Lecture VIII: Non-classical Inheritance Patterns - PDF

stre /21se ↳ e Lecture VIII Non-classical patterns of inheritance. Particularities of single-gene inheritance. Multifactorial inheritance. Genetics of disorders with multifactorial inheritance. Twins and twinning. Nonclassical patterns of single gene inheritance. Particularities of single-gene inher...

stre /21se ↳ e Lecture VIII Non-classical patterns of inheritance. Particularities of single-gene inheritance. Multifactorial inheritance. Genetics of disorders with multifactorial inheritance. Twins and twinning. Nonclassical patterns of single gene inheritance. Particularities of single-gene inheritance. The fragile X syndrome is determined by a mutation with an X-linked dominant pattern of inheritance. The fragile X syndrome is the most common but atypical heritable mental retardation, accounting for about one - third to one - half of all X - liked mental retardation. Fragile X syndrome is caused by a mutation in FMR1 gene, in which a nucleotide triplet CGG is repeated more than 200 times. Healthy individuals may have a number of 5 to 40 CGG repeats. Individuals with 55 to 200 CGG repeats are said to have a FMR1 gene premutation. In women, the premutation can expand to more than 200 CGG repeats during oogenesis. Thus, women with the premutation have an increased risk of having an affected descendent, who has the full mutation. By contrast, in men the premutation does not expand during spermatogenesis. Men pass the premutation only to their daughters, who will not be affected, but may have affected descendents (daughters receive one X chromosome from their father, the other one from the mother). Their sons will not receive the X chromosome, thus, will neither carry the permutation, nor will be affected (the son receives the Y chromosome from the father). The name of the syndrome refers to a cytogenetic marker, a “fragile site” in which the chromatin fails to condense during mitosis, on the X chromosome at Xq27.3. The fragile X is expressed cytogenetically only in a relatively small proportion of cells: 10% - 40% in most fragile X syndrome at males and in lower percent in fragile X syndrome at females. Mitochondrial inheritance It has been recognized for many years that a few pedigrees of inherited diseases cannot be explained by typical Mendelian inheritance of nuclear genes. There are few neuromuscular diseases determined by mitochondrial DNA mutations, such as: hereditary optic atrophy, mitochondrial encephalomyopathy and myoclonus epilepsy. A unique feature of these mitochondrial diseases is its maternal inheritance, because only mothers transmit mitochondrial DNA to their offspring. Pedigree pattern of mitochondrial inheritance Mosaicism Mosaicism for mutations in single genes, in either somatic or germline cells, seems to be a likely explanation for a number of unusual clinical disorders. Somatic mosaicism is defined as the existence of two genetically distinct cell lines within an individual, derived from a postzygotic mutation. It is a mutation occurring during embryonic development, which may affect morphogenesis, but the patient has normal parents. These mutations may affect only a part of the body and are not transmitted to the descendents. Germline mosaicism is represented by a mutation, which has occurred in a germline cell of one of the parents as a new mutation. In this way, normal parents could have children with a single - gene disorder, such as achondroplasia, osteogenesis imperfecta, Duchenne muscular dystrophy. Germline mosaicism can be seen with any inheritance pattern. Mono-allelic expression In most cases, both alleles of a pair are transcribed; this is known as bi-allelic expression. Some genes may show mono-allelic expression (only one allele will be expressed). Monoallelic gene expression is the process in which transcription occurs from only one of two alleles from one pair, in a diploid cell. This is also called allelic exclusion. Monoallelic gene expression may occur:  Depending on the parental origin of the gene = genomic imprinting  Independently, through the random expression of a certain allele, such as: inactivation of an X chromosome in females, a process whereby only one Ig light chain and one heavy chain gene are transcribed in one cell or other mechanisms. Genomic imprinting One assumption of Mendelian inheritance is that the alleles of a given gene from both parents are equally expressed in the offspring, but today, on the basis of molecular investigations, it is known that in some cases the two alleles are expressed in functionally different ways, a phenomenon called as genomic imprinting. In other words, the imprinted allele is inherited in a mendelian manner but its expression is determined by the gender of the transmitting parent. One of the mechanisms involved in this process is a different pattern of methylation of nucleotides in DNA molecules. In a considerable number of genetic disorders, the expression of the disease phenotype depends on whether it has been inherited from the father or from the mother. Example 1: a severe early onset of miotonic dystrophy that occurs when the mutant gene has been inherited maternally, and the relatively early onset in Huntington disease when the mutant gene is inherited paternally. Example 