22 pairs of matching
autosomes and one pair of unlike sex chromosomes, X and Y)
Human cells have 46 chromosomes that
Humans have 46 chromosomes in each cell,
are contained in the nucleus of the cell. The
chromosomes are paired (23 pairs), with 22
22 pairs of autosomes and one pair of sex
pairs called autosomes and one pair of sex chromosomes.
chromosomes. Each pair of autosomes looks
the same. The pair of sex chromosomes do not NOTE In some textbooks, 46,XY is still
look the same because the X chromosome is written as 46 XY. 46,XY is preferable.
longer than the Y chromosome.
1-9 How are chromosomes inherited?
Females have two X chromosomes (i.e. XX)
while males have one X and one Y chromosome One chromosome of each pair of
(i.e. XY). Like the 22 autosomes, the pair of X chromosomes is inherited from the mother
chromosomes in females look alike. and the other chromosome from the father.
Therefore, both the mother and father give one
A picture of the 46 chromosomes is called chromosome to each pair of chromosomes
a karyotype. The normal female karyotype found in the child. Half of the inheritance plan
can be written as 46,XX and the normal male of each individual is inherited from the mother
karyotype as 46,XY. Each pair of autosomes is and the other half from the father. This is
given a number (1 to 22). called sexual reproduction. An infant’s genetic
plan is, therefore, inherited from both parents.

5. INTRODUCTION TO BIR TH DEFECTS 17
Parents cells
(46 chromosomes)
Gametes
(ova or sperm)
(23 chromosomes)
(23) (23)
Zygotes
(fertilised eggs)
(46 chromosomes)
Figure 1-2: The normal chromosome contribution of each parent
This is why the inherited characteristics of the
Each parent gives 23 chromosomes which
parents are shared in the child, and the child
has features of both parents.
combine at fertilisation to give a total of 46
chromosomes in the zygote.
When the ova (female eggs) are produced
in the mother’s ovaries, and the sperms NOTE All living organisms, plants and animals,
(male eggs) in the father’s testicles, the 46 have chromosomes. In humans the 46
chromosomes in the parent’s stem cells divide chromosomes are known as the diploid number
with only one copy of each chromosome pair of chromosomes and the 23 chromosomes
still remaining in each ovum or sperm. The ova in the gametes as the haploid number. The
and sperms (also called gametes or sex cells), process of cell division in which the gametes
therefore, only have 23 chromosomes each. are formed and the number of chromosomes
is halved (from 46 to 23) is called meiosis. After
With fertilisation, a sperm and an ovum meiosis the ovum contains 22 autosomes and
unite and combine their chromosomes to an X chromosome, and each sperm has 22
form the zygote (the first cell which will autosomes plus either an X or a Y chromosome.
eventually develop into the fetus). The zygote Cell division in which the chromosome
therefore has 46 chromosomes, half (23) from number stays the same can also occur (asexual
the mother and half (23) from the father. reproduction) and this is called mitosis. This is
The zygote divides, multiplies and grows to the type of cell reproduction that occurs to make
become an embryo (with cells developing into more cells so that the zygote can multiply and
different organs). The embryo develops into develop into an embryo and fetus, and the body
can grow or replace cells that die off during life.
the fetus (with formed organs). After delivery
the fetus is called the newborn infant.

6. 18 BIR TH DEFECTS
Parents’ cells
(46 chromosomes)
Abnormal cell Normal cell
division division
Gametes
(ova or sperm)
No. of chromosomes
(24) (22) (23)
in gametes
Zygotes
(fertilised eggs)
Trisomy Monosomy
(47 chromosomes) (45 chromosomes)
Figure 1-3: Non-disjunction
1-10 What are chromosome abnormalities? have more or less genetic information than
it should have. The abnormal embryo may
The process of reproduction (when the ova
abort spontaneously or result in an infant
and sperms are made, fertilised and divide
with a birth defect. Chromosomal disorders
after conception) is not always perfect.
usually present with multiple abnormalities,
Abnormalities can occur in the chromosomes
including an abnormal appearance
and they may result in a child with a birth
(dysmorphic features), developmental and
defect. These chromosome abnormalities are
growth delay and malformations. As most
mostly sporadic, i.e. due to chance.
chromosomal abnormalities are not inherited,
Chromosome abnormalities include: the risk of more than one child being affected
(recurrence) is low.
1. An abnormal number of chromosomes in
the cells –
• Trisomy. The risk of the same chromosome disorder
• Monosomy. occurring more than once in a family is low.
• Mosaicism.
2. An abnormal structure of chromosomes in
the cells – 1-11 What are trisomy and monosomy?
• Translocation. This occurs during the formation of the
• Deletion. gametes (ova or sperms) when a pair of the
If a whole chromosome or part of a parent’s chromosome does not split normally.
chromosome is gained or lost in the process Instead of one chromosome of a pair going
of reproduction, then the zygote that results to each gamete, one gamete gets both the
will be abnormal as its genetic plan will paired chromosomes, and therefore has 24

