What is the difference between a congenital anomaly and a hereditary disorder?

The term congenital implies that a condition is present at birth, in other words a birth defect, but does not indicate a specific cause. Hereditary implies that a trait is passed from generation to generation but may or may not be recognized at birth. Although many birth defects are the result of errors in the genetic code, others are caused by environmental factors and some result from a combination of genetic and environmental factors. In a malformation such as cleft palate, for example, it is important to distinguish between effects of a recessive gene and problems caused by a teratogen (agent causing birth defects) such as steroids.

How common are birth defects?

Birth defects are unfortunately not rare. Clinical geneticists often cite an incidence of birth defects in the range of 2-5% for human infants. Many of these are minor anomalies without major consequences, however about 1% of infants exhibit major malformations that may be incompatible with normal life and about 1% will exhibit multiple congenital anomalies. Birth defects are a leading cause of stillbirth and neonatal death and are a significant factor contributing to hospital admissions in older children as well.

Birth defects are also common in cats, but often go unrecognized. Stillborn or anomalous kittens may be ingested by the queen as a means for keeping the nest clean and thus may not be identified if the delivery is not attended. Also, complete necropsies are not usually performed on deceased kittens. However, some data is available suggesting an incidence similar to that in humans.

CFA-Cornell Study

Studies in which necropsies were performed suggest that birth defects are a significant cause of kitten mortality.

Incidence of anomalies in neonatal kitten deaths

Frequently observed anomalies in cats may be breed specific, in other words traits which are usually only seen in particular breeds. Some of these may result from founder effect, a form of genetic drift in which a relatively rare trait appears in a high frequency in a particular population because it has been passed down from an early ancestor that is behind many members of the population. Extensive use of a winning cat and its progeny for breeding can result in widespread dissemination of an undesirable trait throughout a breed, for example the craniofacial anomalies in the contemporary Burmese. Specific sought after traits in a given breed may also predispose the breed to anomalies, for example spina bifida in tailless Manx.

Many genetic diseases go unrecognized and only come to attention when a high degree of kitten mortality is seen. A wide range of inborn errors of metabolism have been reported in cats and the incidence may be higher than suspected as affected kittens may simply be dismissed as fading kittens unless specialized studies are performed.

Birth defects may be familial with multiple affected members of the pedigree or sporadic with no apparent history of similar problems in the line. Whereas familial traits are more often than not due to inherited changes involving genes, sporadic cases may or may not be inherited. A careful evaluation of the complete pedigree including both vertical (parents, grandparents, etc,) and horizontal (cousins, aunts, uncles) relatives is necessary in order to determine mode of inheritance.

What is a gene?

The gene is the fundamental unit of heredity. It occupies a particular position on one of the chromosomes, each of which is essentially a long chain of functional genes interspersed with regions of DNA which does not appear to code for specific traits. The genes are strung together in a particular sequence or order and the position occupied by a particular gene is referred to as a locus, which is simply the location of the gene in relation to all of the other genes of the individual, analogous to a specific address on a street. The order of the genes is constant and does not usually change unless there is a break in the DNA strand and subsequent reattachment of the segment in a different location, a process resulting in changes such as those which cytogeneticists (scientists and technologists who study chromosomes) refer to as translocations and inversions. However, such alterations in chromosome structure are exceptions and are not pertinent to the present discussion, although they often play an important role in speciation (evolution of species) and in certain types of birth defects.

As a general rule, genes are inherited unchanged through the generations, in other words the genetic code remains constant. The genetic information is stored in the nucleus of each cell in the form of DNA and is the form of a string of nucleotides, each of which has a purine or pyrimidine as its base. In DNA, there are four possible bases: adenine, guanine, cytosine, and thymine, often abbreviated as A, G, C, and T. The DNA serves as a template for the formation of RNA, which then carries the information of the genetic code outside the nucleus into the cytoplasm of the cell. (Note: in RNA uracil appears instead of thymine.)