2: increased severity of neurofibromatosis with maternal transmission. Example 3: Differences in expression that depend on the sex of the transmitting parent has also come from the study of two syndromes: Prader - Willi syndrome and Angelmam syndrome. Obesity, short stature, and hypogonadism, small hands and feet and, mental retardation characterize the Prader - Willi syndrome. In many cases there is a microdeletion involving the proximal long arm of chromosome 15 inherited from the patients father. Thus, the genomes of these patients have genetic information (corresponding to the gene originated from fathers), only from their mothers. In contrast, in many patients with the Angelman syndrome, which is phenotypically quite different from Prader - Willi syndrome, there is a deletion of the same chromosomal region on chromosome 15 inherited from the mother. Therefore, the patients have the genetic material only from their fathers. Epilepsy, severe learning difficulties and severe mental retardation characterize Angelman syndrome. Multifactorial inheritance Genetics of disorders with multifactorial inheritance There are many common disorders that appear to run in families but are neither of single gene nor of chromosomal origin. These disorders are said to show multifactorial inheritance, indicating that they are caused by multiple factors, both genetic and environmental. Some of these disorders are congenital defects and others appear as common disorders during adult life, such as: hypertension, asthma or diabetes. Multifactorial inheritance means that many factors are involved in causing a disease. The factors are usually both genetic and environmental, a combination of genes from both parents, in addition to unknown environmental factors, produce the trait or condition. Often one gender (either males or females) is affected more frequently than the other in multifactorial inheritance. There appears to be a different threshold of expression, which means that one gender is more likely to show the problem over the other gender. For example, hip dysplasia is nine times more common in females than males. Multifactorial traits and diseases do recur in families, because they are partly caused by genes. The chance for a multifactorial trait or condition to happen again depends upon how closely the family member with the trait is related to you. For example, the risk is higher if a brother or sister has the trait or disease, than if a first cousin has the trait or disease. This is due to the fact that family members share a certain percentage of genes in common, depending upon their relationship. The tendency of a trait to run in families is called familial aggregation. The most important assumptions of the polygenic, multifactorial model are:  each locus has an additive effect on the phenotype  the loci are independent of each other A useful way of comparing the contributions of genetics and environment to phenotypic variation is the concept of heritability. This represents a ratio of variance caused by additive genetic influence. The higher the heritability, the more important is the contribution of the genetic factors. The quantity of genetic factors is termed ″the liability″ of an individual. This can be the result of a polygenic effect together with environment effects. Multifactorial threshold in congenital defects The basis for a number of common congenital anomalies is a liability to the defect with a threshold marking the point at which the liability is involved in expression of the abnormal phenotype. Several common congenital malformations with an average frequency in population show a pattern predicted by the multifactorial threshold model. These congenital malformations include:  pyloric stenosis,  neural tube defects (anencephaly and spina bifida),  congenital heart defects  cleft lip and palate  positional foot defects  congenital dislocation of hip  hypospadias Pyloric stenosis is a defect of the pylorus in which hypertrophy and hyperplasia of the smooth muscle narrows the antrum of the stomach (the antrum becomes almost obstructed), which leads to feeding problems. Pyloric stenosis is five times as common in boys as in girls, but its family pattern is distinctive: in term of the risk, affected females are much more likely than affected males to have affected children and among the children of both affected males and affected females, the sons are more likely than daughters to be affected. The inheritance does not fit any Mendelian pattern. Sons of affected mothers have the highest risk for pyloric stenosis. Liability to the malformation is assumed to be continuously distributed in the population and to be determined by multiple factors, some genetic (the disorder runs in families) and others possibly environmental. If the underlying liability to a trait is continuous but the threshold is lower in males than in females, affected females have, on the average, more extreme liability than do affected males; thus, the offspring of affected females have a higher mean liability to pyloric stenosis than do offspring of affected males. Sons of affected mothers are the highest risk, about 20%. Neural tube defects Anencephaly and spina bifida are neural tube defects that frequently occur together in families and are