Birth Defects: Introduction to birth defects


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Birth Defects was written for healthcare workers who look after individuals with birth defects, their families, and women who are at increased risk of giving birth to an infant with a birth defect. This book is being used in the Genetics Education Programme which trains healthcare workers in genetic counselling in South Africa. It covers: modes of inheritance, medical genetic counselling, birth defects due to chromosomal abnormalities, single gene defects, teratogens, multifactorial inheritance

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Birth Defects: Introduction to birth defects

  1. 1. 1 Introduction to birth defectsBefore you begin this unit, please take the BIRTH DEFECTScorresponding test at the end of the book toassess your knowledge of the subject matter. Youshould 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. 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 prevalence1-2 Are all birth defects serious? for all defects is 20–30/1000 live births in theNo. 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 diagnosedperson with a serious birth defect may die at or around birth, and by five years of agesoon after birth, or survive with a disability between four and eight percent of childrendue to the direct effect of the birth defect (e.g. in different countries are considered to haveneural 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 haemophilia). Some serious birth defectscan be treated and this may be life-saving or The birth prevalence of serious birthprevent or reduce serious disability. defects varies from 40/1000 live births in industrialised countries to as high as 80/1000Birth defects can cause a wide range of in some developing countries.disability, e.g. physical disability, intellectualdisability, 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 lifeThe frequency of birth defects (i.e. how recorded a birth prevalence of serious defectscommon are individuals with a birth defect) of 15/1000 live births (1.5% of live births). Birthis expressed as population prevalence and defects can be diagnosed at any age from thebirth prevalence: newborn period (birth to 28 days) through to adulthood. Examples of birth defects that1. 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. 3. INTRODUCTION TO BIR TH DEFECTS 153. 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 BIRTHTherefore both the birth prevalence and DEFECTSpopulation prevalence of birth defects indeveloping countries may seem to be muchlower 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 birthIn South Africa about 1 million infants defects. Note that all birth defects are notare 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 birthyear with a severe birth defect. Of these defects).infants, about 25% will die in the first five NOTE The percentages given above areyears of life. for industrialised countries. Figures forIt is estimated that 9 million children are born developing countries are not the world each year with a serious birthdefect. 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. Aminimum 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. 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 YFigure 1-1: Normal karyotype of a male (46,XY) with 23 pairs of chromosomes (22 pairs of matchingautosomes 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. Thechromosomes are paired (23 pairs), with 22 22 pairs of autosomes and one pair of sexpairs called autosomes and one pair of sex chromosomes.chromosomes. Each pair of autosomes looksthe same. The pair of sex chromosomes do not NOTE In some textbooks, 46,XY is stilllook 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 motherchromosomes in females look alike. and the other chromosome from the father. Therefore, both the mother and father give oneA picture of the 46 chromosomes is called chromosome to each pair of chromosomesa karyotype. The normal female karyotype found in the child. Half of the inheritance plancan be written as 46,XX and the normal male of each individual is inherited from the motherkaryotype as 46,XY. Each pair of autosomes is and the other half from the father. This isgiven a number (1 to 22). called sexual reproduction. An infant’s genetic plan is, therefore, inherited from both parents.
  5. 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 parentThis is why the inherited characteristics of the Each parent gives 23 chromosomes whichparents are shared in the child, and the childhas features of both parents. combine at fertilisation to give a total of 46 chromosomes in the zygote.When the ova (female eggs) are producedin 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 46chromosomes in the parent’s stem cells divide chromosomes are known as the diploid numberwith only one copy of each chromosome pair of chromosomes and the 23 chromosomesstill remaining in each ovum or sperm. The ova in the gametes as the haploid number. Theand sperms (also called gametes or sex cells), process of cell division in which the gametestherefore, only have 23 chromosomes each. are formed and the number of chromosomes is halved (from 46 to 23) is called meiosis. AfterWith fertilisation, a sperm and an ovum meiosis the ovum contains 22 autosomes andunite and combine their chromosomes to an X chromosome, and each sperm has 22form 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 chromosometherefore has 46 chromosomes, half (23) from number stays the same can also occur (asexualthe mother and half (23) from the father. reproduction) and this is called mitosis. This isThe zygote divides, multiplies and grows to the type of cell reproduction that occurs to makebecome an embryo (with cells developing into more cells so that the zygote can multiply anddifferent 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 deliverythe fetus is called the newborn infant.