7. INTRODUCTION TO BIR TH DEFECTS 19
1 2 3 4 5
6 7 8 9 10 11 12
13 14 15 16 17 18
19 20 21 22 X Y
Figure 1-4: The karyotype of Down syndrome in a male with an extra chromosome 21 (trisomy 21)
chromosomes, while the other gamete does 45 chromosomes (monosomy), the fetus will
not get a copy of that chromosome and, have cells with 45 chromosomes.
therefore, only has 22 chromosomes. This
abnormal process of cell division, which
results in two abnormal gametes, is known as
Trisomy and monosomy are caused by non-
non-disjunction. disjunction.
When either of these two abnormal gametes
fertilise with a normal gamete (containing 23 1-12 What birth defects are caused
chromosomes) the resulting zygote will have by trisomy and monosomy?
either of the following: Many of the common chromosomal disorders
1. An extra chromosome (trisomy) with 47 (chromosomal birth defects) are caused by
(i.e. 24 +23) chromosomes in the cell. non-disjunction and the resulting trisomy
2. One chromosome less (monosomy) with or monosomy of different chromosomes.
45 (i.e. 22+23) chromosomes in the cell. Most fetuses with trisomy and monosomy
are not capable of living and result in early
From an abnormal zygote with 47 spontaneous abortion.
chromosomes (trisomy) the fetus
that develops will have cells with 47 The chromosomes which can result in an
chromosomes. Similarly, for a zygote with infant being born alive and surviving with

8. 20 BIR TH DEFECTS
trisomy are 13, 18, 21, X and Y. The common As an example, if the non-disjunction was with
trisomies are: chromosome 21 in a female then the newborn
infant would have some cells of 46,XX and
1. Trisomy 21 or Down sydrome (i.e. 47,XY+
others of 47,XX +21 resulting in mosaic Down
21 or 47,XX+21).
syndrome (46,XX/47,XX +21). Mosaicism
2. Trisomy 18 or Edward syndrome (i.e.
causes 1 to 2% of the infants born with Down
47,XY +18 or 47,XX+18).
syndrome. People with Turner syndrome can
3. Trisomy 13 or Patau syndrome (i.e. 47,XY+
also be mosaic (46,XX/45,X0).
13 or 46,XX+13).
4. XXY in a male or Klinefelter syndrome (i.e. NOTE Rarely, people are found with an
47,XXY). extra piece of chromosome material that
5. Trisomy X in a female (i.e. 47,XXX). is called a marker chromosome. How this
6. XYY in a male (i.e. 47,XYY). affects the person depends on what piece
of chromosome is involved. Some people
Down syndrome, with trisomy of chromosome with marker chromosomes are normal, while
21, is the commonest form of chromosomal others can have a chromosome disorder.
birth defect.
In the formation of gametes (ova or sperms, if
The only chromosome that can be lost and none of the chromosome pairs separate, then
result in a live born infant with monosomy is 46 chromosomes will go to one gamete and
a sex chromosome X or Y. Therefore, the only none to the other gamete. If the gamete with 46
monosomy seen is Turner syndrome (i.e. 45,X). chromosomes becomes fertilised with a normal
gamete with 23 chromosomes, the resulting
zygote will have an extra set of chromosomes, i.e.
Down syndrome, with trisomy of chromosome 69 chromosomes (69,XXX or 69,XXY). This is called
21, is the commonest form of chromosomal birth triploidy. It is also possible to have more than one
extra set of chromosomes (polyploidy). Embryos
defect. with polyploidy usually abort spontaneously
early in pregnancy. On the rare occasion when
1-13 What is mosaicism? a triploidy (three sets of chromosomes) infant is
born, it is very abnormal and either dies before
In the normal zygote there are 46 chromo- delivery or very early in the neonatal period.
somes. The zygote then begins dividing by
mitosis to form the embryo which contains 1-14 What is a chromosome translocation?
many cells. This division of the one-celled
zygote results in a doubling of cells to 2, 4, 8, Translocation occurs when a piece of
16, 32 cells and so on, with all the cells having one chromosome breaks off and joins
46 chromosomes. However, in mosaicism, (translocates) onto another chromosome. If
an error occurs in the zygote. Early on in this in this process no genetic material is lost or
dividing process one of the cells is involved in gained, this is called a ‘balanced’ translocation
non-disjunction resulting in one cell having and the person is clinically normal. However,
47 chromosomes (trisomy) and the other if chromosome material is lost or gained then
cell only 45 chromosomes (monosomy). The this is an ‘unbalanced translocation’ and the
monosomy cell usually dies but the trisomy person will be abnormal because their genetic
cell may survive and divide. All future cells that plan has lost or gained genetic material.
come from it will be trisomy cells. Therefore, Persons with balanced translocations are at
the embryo, fetus and infant that result will risk of passing on the abnormal chromosomes
have some cells which are normal with 46 to their offspring, resulting in abnormal
chromosomes and other cells which are embryos with unbalanced translocations. This
abnormal with 47 chromosomes. This is called can be the cause of recurrent spontaneous
mosaicism (the presence of 2 different cell lines abortions. If the embryo survives, the resulting
of the same genetic origin in a person).