considered to have common pathogenesis. Neural tube defects, spina bifida (open spine) and anencephaly (open skull), are seen in 1 to 2 per 1000 live births. During pregnancy, the human brain and spine begin as a flat plate of cells, which rolls into a tube, called the neural tube. If all or part of the neural tube fails to close, leaving an opening, this is known as an open neural tube defect (ONTD). This opening may be left exposed (80% of the time), or covered with bone or skin (20% of the cases). Anencephaly and spina bifida are the most common ONTDs, while encephaloceles are much rarer. Anencephaly occurs when the neural tube fails to close at the base of the skull, whereas spina bifida occurs when the neural tube fails to close somewhere along the spine. Babies with anencephaly are stillborn or usually live for only a few days after delivery. Babies born with spina bifida may have minimal or transient (temporary) problems, or may have permanent, often serious, physical problems. These may include paralysis, lack of bowel and bladder control, club feet, hydrocephaly (a condition marked by an accumulation of spinal fluid in the head) and mental retardation. In most cases, one or more surgeries after birth may be necessary. In spina bifida, there is a failure of fusion of the arches of the vertebrae, typically in lumbar region, but also possible in other regions. There are varying degrees of severity, ranging from spina bifida occulta, in which the defect is in the bony arch only, to spina bifida aperta, often associated with meningocele (protrusion of meninges) or meningomyelocele (protrusion of neural elements as well as meninges). The incidence of neural tube defects is a little higher in females than in males. The frequency also appears to vary with social factors and season of birth. It has been believed that nutritional factors may account for at least part of the variation. A small proportion of neural tube defects can have other causes: for example, amniotic bands (fibrous connections between the amnion and fetus, caused by early rupture of the amnion, which may disrupt structures during their embryological development), multifactorial, some single - gene defects with pleiotropic expression, some chromosome disorders and, some teratogenic factors. Most neural tube defects are presumed to have multifactorial inheritance. ONTDs happen to couples without a prior family history of these defects in over 90% of cases. ONTDs are seen five times more often in females than males. Once a child has been born with an ONTD in the family, the chance for an ONTD to happen again is increased to 3 to 5%. It is important to understand that the type of neural tube defect can differ the second time. For example, one child could be born with anencephaly, while the second child could have spina bifida and not anencephaly. ONTDs can be diagnosed before birth by measuring a protein called alpha-fetoprotein present in the amniotic fluid. Fetal ultrasound during pregnancy can also give information about the possibility of an ONTD, but is not 100% accurate, since some babies with an ONTD may look the same on ultrasound as those without these defects. Measurement of the AFP, and other biochemical markers from amniotic fluid, is over 95% accurate for detecting ONTDs. Small or closed defects (which do not leak spinal fluid) may not be picked up by this test. Congenital heart defects Congenital heart defects are very common, with a frequency of about 8 - 12 cases per 1000 births. They are a heterogeneous group, caused in some cases by single - gene or chromosomal mechanisms and in other cases resulting from teratogenic exposure such as: rubella infection, maternal diabetes, viral infection, anticonvulsivants, etc. In most cases, however, the cause is regarded to be multifactorial. There are many types of congenital heart defects with different population incidences and risk and having a multifactorial threshold model. Ventricular septal defect has the highest incidence, followed by defect of ductus arterious, atrial sept defect, and aortic stenosis a. o. Cleft lip and cleft palate Oro-facial clefts (cleft lip with or without cleft palate) are among most common congenital defects. It is estimated that 1 case occurs in every 500-55o births. They are caused by th a failure of fusion of the frontal process with the maxillary process at about 35 day of gestation. About 60-80% of affected cases are males. The etiology of orofacial clefts is heterogeneous. Most isolated forms are caused by the interaction of genetic and environmental factors, showing multifactorial inheritance. They may also occur in single - gene syndromes, in chromosomal disorders and many cases result from teratogenic exposure (rubella, anticonvulsants, other drugs). Severity and recurrence risk increase from unilateral to bilateral malformations and from isolated cleft lip to cleft lip associated with cleft palate. Congenital dislocation of hip Congenital dislocation of hip is characterized by the displacement of the femoral head outside the acetabulum, occurring as a congenital subluxation. Also called hip dysplasia, it is nine times more common in females than males. Genetic and environmental factors are thought to have important role in the etiology. One of the environmental