The bases of the RNA are read or interpreted in groups of three and each triplet codes for a particular amino acid in a protein chain. This can be thought of as a language in which there are four letters of the alphabet and each word has three letters. For example, the sequence CGU is the instruction to add arginine to the protein, whereas GGU would represent guanine. The resulting proteins are like sentences in this analogy. These proteins can be structural, the building blocks of the body, or regulatory, for example enzymes which control metabolic reactions.

The genetic code also has instructions that indicate the beginning and end of a gene. For example the sequence UGA is a stop codon, indicating that the gene has ended and processing of the chain is to stop. AUG is often a signal to indicate the beginning of a gene, although it can also represent the amino acid methionine. Stop codons can be thought of as periods ending a sentence, whereas the initiator codon is like a capital letter, sometimes signaling the beginning of a sentence but sometimes with other interpretations depending on context.

The genetic code is universal in that DNA is made of the same molecules and the triplets are interpreted in the same way, regardless of whether the DNA is from a human or a fruit fly. However, the sequences differ from one organism to another, both within and between species.

What is an allele?

An allele is an alternate form of a gene. In a population, there may be two or more variations of an individual gene. The various forms of the gene are said to be allelic to one another. For example, one of the genes responsible for pigmentation in the cat has an allele which changes black to chocolate. A third allele results in cinnamon instead. Thus there are three alleles for the gene at this particular locus. In other words, in this example there is one gene with three variations in the population of domestic cats. Some genes can have many alleles. Such genes are often useful in establishing the identity of a sample or in determining the relationships among individuals and because of this they are often used in forensics and in parentage disputes.

How are alleles inherited?

Each individual receives two copies of most genes (there are some exceptions, most notably genes involving the sex chromosomes). The maternal copy and the paternal copy can be the same, in which case the individual is said to be homozygous at the given locus. On the other hand, the two alleles may be different, in which case the individual is said to be heterozygous. In most instances an individual who is heterozygous at a given locus will have one copy of the usual allele (often referred to as the wild type allele, a term frequently used in fruit fly genetics) and one copy of a mutated allele. Sometimes an individual can have two different mutated alleles. Such an individual may be referred to as a compound heterozygote. The term hemizygous is sometimes used when there is only one copy of the gene present and no second allele, for example a locus on the X-chromosome in a male with only a single X.

Some alleles are only expressed if both copies are identical. Such a trait is said to be recessive. An allele which is expressed even if the individual is heterozygous (and thus has only one copy of the allele) is said to be dominant. The color which cat fanciers refer to as blue is a simple example of a recessive trait. A cat with two copies of the allele for blue will be blue, whereas a cat with only one copy will not express the trait and will be black instead. However, this black would be a carrier for the recessive and could in turn have blue kittens if bred to a blue or another carrier. Blue is recessive because the allele is hidden when there is only a single copy, a black carrying blue being indistinguishable from a black which is homozygous for non-dilute.

Sometimes when an individual is heterozygous both alleles are expressed. A cat with one copy of the chocolate and one of the cinnamon allele will be a reddish brown color, intermediate between the usual homozygous chocolate and the homozygous cinnamon coloration. When two alleles are both expressed simultaneously and neither is fully dominant over the other, the term co-dominance is sometimes used. One of the best examples is the human ABO blood group gene. There are four phenotypes (physical expressions) of this gene, referred to as types A, B, AB, and O. These are the result of different combinations of three alleles, referred to as A, B, and O. A and B are co-dominant with one another, whereas O is recessive to both A and B. An individual who is homozygous for A or who is heterozygous for A and O will be type A since A is dominant. Someone with BB or BO alleles will be type B. An individual with one copy of A and one of B will express both and be type AB since these alleles are co-dominant. An individual who is homozygous for the recessive O will be type O. The blood type of the child will depend on the combination of alleles inherited from the parents. Thus it is possible for a type A mother and a type B father to have a type O child, if they are each heterozygous and carry the recessive type O. (This family could also have children who are type A, type B, and type AB as well.)