9. INTRODUCTION TO BIR TH DEFECTS 21
infant will be abnormal. This risk varies biochemical product (e.g. production of a
according to the type of translocation. protein or an enzyme).
Genes make up the smallest parts of the
1-15 What is a chromosome deletion? genetic code. Children look like their parents
This occurs when a piece of a chromosome, because their genes are a mixture that is
big or small, is missing. There are several inherited from both mother and father. As this
recognised syndromes in which a known piece combination varies with each child, siblings
of chromosome is missing. These include: look alike and yet have their differences. The
only individuals with identical genes are
1. Prader Willi syndrome with deletion of a identical twins.
specific piece of chromosome 15.
2. Deletion 22 syndrome with deletion of a
specific piece of chromosome 22. A gene is a small section of a chromosome and
3. Cri du chat (cry of a cat) syndrome controls a cell function. Genes occur in pairs, one
with loss of a piece of the small arm of being inherited from each parent.
chromosome 5.
NOTE Sometimes a piece of chromosome copies 1-17 What is a single gene defect?
itself and therefore the chromosome has two
identical pieces of the chromosome and the
On the chromosomes, a person’s genetic plan is
genetic plan has extra chromosome material. coded (‘written’) in thousands of genes. Genes
This is called chromosomal duplication. There on the 22 autosomes and two X chromosomes
are recognised chromosome duplication always occur in pairs (alleles). One gene in
syndromes, e.g. Cat Eye syndrome in which each matching pair is inherited from the
a piece of chromosome 22 is duplicated. mother and the other gene in that pair is
A piece of one end of a chromosome may inherited from the father. Each pair of genes
come off (deleted) making it sticky. This end together codes for an inherited biochemical
then sticks to the other end making a ‘ring’ product (e.g. blood clotting factor) or physical
chromosome. Because genetic material is feature (e.g. eye colour) and gives the cell an
lost from the one end of the chromosome instruction to carry out a particular activity.
in the process, the person usually has a If the structure of the gene is abnormal, the
chromosome disorder, often associated with instruction will also be abnormal and this may
growth failure and intellectual disability.
be harmful to the individual. A birth defect
that results from an abnormality in a gene is
called a single gene defect.
INHERITANCE OF SINGLE
GENE DEFECTS A birth defect caused by an abnormality in a
gene is called a single gene defect.
1-16 What is a gene?
NOTE It is estimated that humans have about
The genetic material on chromosomes 20 000 pairs of genes. Over 6000 single
is divided up into smaller packages of gene defects have been described.
DNA called genes. Like chromosomes,
genes occur in pairs, one gene from each 1-18 How do genes become abnormal?
parent. Together, each pair of genes usually
determines a single inherited function by Almost all genes are normal and give the
giving a set of instructions to the cell, such as cell correct instructions. However, a gene
a physical feature (e.g. hair colour) or a single can become abnormal by mutation. With a
mutation, the DNA structure of a gene changes.