influences thought to contribute to hip dysplasia is the baby's response to the mothers' hormones during pregnancy. Once a child has been born with hip dysplasia, the chance for it to happen again in a male or female child is about 6 percent overall. In other words, there is a 94 percent chance that another child would not be born with hip dysplasia. The defect appears to be inherited as a multifactorial trait, as familial aggregation and high concordance rate for monozygotic twins have been noticed. Club foot concordance rate: the probability that two individuals will have the same phenotype given that one of the pair have the characteristic Club foot is a common congenital anomaly that shows familial aggregation. Many types of transmission have been reported: autosomal recessive, X-linked recessive, multifactorial. Deformities include: adduction of the forefoot, inversion of the heel, plantar flexion, dorsal flexion. About 70% of these malformations occur in males. Surgery is needed in order to correct these defects. Etiology may be:  multifactorial  chromosomal syndromes (especially trisomy 13)  single-gene syndromes  teratogenes, such as: rubella virus, anticonvulsivants, etc. Complex disorders of adult life Several common chronic disorders are definitely familial, and in a broad sense they behave as multifactorial threshold traits, but depending on the effect of environment. Examples of complex disorders of adult life:  coronary artery disease  high blood pressure  congenital heart defects  hypertrophic cardiomyopathy  obesity  diabetes mellitus  asthma  mental and behavioral disorders Coronary artery disease Coronary artery disease is a major health problem, particularly in males aged 45 or more. Most cases appear to be multifactorial with an effect of environment. Familial hypercholesterolemia, an AD defect of the low-density lipoprotein receptors accounts for about 5% of survivors of myocardial infarction. Although there are other single-gene causes, the adverse risk factors associated with coronary artery disease include nongenetic as well as genetic factors, most cases of coronary artery disease showing multifactorial inheritance: Genetic factors Nongenetic factors male sex increasing age family history of coronary disease sisi single-gene abnormalities of lipoproteins and lipids hypertension smoking stress physical inactivity obesity diabetes mellitus The risk factors for coronary artery disease include several other multifactorial disorders with genetic components: hypertension, obesity, and diabetes mellitus. In this context, the abnormal phenotype associated with these disorders contributes to an environment that enhances the risk of coronary artery disease. One feature of coronary artery disease that is consistent with multifactorial inheritance is that whereas males are at higher risk of death from myocardial infarction both in the population and within affected families, the recurrence risk in relatives is somewhat greater when the proband (the patient) is female. However, the risk of ischemic heart disease in some families is greater when there is a family history with first-degree relatives having this disorder. High blood pressure is a major cardiovascular risk factor, which is in part genetically determined. With the notable exception of two AD forms of hypertension related to an abnormality in aldosterone secretion and to an overactivity of the epithelial sodium channel, there is no indication on the number of genetic loci involved in hypertension. Even though the genetic loci controlling blood pressure are unknown, a first approach is to study genes that may contribute to the variance of blood pressure due to their well-known effect on the cardiovascular system. The genes of the renin angiotensin aldosterone system are a good illustration of such a “candidate gene” approach, since this system is well known to be involved in the control of blood pressure and in pathogenesis of several forms of human hypertension. Hypertrophic cardiomyopathy Hypertrophic cardiomyopathy is characterized by a hypertrophied left and/or right ventricle, rapid upstroke pulse, prominent apex beat and a late systolic ejection. Genetic mutations cause a significant percentage of cardiomyopathies. In hypertrophic cardiomyopathy mutations in genes encoding the heavy chains of myosin and myosin binding protein C (MYH7 and MYBPC3) explain 75% of inherited forms, leading to the observation that this form is a disease of sarcomeres. Many mutations are variants or rare mutations, often occurring in a particular family. By contrast, dilated cardiomyopathy is more heterogeneous from the geneticpoint of view, with mutations of cytoskeletal, nucleoskeletal, mitochondrial genes, etc. Over 50 unique gene variants have been identified in this form. Cardiomyopathies with or without arrhythmias are associated with some monogenic diseases (lipidosis). Congenital heart defects Congenital heart anomalies are the most common forms of birth defects. They have a complex etiology:  chromosomal abnormalities, such as trisomy 13, 18 or 21  single-gene disorders, such as some metabolic diseases  multifactorial  teratogenic, due to rubella, maternal drug ingestion, maternal diabetes a.o. Obesity Large differences in body weight and fat distribution, even