  6. 6. 18 BIR TH DEFECTS Parents’ cells (46 chromosomes)Abnormal cell Normal celldivision 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-disjunction1-10 What are chromosome abnormalities? have more or less genetic information than it should have. The abnormal embryo mayThe process of reproduction (when the ova abort spontaneously or result in an infantand sperms are made, fertilised and divide with a birth defect. Chromosomal disordersafter conception) is not always perfect. usually present with multiple abnormalities,Abnormalities can occur in the chromosomes including an abnormal appearanceand they may result in a child with a birth (dysmorphic features), developmental anddefect. These chromosome abnormalities are growth delay and malformations. As mostmostly 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 theIf 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 goingof reproduction, then the zygote that results to each gamete, one gamete gets both thewill be abnormal as its genetic plan will paired chromosomes, and therefore has 24
  7. 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 YFigure 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 willnot get a copy of that chromosome and, have cells with 45 chromosomes.therefore, only has 22 chromosomes. Thisabnormal process of cell division, whichresults in two abnormal gametes, is known as Trisomy and monosomy are caused by non-non-disjunction. disjunction.When either of these two abnormal gametesfertilise with a normal gamete (containing 23 1-12 What birth defects are causedchromosomes) the resulting zygote will have by trisomy and monosomy?either of the following: Many of the common chromosomal disorders1. 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 trisomy2. 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 earlyFrom an abnormal zygote with 47 spontaneous abortion.chromosomes (trisomy) the fetusthat develops will have cells with 47 The chromosomes which can result in anchromosomes. Similarly, for a zygote with infant being born alive and surviving with
  8. 8. 20 BIR TH DEFECTStrisomy are 13, 18, 21, X and Y. The common As an example, if the non-disjunction was withtrisomies are: chromosome 21 in a female then the newborn infant would have some cells of 46,XX and1. 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). Mosaicism2. 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 can3. 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 that5. Trisomy X in a female (i.e. 47,XXX). is called a marker chromosome. How this6. XYY in a male (i.e. 47,XYY). affects the person depends on what piece of chromosome is involved. Some peopleDown syndrome, with trisomy of chromosome with marker chromosomes are normal, while21, is the commonest form of chromosomal others can have a chromosome disorder.birth defect. In the formation of gametes (ova or sperms, ifThe only chromosome that can be lost and none of the chromosome pairs separate, thenresult in a live born infant with monosomy is 46 chromosomes will go to one gamete anda sex chromosome X or Y. Therefore, the only none to the other gamete. If the gamete with 46monosomy 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 when1-13 What is mosaicism? a triploidy (three sets of chromosomes) infant is born, it is very abnormal and either dies beforeIn the normal zygote there are 46 chromo- delivery or very early in the neonatal period.somes. The zygote then begins dividing bymitosis to form the embryo which contains 1-14 What is a chromosome translocation?many cells. This division of the one-celledzygote results in a doubling of cells to 2, 4, 8, Translocation occurs when a piece of16, 32 cells and so on, with all the cells having one chromosome breaks off and joins46 chromosomes. However, in mosaicism, (translocates) onto another chromosome. Ifan error occurs in the zygote. Early on in this in this process no genetic material is lost ordividing process one of the cells is involved in gained, this is called a ‘balanced’ translocationnon-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 thencell only 45 chromosomes (monosomy). The this is an ‘unbalanced translocation’ and themonosomy cell usually dies but the trisomy person will be abnormal because their geneticcell 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 atthe embryo, fetus and infant that result will risk of passing on the abnormal chromosomeshave some cells which are normal with 46 to their offspring, resulting in abnormalchromosomes and other cells which are embryos with unbalanced translocations. Thisabnormal with 47 chromosomes. This is called can be the cause of recurrent spontaneousmosaicism (the presence of 2 different cell lines abortions. If the embryo survives, the resultingof the same genetic origin in a person).