10. 22 BIR TH DEFECTS
A mutation is a change in gene structure that can A dominant gene controls the function of that
cause abnormal gene fuction and a birth defect. gene pair.
Mutations are rare and may occur sponta- If the dominant gene is abnormal, then the
neously or be caused by environmental instructions sent from that gene pair will
factors, including radiation (solar radiation also be abnormal. As a result the cell may not
from the sun, nuclear radiation or excessive function normally, causing a birth defect.
X-rays). These abnormal genes can be passed
If the dominant gene is on one of the 22
onto the next generation in the same way as
autosomes, it is called an autosomal dominant
normal genes are inherited. As a result, single
gene. A clinical disorder caused by a mutation
gene defects are usually inherited (unlike
in an autosomal dominant gene is called
chromosomal defects).
an autosomal dominant disorder. These
conditions may be mild or severe but usually
Single gene defects are usually inherited. are not lethal (otherwise they probably would
not be passed on to the next generation).
NOTE In a mutation, the gene gives instructions Males and females are equally affected by
for an incorrect sequence of amino acids autosomal dominant disorders.
and, therefore, an abnormal protein or
enzyme is formed. A mutated gene may 1-21 How are autosomal
cause a clinical problem (e.g. haemophilia), a
dominant genes inherited?
mild variant (e.g. red hair) or rarely a survival
advantage (e.g. resistance against malaria). If either the father or mother has an autosomal
dominant gene, there is a 50% chance of
1-19 What type of genes occur? passing that gene on to each of their children.
Both sons and daughter have an equal chance
A gene may be either a dominant or a recessive of inheriting an autosomal dominant gene.
gene. Both dominant and recessive genes may
be normal or abnormal.
There is a 50% chance of inheriting a dominant
gene from a parent.
Genes can be either dominant or recessive.
If the autosomal dominant gene causes an
abnormality of structure or function, the
DOMINANT INHERITANCE genetic abnormality will be present in the
parent with that gene, and also in each child
that inherits that abnormal gene. Autosomal
1-20 What is a dominant gene? dominant disorders are, therefore, passed from
In a pair of genes (alleles), the individual one generation to the next. The clinical effect
genes may be of different strengths, with of the abnormal gene will usually be present in
the one being ‘stronger’ and the other being both parent and child.
‘weaker’. The ‘stronger’ gene dominates While most autosomal dominant genes are
(overpowers) the ‘weaker’ gene. Therefore, the inherited, an autosomal dominant gene may
‘stronger’ gene is called a dominant gene. The also appear in a person for the first time in a
dominant gene controls the function of that family as a result of a new mutation. That gene
gene pair (alleles). will not be present in either parent. Therefore,
the parents will be normal but the child will
have the disorder. However, the new mutated
gene can be passed onto future generations in

11. INTRODUCTION TO BIR TH DEFECTS 23
Autosomal dominant inheritance
Figure 1-5: The pattern of autosomal dominant inheritance. There is a 50% chance that the autosomal
dominant gene (e.g. D) will be passed from the affected parent to each child no matter whether a boy or girl.
the same way as other autosomal dominant RECESSIVE INHERITANCE
genes are inherited.
NOTE In a single family, some members will show
1-22 What is a recessive gene?
all the clinical features caused by the dominant
gene while others who inherit the gene may If a dominant gene overpowers (suppresses)
only show (express) some features. This is known a ‘weaker’ gene, the weaker gene is called a
as variable expression (e.g. neurofibromatosis). recessive gene. The dominant gene will control
Some family members with a dominant gene the function of that pair of genes. As a result,
may not show any features of that gene at all. This
the instructions sent to the cell will be that
is called variable penetrance (e.g. polydactyly).
of the dominant gene only. Therefore, the
NOTE If both parents have the same dominant
recessive gene will have no control over the cell
gene, there is a 75% chance (3 out of 4) and its effect will be ‘hidden’ or suppressed.
that each child will inherit that gene. There A person is called a carrier if she/he carries a
is also a 25% chance (1 in 4) of the child
‘hidden’ recessive gene. In a carrier the effect
inheriting both dominant genes, which
is usually fatal if the dominant genes are
of an abnormal recessive gene is not seen and
abnormal. Therefore, all children will inherit the individual appears normal.
either one or both dominant genes. A person who has both a dominant and
a recessive gene (a carrier), is said to be
heterozygous for that pair of genes. If both
genes are the same (both genes are dominant