among people of the same sex and age are due to genetic factors, although surely that environment also plays a role. Two recent studies of body weight in monozygotic twins (MZ) demonstrate the twin method of assessing the relative importance of genes and environment in obesity. The comparison of MZ twins reared together or apart and of dizygotic twins (DZ) reared together or apart is a classical way of measuring heritability of complex traits. Several studies showed thus that the genetic component represented by a high heritability is important in weight gain and also in overfeeding. Diabetes mellitus The genetics of diabetes mellitus is complex; many studies have shown that diabetics have a positive family history- in other words, there is a familial aggregation of diabetes. The study of twins (MZ and DZ) leaves no doubt as to the importance of genetic factors in the etiology of diabetes as well as predisposing nongenetic factors. In fact, in diabetes it is known that there is a complex genetic heterogeneity; the clinical genetic studies have suggested that juvenile - and adult - onset diabetes differed genetically. Diabetes mellitus may be divided into two types: insulin-dependent diabetes mellitus type I (IDDM) and non-insulin-dependent diabetes mellitus type II (NIDDM). They differ in typical age, of onset monozygotic twin concordance, and HLA associations. IDDM type I is an autoimmune, polygenic disease. The concordance rate (30 to 50 percent) for IDDM in monozygotic twins (Mz) provides strong support for the hypothesis that genetic factors contribute to the predisposition to IDDM. Nevertheless, the fact that the concordance rate is less than 100 percent is usually interpreted as evidence those environmental factors may contribute as well. About 95% of all IDDM patients (in comparison with about half the normal population) have HLA-DR3 or HLA-DR4; heterozygotes DR3/DR4 are particularly susceptible to IDDM. This is one of the strongest HLA-disease associations known. Families’ studies suggest that the HLA association account for more than half the heritability of IDDM. The most recent data have suggested another strongest association of IDDM with the HLA-DQ locus. Variable Onset age IDDM usually40 years MZ twins concordance 30-50% close to 100% HLA associations none strong New insights into the basis of IDDM have come from molecular analysis of the HLA class II genes, which are responsible for immune responsiveness. Thus, in the DR4 haplotype, the presence of aspartic acid (Asp) at position 57 of the DQ  chain is closely associated with resistance to IDDM, whereas other amino acids at this position (alanine, valine or serine) confer susceptibility. About 90 percent of patients with IDDM are homozygous for DQ  genes that do not encode Asp at position 57. Although there is a strong association of IDDM with HLA genes, there are probably other susceptibility genes outside the major histocompatibility complex and nongenetic factors involved in the etiology of this disease. Unlike type I, type II diabetes mellitus (NIDDM) is not an autoimmune disease. Available evidence strongly suggests that the susceptibility to type II diabetes mellitus be determined primarily by genetic factors. The concordance of diabetes type II in MZ twins is close to 100%. Asthma, a reversible obstructive pulmonary disease closely associated with bronchial hyper-responsiveness and airways inflammation is a complex disorder with genetic susceptibility. Although an increased risk to relatives has been reported, the asthmatic phenotype is not inherited in a simple Mendelian fashion. Family studies are complicated because the clinical expression of this disorder is affected by age and gender as well as by exposure to allergens, pollutants and viral respiratory infections. Studies on monozygotic and dizygotic twins are used as a first step in determining the role of genetics in a multifactorial disorder. Thus, many twin studies showed significant differences of the concordance in MZ twins, 19% compared with 4,8% in DZ twins. These studies provide evidence for a genetic component in the development of asthma. In addition to twin studies, many family studies have also demonstrated a heritable polygenic component to susceptibility to asthma. Mental and behavioral disorders Several other common complex genetic polygenic, multifactorial disorders are:  schizophrenia  bipolar/unipolar psychosis  autism  dyslexia and specific learning disorders  attention deficit and hyperactivity disorders  addiction In schizophrenia, family, twin, and adoption studies suggest that 65-85% of the susceptibility to disease can be attributed to genes. In linkage studies, families with ill members have been tested by genotyping the variable sequences (allele) at DNA marker loci. If a disease gene is close to a marker, then offspring who inherit the disease allele will also tend to inherit nearby marker allele (linkage) because meiotic recombination is unlikely across a short chromosomal distance. Linkage analysis determines whether ill relatives have inherited the same marker allele more of than expected by chance. Thus, linkage studies can focus on the candidate regions for schizophrenia. These regions have been found many chromosomes, eg. 2q, 4q, 9q, 11q, 6p, 8p and 22q; it is