What is a mutation?

A mutation is quite simply a change in the DNA sequence. The presence of alleles is a reflection of prior mutation events. Were it not for mutations, every individual would be exactly the same as every other individual (with the exception of environmentally controlled characteristics). All of the variations that we see within a species are the results of mutations.

The simplest form of mutation is a change from one nucleotide base to another in the DNA chain. Such a simple change can in turn result in the substitution, deletion, or addition of one or more of the amino acids in the protein chain, or can even cause the chain to not be formed at all. Some such changes have little or no effect on the resulting phenotype (physical appearance), whereas others can have significant implications for the health or even the existence of the affected individual. The genes responsible for formation of human hemoglobin have undergone many mutations, resulting in the various hemoglobinopathies. Even a simple substitution of one base for another can have profound consequences. A change from CTC to CAT in the DNA sequence of the sixth codon of the gene coding for beta globin will result in substitution of valine for glutamic acid in the resulting protein chain. This change alters the shape of the protein and impairs oxygen carrying capacity, resulting in the red blood cells taking on a sickle-like shape. This is the basis for sickle cell anemia.

Not all mutations are bad. Some may actually increase the individual's likelihood for survival and reproduction. Sometimes a mutation may have different consequences for the heterozygote and the homozygote. The mutation for sickle cell hemoglobin (hemoglobin S or Hb S) is interesting in that it has unexpectedly different effects with regard to survival of the homozygote and the heterozygote. The individual with two copies of the Hb S allele is at a distinct disadvantage and may not survive to reproductive age in the absence of medical intervention to counteract the effects of the resulting anemia and vascular compromise. One would expect such a deleterious gene to gradually be lost from the population, however the opposite appears to have occurred and the allele is seen in an unexpectedly high frequency in many parts of the world. The explanation appears to be a selective advantage for the HbS heterozygote in that these individuals have a natural resistance to malaria, whereas individuals without the mutation are susceptible to the infection. Thus the recessive mutation is maintained in a relatively high frequency despite the disadvantage associated with the homozygous condition. No one knows precisely when or where the original sickle cell mutation occurred, however the mutated allele has been passed on for many generations unchanged and the identical altered sequence is seen in many American blacks, inherited from African ancestors living in areas with a high incidence of mosquitoes carrying the malaria pathogen.

Some genes appear to be especially susceptible to mutations. Such genes may contain a region which repeatedly undergoes the same alteration in structure, resulting in a high rate of spontaneous occurrence of an allele which was not present in either parent. Achondroplasia, Marfan syndrome, and neurofibromatosis are examples of genes in the human which appear to be hot spots for mutation due to the presence of sequences which are especially susceptible to copying errors during DNA replication. Most individuals with achondroplasia, for example, will share the same alteration in their DNA sequence as other individuals with the same condition, even through they may not have inherited the trait from a common ancestor.

Sometimes a gene can be susceptible to a wide range of mutations which may occur in multiple locations scattered throughout the gene. Cystic fibrosis is a condition associated with respiratory, digestive, and fertility problems in humans. The cystic fibrosis gene is a relatively large gene and over a hundred different mutations are known to exist within its sequence. Differences in cystic fibrosis expression from one family with the condition to another may be the result of each family carrying different mutations. Two families may have cystic fibrosis due to alteration in the CFTR gene, but one family may be more severely affected than another because the separate mutations differ in their manifestations. Duchenne muscular dystrophy is another condition in which numerous mutations are known to exist.

Can one gene modify the effects of another gene?

Many genes do not function in isolation but rather in concert with other genes. A well-known example in cats is the recessive trait for long hair. A cat which is homozygous for longhair will have a longer coat than one which is homozygous shorthair. Both the Balinese and the Himalayan breeds are homozygous for longhair, yet the latter has a much longer and thicker coat. The difference is not in the genetic mutation which distinguishes longhair and shorthair but rather in other genes which modify the length of the coat. The same modifiers affect shorthairs as well, for example consider the difference between an Exotic Shorthair and an Oriental Shorthair. The differing shades of color in blue cats would be another example.