12. 24 BIR TH DEFECTS
Autosomal recessive inheritance
(both parents carriers)
Carrier Carrier
father mother
R r R r
R R R r R r r r
Normal Carrier Carrier Affected
son daughter son daughter
Figure 1-6: The pattern of autosomal recessive inheritance. If both parents are heterozygous for a recessive
gene (e.g. r), there is a 25% chance that a child will be homozygous and a 50% chance that a child will also be
heterozygous for that gene.
or both recessive), the person is said to be 1-23 How are autosomal
homozygous for that pair of genes. Only if recessive genes inherited?
both genes are recessive will the recessive
If both parents are carriers (i.e. they are
genes together control that function of the
heterozygous) for the same recessive gene,
cells. They are able to do this as there is no
their children will have a 25% chance of
dominant gene. Recessive genes may be
inheriting the recessive gene from both
normal (e.g. carry instructions for blue eyes)
mother and father (i.e. the child will be
or abnormal (e.g. carry instructions for
homozygous). Their children will also have
oculocutaneous albinism). If both recessive
a 50% chance of inheriting a recessive gene
genes are abnormal, that function of the cell
from only one parent to become a carrier (i.e.
will also be abnormal. A clinically normal
heterozygous). Getting the same recessive
carrier has both a normal (dominant) and an
gene from both parents is commoner if
abnormal (recessive) gene for that feature.
the parents are closely related, e.g. siblings,
A recessive gene on an autosome is called an cousins or an uncle and a niece (intermarriage
autosomal recessive gene. or a consanguineous relationship), as they
may inherit the same recessive gene from a
NOTE We all carry five to 10 abnormal recessive common ancestor (e.g. grandparent).
genes. As we are heterozygous for that gene
(single copy), it generally has no effect on our With autosomal recessive inheritance, the
health. Only if we are homozygous (double dose) parents and grandparents are usually normal
for the same gene will we be clinically affected. and do not show the effect of the recessive
gene. If a child inherits two abnormal

13. INTRODUCTION TO BIR TH DEFECTS 25
X-linked recessive inheritance
(mother carrier)
Normal Carrier
father mother
x y x x
x x x y x x x y
Normal Normal Carrier Affected
daughter son daughter son
Figure 1-7: The pattern of X-linked recessive inheritance. There is a 50% chance that the recessive gene from
the mother will be inherited by both sons and daughters. Only sons will be clinically affected as the X-linked
recessive gene in daughters will be paired by a normal matching gene from the father.
autosomal recessive genes (i.e. one from each 1-24 What is X-linked recessive inheritance?
parent), they will have an autosomal recessive
If a recessive gene is on an X chromosome, it
disorder. The risk of an autosomal recessive
is called an X-linked recessive gene (X-linked
disorder is much higher if the parents are
dominant genes and Y-linked genes are very
closely related (consanguineous).
rare).
The majority of single gene defects are
X-linked recessive genes are inherited by girls
autosomal recessive. Males and females are
in the same way as autosomal recessive genes.
equally at risk of an autosomal recessive
Girls have two X chromosomes and all the
disorder.
X-linked genes are in pairs. However, as the
If only one parent is heterozygous (a carrier), X and Y chromosomes are not identical (the
the children cannot be affected but they have a Y chromosome is very short) the X-linked
50% risk of inheriting the recessive gene and, recessive genes in a male are not matched to a
therefore, also being a carrier. gene on the Y chromosome. Therefore, the X-
linked gene, whether dominant or recessive,
alone controls that cell function in males.
If both parents are carriers of a recessive gene,
As with autosomal recessive inheritance, a
there is a 25% chance (1 in 4) that their child will mother have a 50% chance (1 in 2) of passing
inherit both recessive genes. her X-linked recessive gene to both her sons
and daughters. However, it will only influence
the function of the cell in her sons. It has no
effect in her daughters as the gene is matched

14. 26 BIR TH DEFECTS
Autosomal dominant Autosomal recessive X-linked recessive
Achondroplasia Adrenogenital syndrome Duchene muscular
dystrophy
Apert syndrome Congenital hypothyroidism Fragile X syndrome
Crouzon syndrome Cystic fibrosis Glucose 6 phosphate
dehydrogenase deficiency
Hypercholesterolaemia Fanconi anaemia Haemophilia
Huntington disease Galactosaemia Hunter syndrome
Marfan syndrome Oculocutaneous albinism Incontinentia pigmenti
Neurofibromatosis Phenylketonuria Vitamin D resistant rickets
Polydactyly Sickle cell anaemia
Treacher Collins syndrome Spinal muscular atrophy
Tuberous sclerosis Tay Sachs disease
Waardenburg syndrome Thalassaemia
Table 1-1: Examples of single gene disorders and their mode of inheritance
by a gene on the other X chromosome,
X-linked recessive genes are carried by mothers
inherited from the father.
and affect 50% of their sons.
Therefore, disorders caused by X-linked
recessive genes are carried by females and affect
males. Males have unaffected sons as they give
them their Y and not their X chromosomes.
SINGLE GENE DISORDERS
However, there is a 100% chance that each
daughter of an affected male will be a carrier. 1-25 What are the common
Disorders caused by an X-linked recessive single gene disorders?
gene are called X-linked recessive disorders, The most common autosomal dominant
e.g. colour blindness and haemophilia. disorders are:
1. Polydactyly (extra digits).
X-linked recessive disorders affect males and not 2. Achondroplasia (short-limbed dwarfism).
females. 3. Neurofibromatosis.
NOTE In males, an X-linked recessive gene acts
The most common autosomal recessive
as if it were a dominant gene as it is unopposed disorders are:
by the function of a matching gene. Females 1. Sickle cell anaemia.
may have X-linked recessive disorders (e.g. 2. Thalassaemia.
colour blindness) if they inherit the abnormal
3. Oculocutaneous albinism.
recessive gene from both parents, i.e. both
their X chromosomes carry the abnormal gene. 4. Cystic fibrosis (the one autosomal recessive
Their father will be affected by the disorder disorder that is common in people of
while their mother will be a carrier. Rarely, European descent).
females who carry an X-linked gene may show
The most common X-linked recessive
mild signs of the disorder, e.g. haemophilia.
conditions are:

15. INTRODUCTION TO BIR TH DEFECTS 27
1. Red–green colour blindness. single limb, organ or system. They often
2. Haemophilia. present in infancy or childhood as congenital
3. Glucose-6-phosphate dehydrogenase malformations such as:
deficiency (G6PD).
1. Neural tube defects.
Some single gene disorders are more common 2. Isolated hydrocephalus.
in particular populations or regions, e.g. sickle 3. Clubfoot.
cell anaemia in West Africa, cystic fibrosis 4. Cleft lip and/or palate.
in Europe, thalassaemia in Mediterranean 5. Congenital heart defects.
countries, polydactyly in black South Africans.
Most autosomal recessive conditions are found
in, or come from, tropical countries. Cystic
Multifactoral birth defects are common but
fibrosis is the one autosomal recessive disorder usually involve a single limb, organ or system
that is common in people of European descent. and have a low risk of recurrence.
Some conditions, such as polycystic kidneys,
osteogenesis imperfecta, retinitis pigmentosa
and mental retardation, may be inherited by TERATOGENS
more than one mode of inheritance, e.g. in
some families as a dominant while in other
families as a recessive disorder. 1-27 What is a teratogen?
A teratogen is a fetal environmental factor that
can cause a birth defect. This is different from
MULTIFACTORIAL multifactorial birth defects as teratogens cause
birth defects without an obvious genetic factor.
BIRTH DEFECTS Therefore the chromosomes and genes are
normal in children with birth defects caused
by a teratogen.
1-26 What are multifactorial birth defects?
A teratogen can be a chemical substance like
These are birth defects that have a combined
alcohol, an infection like the rubella virus
genetic and environmental cause. The
(German measles) or a physical agent like
environmental factor (or factors) is often
X-rays. Teratogens interfere with normal
not known. The person affected with
development of the embryo usually early in
a multifactorial birth defect inherits a
pregnancy, but some can also damage the fetus
combination of genes from their parents that
later in pregnancy. If exposure to the teratogen
places them at an increased risk for a birth
is removed, there is little risk of a similar birth
defect. If that individual then experiences
defect in a further child in that family.
certain environmental factors, the result will
be a multifactorial birth defect. Multifactorial
birth defects, therefore, require both genetic 1-28 When does a teratogen
and environmental factors before they do the most damage?
present. Neither the genetic factor nor the The development of an infant from conception
environmental factor alone will cause the birth to birth is divided into three phases. The effect
defect. The risk that another child of the same of teratogens is different in each of these phases:
parents will be affected by a multifactorial
birth defect is small (about 5%). The risk of 1. The pre-implantation phase: (1–17 days
recurrence increases if more than one family post conception or two to four weeks after
member is affected. the start of the last menstrual period).
During this phase the fertilised egg
Multifactorial birth defects are the commonest (zygote) develops from one cell to a ball of
form of birth defect and usually affect a