obvious that more chromosomal regions contain schizophrenia susceptibility genes, which suggests that the disease has amultifactorial inheritance. In bipolar disorder linkage studies have shown that there are marker loci on the long arm of chromosome 18 (18q), but there is compelling evidence from twin, family and adoption studies to suggest that bipolar disorder results from multiple genetic loci acting independently or in concert; some of the genes are probably located on chromosome 8, others on chromosome 21q. Most of these disorders are heterogeneous and a large part of their analysis will involve dissecting the heterogeneity, finding genes responsible for different genetic forms and establishing risk factors, separate from the genetic background, that increase the probability that the disease will develop in an individual patient. Many methods of genetic linkage analysis show in these disorders multifactorial and polygenic traits. Autism is a behavioral disorder characterized by abnormalities in language and social communication, stereotype, repetitive movements, tics, abnormalities in reciprocal social interaction. Implication of genetic factors in its etiology was sustained by family studies that revealed familial aggregation, twin studies (higher concordance in monozygotic than in dizygotic twins) and associations with chromosomal abnormalities. All these studies suggest that genetic liability plays an important role, together with social factors, obstetric complications a.o. Dyslexia and other specific learning disabilities: Patients with these disabilities have difficulties in learning, reading and spelling despite normal intelligence and without neurological handicap. Linkage analysis revealed that few loci are involved in the etiology, thus, this trait is called oligogenic. Attention deficit and hyperactivity disorder is the most common impediment to learning seen in children. Patients have difficulty in attention, impulsivity, hyperactivity. There is evidence for a substantial genetic influence in this disorder. Twin studies, as well as family and adoption studies have shown that few loci together with environmental factors cause the disease. Addiction. Genetic factors play an important role in different types of addictions, but addiction vulnerability is a very complex trait, multiple genes and environment can have additive effects. As for the other multifactorial disorders, inheriting susceptibility does not necessarily mean that a person will have the disease. Characteristics of multifactorial inheritance 1. Although the disorder is familial, there is no distinctive pattern of inheritance within a single family. 2. The risk to first - degree relatives is evaluated in the following way: the lower the population incidence, the greater the relative increases in risk for first - degree relatives. 3. The risk is lower for second - degree than for first - degree relatives. 4. The recurrence risk is higher when more than one family member is affected. 5. The more severe the malformation, the greater the recurrence risk. 6. If a multifactorial trait is more frequent in one sex than in the other, the risk is higher for relatives of patients of the less susceptible sex. 7. If the amordance rate in DZ twins is less than half the rate in MZ twins, the trait cannot be AD, and if it is less than a quarter of the MZ rate, it cannot be autosomal recessive. 8. An increased recurrence risk when the parents are consanguineous suggests that multiple factors with additive effects may be involved. Twins and twinning Twins can be either dizygotic (fraternal) or monozygotic (identical). Dizygotic twins (DZ) are the result of two different ova fertilized by two different sperm. Monozygotic twins (MZ) are the result of one ovum fertilized by one sperm that divides to form two embryos. Twins and genetic studies In the past, the only way of differentiating between MZ and DZ twins at birth was their sex, appearance and placentation. Today, cord blood type, HLA antigens and DNA fingerprinting are all used to differentiate between MZ and DZ twin pairs. However, DNA fingerprinting has become the only accurate method. The importance of twins in genetic studies was first recognized by Galbon, who in 1875 suggested the study of twins as a model for investigating the differences between the environmental and genetic effects on disease. Comparison of concordance rate in MZ and DZ twins is a standard method used in medical genetics for comparison of the effects of genes and environment. Concordant in human genetics means a twin pair in which both members exhibit a certain trait. Discordant means a twin pair of which one member shows a certain trait and the other does not. If MZ pairs are not completely concordant for a given trait, genetic factors alone cannot account for the trait. Comparison of concordance rates in MZ and DZ twins is used to measure the “heritability” of complex traits. There are many types of studies in which twins can provide valuable information. The purpose of all twin studies is to obtain results that are applicable not only to twins but also to the human population. In studies that compare the differences between MZ and DZ twins with regard to a specific trait and then draw conclusions for the general population, it is