  9. 9. INTRODUCTION TO BIR TH DEFECTS 21infant will be abnormal. This risk varies biochemical product (e.g. production of aaccording to the type of translocation. protein or an enzyme). Genes make up the smallest parts of the1-15 What is a chromosome deletion? genetic code. Children look like their parentsThis occurs when a piece of a chromosome, because their genes are a mixture that isbig or small, is missing. There are several inherited from both mother and father. As thisrecognised syndromes in which a known piece combination varies with each child, siblingsof chromosome is missing. These include: look alike and yet have their differences. The only individuals with identical genes are1. 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 and3. 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 SINGLEGENE 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 aboutThe genetic material on chromosomes 20 000 pairs of genes. Over 6000 singleis 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 usuallydetermines a single inherited function by Almost all genes are normal and give thegiving a set of instructions to the cell, such as cell correct instructions. However, a genea 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. 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 theneously or be caused by environmental instructions sent from that gene pair willfactors, including radiation (solar radiation also be abnormal. As a result the cell may notfrom 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 22onto the next generation in the same way as autosomes, it is called an autosomal dominantnormal genes are inherited. As a result, single gene. A clinical disorder caused by a mutationgene defects are usually inherited (unlike in an autosomal dominant gene is calledchromosomal 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 of1-19 What type of genes occur? passing that gene on to each of their children. Both sons and daughter have an equal chanceA gene may be either a dominant or a recessive of inheriting an autosomal dominant gene.gene. Both dominant and recessive genes maybe 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, theDOMINANT INHERITANCE genetic abnormality will be present in the parent with that gene, and also in each child that inherits that abnormal gene. Autosomal1-20 What is a dominant gene? dominant disorders are, therefore, passed fromIn a pair of genes (alleles), the individual one generation to the next. The clinical effectgenes may be of different strengths, with of the abnormal gene will usually be present inthe 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 adominant gene controls the function of that family as a result of a new mutation. That genegene 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. 11. INTRODUCTION TO BIR TH DEFECTS 23 Autosomal dominant inheritanceFigure 1-5: The pattern of autosomal dominant inheritance. There is a 50% chance that the autosomaldominant 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 INHERITANCEgenes 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. 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 daughterFigure 1-6: The pattern of autosomal recessive inheritance. If both parents are heterozygous for a recessivegene (e.g. r), there is a 25% chance that a child will be homozygous and a 50% chance that a child will also beheterozygous for that gene.or both recessive), the person is said to be 1-23 How are autosomalhomozygous 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 aregenes 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 ofdominant gene. Recessive genes may be inheriting the recessive gene from bothnormal (e.g. carry instructions for blue eyes) mother and father (i.e. the child will beor abnormal (e.g. carry instructions for homozygous). Their children will also haveoculocutaneous albinism). If both recessive a 50% chance of inheriting a recessive genegenes 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 recessivecarrier has both a normal (dominant) and an gene from both parents is commoner ifabnormal (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 (intermarriageautosomal 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. 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 sonFigure 1-7: The pattern of X-linked recessive inheritance. There is a 50% chance that the recessive gene fromthe mother will be inherited by both sons and daughters. Only sons will be clinically affected as the X-linkedrecessive 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, itdisorder. The risk of an autosomal recessive is called an X-linked recessive gene (X-linkeddisorder is much higher if the parents are dominant genes and Y-linked genes are veryclosely related (consanguineous). rare).The majority of single gene defects are X-linked recessive genes are inherited by girlsautosomal 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 thedisorder. X-linked genes are in pairs. However, as theIf only one parent is heterozygous (a carrier), X and Y chromosomes are not identical (thethe children cannot be affected but they have a Y chromosome is very short) the X-linked50% risk of inheriting the recessive gene and, recessive genes in a male are not matched to atherefore, 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. 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 ThalassaemiaTable 1-1: Examples of single gene disorders and their mode of inheritanceby a gene on the other X chromosome, X-linked recessive genes are carried by mothersinherited from the father. and affect 50% of their sons.Therefore, disorders caused by X-linkedrecessive genes are carried by females and affectmales. Males have unaffected sons as they givethem their Y and not their X chromosomes. SINGLE GENE DISORDERSHowever, there is a 100% chance that eachdaughter of an affected male will be a carrier. 1-25 What are the commonDisorders caused by an X-linked recessive single gene disorders?gene are called X-linked recessive disorders, The most common autosomal dominante.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. 15. INTRODUCTION TO BIR TH DEFECTS 271. Red–green colour blindness. single limb, organ or system. They often2. Haemophilia. present in infancy or childhood as congenital3. Glucose-6-phosphate dehydrogenase malformations such as: deficiency (G6PD). 