16. 28 BIR TH DEFECTS
many cells (the conceptus). The conceptus 3. The fetal phase: (six days after conception
floats in a layer of fluid which carries it to birth or from 10 weeks after the start of
from the fallopian tube into the uterus. the last menstrual period to delivery).
At about 17 days post conception (four By six days after conception the embryo has
weeks after the start of the last menstrual turned into a fetus with fully formed organs.
period) the conceptus begins to burrow The fetus still needs to grow and mature
into the lining of the uterus. Implantation before being born. Teratogens generally do
and the development of the placenta and little damage to the fetus in this phase of
umbilical cord now begin. development, but there are some exceptions.
Before implantation it is very difficult For example, the fetal brain, which can be
for a teratogen to get to the developing damaged more easily than other organs,
conceptus and damage it. In the unlikely can still be affected in this phase by some
event that a teratogen does damage the teratogens, particularly drugs like alcohol.
conceptus, it is so small and fragile that
it would die. Implantation would not 1-29 What are examples of teratogens?
happen and the women would not even 1. Maternal infections:
know she had conceived. Therefore, • Rubella virus.
teratogens do NOT cause birth defects in • Cytomegalovirus (CMV).
the pre-implantation phase (1–17 days post • Toxoplasmosis.
conception or two to four weeks after the • Herpes simplex virus.
last menstrual period). • Varicella virus (chicken pox and herpes
zoster).
Teratogens do not cause birth defects during the NOTEToxoplasmosis, Rubella, Cytomegalovirus
pre-implantation phase of development. and Herpes are known as the TORCH organisms.
2. Maternal illnesses:
2. The embryonic phase: (17–6 days post • Diabetes mellitus.
conception or 4–10 weeks after the start of • Epilepsy.
the last menstrual period). 3. Radiation in very large doses:
With implantation and the development of • Excessive amounts of X-ray.
the placenta, the developing infants is now • Nuclear radiation (e.g. Chernobyl).
called an embryo. The embryo and mother 4. Drugs:
are in very close contact and a teratogen • Alcohol.
can now move easily from the mother • Retinoic acid (for severe acne).
through the placenta to the embryo. • Some antibiotics (e.g. tetracycline,
During this phase the organs of the body streptomycin).
are developing. They are very sensitive • Anti-cancer drugs (e.g. methotrexate,
and are easily damaged by teratogens. thalidomide).
Teratogens do the most damage in the • Warfarin (an anticoagulant).
embryonic phase. Structural birth defects • Some anti-convulsants (e.g. phenytoin,
that occur during the embryonic phase are valproic acid).
called malformations, e.g. a cleft lip. • Lithium (an antidepressant).
5. Environmental pollutants:
• Methyl mercury.
Teratogens cause the most damage in the
• There are probably many more which
embryonic phase of development from four to 10 have not yet been identified.
weeks after the start of the last menstrual period.

17. INTRODUCTION TO BIR TH DEFECTS 29
CONSTRAINT CASE STUDY 1
A newborn infant at a district hospital is
1-30 What is constraint? recognised as having a birth defect. The
External forces can result in birth defects after midwife comments that she very rarely sees
the fetus is normally formed (i.e. it is not a birth defects. The doctor does not know the
malformation). The cause of this type of birth cause of the birth defect.
defects is called constraint. There are two types
of birth defects due to constraint: 1. What is a birth defect?
1. Occasionally a normally formed fetus It is an abnormality of function or structure in
is pushed out of shape by mechanical a person which is present from birth.
force in the uterus (e.g. in multiple
pregnancies, where there is little space in 2. Why are birth defects rarely seen?
the uterus, or with oligohydramnios or
large uterine fibroids). The head or chest Because many birth defects are not
may have an abnormal shape or the limbs recognised. A child may even die of a birth
may be bent. This type of birth defect is defect without the correct diagnosis being
called a deformity. Deformities usually made. As a result, birth defects are commoner
correct themselves after delivery once the than they seem to be.
pressure has been removed.
2. Sometimes an amniotic band may damage 3. What is birth prevalence?
a limb or other part of the body. A finger, The birth prevalence of a birth defect is the
toe or part of a limb may be amputated number of infants born with that birth defect
or have a constriction ring. The amniotic per 1000 liveborn infants. In contrast, the
band results from a tear in the amnion prevalence of a birth defect is the number of
early in pregnancy. This uncommon form individuals with that defect per 1000 people in
of birth defect is called a disruption. that population.
Constraint is the type of birth defect caused 4. What are the main known
by local mechanical pressure in the uterus causes of a birth defect?
deforming or disrupting part of the fetus. Birth defects may be caused by:
• Problems at conception, such as
Birth defects may, therefore be divided into:
chromosomal disorders, single gene
1. Malformations. Congenital malformations defects or mutifactorial disorders
develop during the first trimester and are (genetic causes).
caused by failure of the embryo to develop • Problems after conception, such
normally. as teratogens or constraint (fetal
2. Deformations. environmental causes).
3. Disruptions.
Placing a birth defect into one of these three 5. How often is a cause for a
categories helps to identify the probable cause birth defect not found?
and timing of the defect. About 50%.