necessary to know whether nongenetic factors act differently on MZ and DZ twins, under the assumption that MZ and DZ twins are exposed to the same pre- and postnatal environmental factors. The incidence of MZ twins is thought to be constant throughout the world. By contrast, the incidence of DZ twins varies from population to population, with a higher prevalence in some areas, such as Africa. In North America, the incidence of twins (the combination of MZ and DZ) is estimated at 1 in every 80 births. The number of twin conceptions is harder to asses, since studies have shown that at least th 70% of twin pregnancies diagnosed by ultrasound examination before the 10 week miscarry or convert to singleton. Several investigators have confirmed that the number of twins at delivery is considerably less than the number of twin conceptions seen on ultrasound examination in early pregnancy. The “disappearance” of the co-twin recognized on ultrasound examination seems to occur during the second half of the first trimester or early in the second trimester. Dizygotic twins Dz twins are derived from the fertilization of two ova by two sperm and may be of the same or different sex. Their genetic contribution is different, since it comes from two different ova and two different sperm. Multiple ovulation, that is, the release of more than one ovum from the ovaries is necessary for DZ twinning. Women who have given birth spontaneously (without the use of fertility drugs) to DZ twins are known to have higher levels of follicle–stimulating hormone (FSH) and luteinizing hormone (LH). This evidence has led to the now established association of increased levels of FSH and LH and DZ twinning. DZ twins produced by the fertilization of multiple ova may be the result of superfecundation. DZ twins would be expected to have two placentas, two chorions and two amnious. However, placentas in DZ conceptions may fuse and look like one. There are many reports of familial DZ twining. The female members of these families are thought to have an inherited predisposition to multiple ovulation and a higher number of DZ twin pair when compared to the general population. An established association between higher gonadotropin levels and higher incidence of DZ twins in certain families is thought to be the basis for familial DZ twinning. The use of fertility drugs may artificially duplicate what is a natural occurrence in some families. Monozygotic twins MZ, or “identical” twins are the result of the fertilization of one ovum by one sperm. The single fertilized ovum then divides into two embryos; both embryos are thought to have the same genetic contribution; in the past, it have been expected to be genetically identical. However, with new molecular genetic techniques, it has become clear that some MZ twins are not completely identical. MZ twins may have separate or contiguous placentas and may be monochorionic monoamniotic. A few families have been reported in which MZ twinning occurs more frequently than expected. Because familial MZ twinning is inherited both maternal and paternal side of the family it has been suggested that it may be caused by a single gene effect. Although, the etiology of MZ twinning in humans is unknown, several mechanisms have been proposed. In 1970, Bulmer suggested that MZ twinning is associated with disturbance of developmental clocks or thresholds and that delayed fertilization or delayed implantation may play a role in MZ twinning. Edwards in 1986 suggested that abnormalities or rupture of the zona pellucida may lead to herniation of the blastocyst and predispose to MZ twinning. Other investigators have suggested that twinning itself may a type of congenital anomaly of development. MZ twins may sometimes be discordant for a variety of congenital defects and genetic disorders. In addition to environmental differences and chance variation, the following reasons for discordance are recognized:  mechanisms of embryological development, such as vascular abnormalities, that can lead to discordance for malformation;  postzygotic changes such as somatic mutation leading to discordance for cancer, or somatic rearrangement of immunoglobulin genes;  chromosome abnormalities originating in one zygote after the twinning event;  uneven X inactivation between female MZ twins with the result that one twin preferentially expresses the paternal X, the other the maternal X. Studies of MZ and DZ twins reared apart have been helpful in establishing the significance of genetic and environmental factors regarding susceptibility of several diseases with multifactorial inheritance. For example, these studies have been helpful in measuring the extent of genetic contribution compared to environmental contribution in complex psychiatric disorders like schizophrenia and bipolar disorders. Regarding to diabetes mellitus studies of MZ and DZ twins’ leave no doubt as the importance of genetic factors in the etiology of diabetes, as well as predisposing non-genetic factors. Thus, the concordance of diabetes insulin-dependent type I (IDDM) in MZ twins is 3040%, whereas in noninsulin-dependent diabetes type II (NIDDM) the concordance is close to 100%. Higher concordance in MZ twins in comparison with DZ twins has also been observed in many other multifactorial diseases.