1. Neural tube defects.Some single gene disorders are more common 2. Isolated particular populations or regions, e.g. sickle 3. Clubfoot.cell anaemia in West Africa, cystic fibrosis 4. Cleft lip and/or Europe, thalassaemia in Mediterranean 5. Congenital heart defects.countries, polydactyly in black South Africans.Most autosomal recessive conditions are foundin, or come from, tropical countries. Cystic Multifactoral birth defects are common butfibrosis is the one autosomal recessive disorder usually involve a single limb, organ or systemthat is common in people of European descent. and have a low risk of recurrence.Some conditions, such as polycystic kidneys,osteogenesis imperfecta, retinitis pigmentosaand mental retardation, may be inherited by TERATOGENSmore than one mode of inheritance, e.g. insome families as a dominant while in otherfamilies 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 fromMULTIFACTORIAL 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 likeThese are birth defects that have a combined alcohol, an infection like the rubella virusgenetic and environmental cause. The (German measles) or a physical agent likeenvironmental factor (or factors) is often X-rays. Teratogens interfere with normalnot known. The person affected with development of the embryo usually early ina multifactorial birth defect inherits a pregnancy, but some can also damage the fetuscombination of genes from their parents that later in pregnancy. If exposure to the teratogenplaces them at an increased risk for a birth is removed, there is little risk of a similar birthdefect. If that individual then experiences defect in a further child in that family.certain environmental factors, the result willbe a multifactorial birth defect. Multifactorialbirth defects, therefore, require both genetic 1-28 When does a teratogenand environmental factors before they do the most damage?present. Neither the genetic factor nor the The development of an infant from conceptionenvironmental factor alone will cause the birth to birth is divided into three phases. The effectdefect. The risk that another child of the same of teratogens is different in each of these phases:parents will be affected by a multifactorialbirth defect is small (about 5%). The risk of 1. The pre-implantation phase: (1–17 daysrecurrence increases if more than one family post conception or two to four weeks aftermember is affected. the start of the last menstrual period). During this phase the fertilised eggMultifactorial birth defects are the commonest (zygote) develops from one cell to a ball ofform of birth defect and usually affect a
  16. 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. 17. INTRODUCTION TO BIR TH DEFECTS 29CONSTRAINT CASE STUDY 1 A newborn infant at a district hospital is1-30 What is constraint? recognised as having a birth defect. TheExternal forces can result in birth defects after midwife comments that she very rarely seesthe fetus is normally formed (i.e. it is not a birth defects. The doctor does not know themalformation). The cause of this type of birth cause of the birth defect.defects is called constraint. There are two typesof 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 asBirth defects may, therefore be divided into: chromosomal disorders, single gene1. 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 (fetal2. Deformations. environmental causes).3. Disruptions.Placing a birth defect into one of these three 5. How often is a cause for acategories helps to identify the probable cause birth defect not found?and timing of the defect. About 50%.
  18. 18. 30 BIR TH DEFECTS6. Are all birth defects due 5. Is trisomy the only way to getto genetic causes? extra genetic material?No. Birth defects due to teratogens and No. With translocation a piece of oneconstraint are not due to genetic causes. chromosome may be moved onto anotherTherefore, 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 2An infant is brought to hospital with multiple CASE STUDY 3abnormalities which were present at birth. Thedoctor thinks that the birth defects are due to Parents with brown eyes have a son with bluea chromosomal abnormality. A blood sample eyes. The father asks the genetic nurse howis 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 colour1. What is a chromosome? of a person’s eyes?Chromosomes are packages of DNA (a A single pair of genes. The gene for brown eyescollection of genes) which makes up the is a dominant gene while the gene for blue eyesgenetic 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 thedue to chromosomal defects? genes for eye colour carried by your parents.Yes. Chromosomal defects usually causemultiple abnormalities including dysmorphic 3. How can two brown-eyed parentsfeatures, 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 brown3. What is a trisomy? eyes (dominant) and another for blue eyesWith a trisomy the cells have three instead of (recessive). If they both give their recessivetwo copies of a particular chromosome. For gene (for blue eyes) to their child, that childexample, in Down syndrome due to trisomy, will be homozygous for the blue-eyed genethere are three instead of the normal two and, therefore, have blue eyes.chromosomes 21. 4. What is the chance of their future4. 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 homozygousgametes (egg or sperm), one gamete receives (having both genes recessive) if your parentstwo chromosomes in error while the other are heterozygous. If one or both parents havegamete does not receive a chromosome (from two dominant genes for brown eyes, all theirthat pair of chromosomes). children will have brown eyes.
  19. 19. INTRODUCTION TO BIR TH DEFECTS 315. 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 maybe abnormal and, therefore, cause a clinicaldisorder when the child is homozygous. CASE STUDY 5 Healthy parents of six children plan toCASE STUDY 4 have one last child. They have three normal daughters and one normal son. However, their other two sons both have a similar birthA young couple wants to get married. defect. The mother’s sister also has a son withHowever, the man has a serious birth defect the same birth defect. They want to know whatwhich has been diagnosed as an autosomal the risk is of the planned child having the birthdominant disorder. They ask their general defect that is common in the family.practitioner what the chances are that theirchildren will inherit the problem. Theymention that they are cousins. 1. What type of gene defect affects a number of children born to normal parents?1. What is an autosomaldominant disorder? The pattern of inheritance suggests a recessive gene (either autosomal or X-linked).It is a clinical problem caused by having anabnormal 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, itOne of the 22 pairs of non-sex chromosomes. strongly suggests an abnormal X-linkedThe X and Y chromosomes are not autosomes. recessive gene defect. The fact that the mother’s sister also has an affected son3. What is a dominant disorder? indicates an abnormal gene carried by theIt is a clinical condition caused by an females and affecting the males in the family.abnormal dominant gene. A dominant gene isa ‘strong’ gene that will overpower a recessive 3. Which parent is probably agene 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 further4. What is the risk that their children son being affected?will inherit their father’s abnormalautosomal dominant gene? 50%.50%. Therefore, the risk of having the samebirth 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 childreninheriting the autosomal dominant disorder.It would, however, increase the risk of both