18. 30 BIR TH DEFECTS
6. Are all birth defects due 5. Is trisomy the only way to get
to genetic causes? extra genetic material?
No. Birth defects due to teratogens and No. With translocation a piece of one
constraint are not due to genetic causes. chromosome may be moved onto another
Therefore, they usually do not recur in the chromosome. If the gamete gets the chromo-
same family. some with the extra piece but not the chromo-
some that has lost a piece, that gamete will
have extra genetic material.
CASE STUDY 2
An infant is brought to hospital with multiple CASE STUDY 3
abnormalities which were present at birth. The
doctor thinks that the birth defects are due to Parents with brown eyes have a son with blue
a chromosomal abnormality. A blood sample eyes. The father asks the genetic nurse how
is sent to a genetic laboratory. The report states brown-eyed parents can have a blue-eyed child.
that the infant has a trisomy.
1. What determines the colour
1. What is a chromosome? of a person’s eyes?
Chromosomes are packages of DNA (a A single pair of genes. The gene for brown eyes
collection of genes) which makes up the is a dominant gene while the gene for blue eyes
genetic plan for the structure and functions of in a recessive gene.
the body.
2. Is the colour of a person’s eyes inherited?
2. Are multiple birth defects often
Yes. The colour of your eyes depends on the
due to chromosomal defects?
genes for eye colour carried by your parents.
Yes. Chromosomal defects usually cause
multiple abnormalities including dysmorphic 3. How can two brown-eyed parents
features, growth and developmental delay and have a child with blue eyes?
malformations.
Because both parents are heterozygous,
i.e. they each have one gene for brown
3. What is a trisomy?
eyes (dominant) and another for blue eyes
With a trisomy the cells have three instead of (recessive). If they both give their recessive
two copies of a particular chromosome. For gene (for blue eyes) to their child, that child
example, in Down syndrome due to trisomy, will be homozygous for the blue-eyed gene
there are three instead of the normal two and, therefore, have blue eyes.
chromosomes 21.
4. What is the chance of their future
4. What is the cause of trisomy? children also having blue eyes?
Non-disjunction. During the formation of the 25%. This is the chance of being homozygous
gametes (egg or sperm), one gamete receives (having both genes recessive) if your parents
two chromosomes in error while the other are heterozygous. If one or both parents have
gamete does not receive a chromosome (from two dominant genes for brown eyes, all their
that pair of chromosomes). children will have brown eyes.

19. INTRODUCTION TO BIR TH DEFECTS 31
5. Are recessive genes always abnormal? parents being carriers (heterozygous) for an
abnormal recessive gene.
No. Many recessive genes (such as eye colour)
are normal. However, recessive genes may
be abnormal and, therefore, cause a clinical
disorder when the child is homozygous. CASE STUDY 5
Healthy parents of six children plan to
CASE STUDY 4 have one last child. They have three normal
daughters and one normal son. However,
their other two sons both have a similar birth
A young couple wants to get married.
defect. The mother’s sister also has a son with
However, the man has a serious birth defect
the same birth defect. They want to know what
which has been diagnosed as an autosomal
the risk is of the planned child having the birth
dominant disorder. They ask their general
defect that is common in the family.
practitioner what the chances are that their
children will inherit the problem. They
mention that they are cousins. 1. What type of gene defect
affects a number of children
born to normal parents?
1. What is an autosomal
dominant disorder? The pattern of inheritance suggests a recessive
gene (either autosomal or X-linked).
It is a clinical problem caused by having an
abnormal dominant gene on an autosome.
2. Why are some of the boys and
none of the girls affected?
2. What is an autosome?
This may be due to chance. However, it
One of the 22 pairs of non-sex chromosomes.
strongly suggests an abnormal X-linked
The X and Y chromosomes are not autosomes.
recessive gene defect. The fact that the
mother’s sister also has an affected son
3. What is a dominant disorder? indicates an abnormal gene carried by the
It is a clinical condition caused by an females and affecting the males in the family.
abnormal dominant gene. A dominant gene is
a ‘strong’ gene that will overpower a recessive 3. Which parent is probably a
gene with which it is paired. The dominant carrier of the abnormal gene?
gene will determine the effect that pair of
The mother.
genes has on the cell.
4. What is the risk of a further
4. What is the risk that their children
son being affected?
will inherit their father’s abnormal
autosomal dominant gene? 50%.
50%. Therefore, the risk of having the same
birth defect (disorder) is also 50%. 5. What is the risk of a further
daughter being affected?
5. Does it matter that they are cousins? Nil. However, she has a 50% chance of being a
carrier.
This will not affect the risk of the children
inheriting the autosomal dominant disorder.
It would, however, increase the risk of both