What is meant by variable expressivity?

Sometimes a given gene will affect various organ systems with a range of resultant phenotypes. The phenomenon of multiple distinct effects that at first may appear to be unrelated is referred to as pleiotropy. For example, Marfan syndrome in humans is a disorder of connective tissue. Affected individuals are unusually tall with long extremities in relation to the trunk. They often exhibit pectus excavatum or carinatum, hyperextensible joints, aortic aneurysms, and subluxation of the lens of the eye. However not every patient will have every manifestation. This variation in expression is referred to as variable expressivity. The differing tail lengths in cats with the Manx mutation would be another example of what might be considered variable expressivity. A more dramatic example is the "twisty cat" trait that results in gives some family members with polydactyly and others with a missing radius (one of the long bones of the front leg). Variable expressivity refers to the manner and degree of expression of a gene in the individual, whereas the term penetrance is used when discussing populations.

What is meant by incomplete penetrance?

Sometimes a gene may be present but is not expressed. When only a certain percentage of individuals with the allele exhibit the associated phenotype, the gene is said to have incomplete penetrance. Penetrance refers to the proportion of individuals within a population who express the trait. Sometimes penetrance is age dependent, for example Huntington disease is not usually expressed until adulthood. Examples of delayed or age-dependent penetrance in the cat include polycystic kidney disease and cardiomyopathy. The term non-penetrant is used to describe individuals known to carry the allele in question but who do not have evidence of expression of the trait. Penetrance is often expressed as a percentage.

What is meant by genetic heterogeneity?

Sometimes two individuals who are homozygous for a recessive trait such as deafness will have unaffected offspring. Although a spontaneous mutation is one possible explanation, another would be genetic heterogeneity. If the parents are affected by different recessive genes, the resulting progeny would not be homozygous at either locus and so would be predicted to be unaffected, although there are exceptions (see digenic inheritance). Genetic heterogeneity of this type implies that a particular phenotype can be caused by mutations at more than one genetic locus. Polydactyly would be a dominant example of genetic heterogeneity in cats. Hairlessness and rex coats would be recessive examples. The type of genetic heterogeneity involving separate loci is sometimes referred to as locus heterogeneity. The identical phenotypes resulting from different genotypes are sometimes referred to as phenocopies.

There can also be heterogeneity within a given genetic locus. This could occur when more than two alleles are known to exist for a particular gene. An individual with two different mutations at the same locus is often referred to as a compound heterozygote.

What is digenic inheritance?

On rare occasions when two different loci can result in a given condition there may be an individual who is heterozygous for a recessive mutation at each of the loci. Although one would not usually expect either to be expressed, there are conditions in which this double heterozygote may indeed be affected. This phenomenon, known as digenic inheritance, is not common but has been postulated as an explanation for some human pedigrees with retinitis pigmentosa, a condition leading to blindness.

What is meant by qualitative versus quantitative characteristics?

Many traits can readily be categorized based upon the recognition of a discrete quality which is either present or absent in the various individuals. For example, it is easy to classify cats based on whether they express the sex linked orange trait or the dominant white trait. Such traits are often referred to as qualitative traits and are frequently inherited in a simple Mendelian (single gene) manner.

Other traits do not fall into discrete categories but rather exhibit continuous variation. These traits are quantitative in nature. Examples of quantitative traits in humans include height, weight, and intelligence. They generally follow a normal distribution (bell-shaped) curve.

What is multifactorial or polygenic inheritance?

Although many traits are the result of the expression of a single gene, others are the result of interactions among multiple genes and possibly environmental factors as well. Quantitative traits such as milk yield in dairy cattle or weight of piglets at weaning would be typical examples in which multiple factors contribute to the outcome.

Some qualitative traits are also multifactorial in their transmission. In humans, cleft palate and spina bifida follow a multifactorial pattern of inheritance. An easy way to visualize this is to think of each parent as contributing various risk factors. There is a threshold for expression of the trait and when the number of risk factors passed on to the child exceeds the threshold, the child will be affected. The recurrence risk for multifactorial inheritance is usually cited in the 3-5% range, less than for a Mendelian trait but certainly still significant.

What is imprinting and does the parent of origin matter for a given allele?

Although traditionally geneticists have claimed that the allele inherited from the mother and the allele from the father are expressed equally during formation of the embryo, we now know that this is not always the case. In a process referred to as imprinting, certain genes may be turned on or off during meiosis (the process of cell division which gives rise to the egg and sperm), analogous to flipping a switch. As a result, the allele from either the mother or the father may be preferentially expressed. If the maternal derived allele in inactivated, the gene is said to be maternally imprinted. A paternally imprinted gene would exhibit inactivation of the allele derived from the father.

Are there mutations which are unstable?

Most mutations, once they occur, remain stable within the genome and are passed down to subsequent generations unchanged. However, there are indeed genes which change in their degree of expression from one generation to the next. For example, a pedigree might include a mildly affected grandparent, a moderately affected parent, and a severely affected child. This increase in severity from one generation to the next is referred to as anticipation.

The genes which exhibit this instability are characterized by regions of DNA composed of repeating sequences of three nucleotides each. The number of trinucleotide repeats varies from one individual to another in the population and the length of the affected region can expand dramatically during meiosis, the process of cell division which gives rise to the egg and sperm. This can result in a child with far more repeats than were present in the parent. Although the mechanism is not fully understood, the increase in number of repeats appears to correspond to the increase in severity for such conditions. Examples of dynamic mutations with triplet repeat sequences in humans include fragile X syndrome, Huntington disease, myotonic dystrophy, and spinobulbar muscular atrophy.

What are the differences between malformations, deformations, disruptions, and dysplasias?

These are all terms that are used to describe anomalous development. They are useful in that they distinguish the morphogenesis of the various conditions, in other words they categorize the type of process that went wrong.

A malformation is a defect involving an organ or region of the body as a result of an intrinsically abnormal developmental process. In simple terms, the organ is formed improperly. This is often the result of an abnormal gene, resulting in instructions that cannot be properly interpreted by the developing embryo. Polydactyly would be considered a malformation.

A deformation is the result of mechanical forces. For example, an infant who is unable to move inside the uterus will often exhibit club foot because the legs are deformed to take the shape of the uterus. A small tree which is bent by ice and so grows at an angle is another example of a deformation. The problem is not the result of intrinsic changes in the genetic code but rather is the consequence of forces outside the developing organism.

A disruption is said to occur when normal development is disrupted or interfered with by some extrinsic agent. For example, a band of membrane can wrap around one of the extremities of the developing embryo and can result in a congenital amputation. Birth defects caused by teratogenic drugs (a teratogen is an agent which causes birth defects) are also disruptions in that development was normal until the agent was introduced and the resultant changes are not hereditary but are due to the disrupting insult during a critical period of development.

A dysplasia is the result of abnormal organization of cells into tissues and organs, typically due to expression of a mutant allele. Dysplasias can affect many different parts of the body, depending upon where the particular tissue type is found. Connective tissue disorders such as Ehlers-Danlos syndrome, a type of condition which has been reported in Himalayans and is a concern in some sphynx, and Marfan syndrome are examples.

What do the terms syndrome, sequence, and association mean?

A syndrome is a pattern of anomalies which is recurrent and the various anomalies are thought to be the result of a single pathogenic process. Down syndrome, a disorder resulting from an extra chromosome, would be a well-known example in humans.

A sequence is a pattern of events which are the consequence of one initial anomaly, essentially a cascade or domino effect. For example, lack of kidneys can lead to decreased amniotic fluid which can result in deformation of the extremities due to uterine constraint. Spina bifida in a Manx kitten can lead to an abnormal gait, urinary and fecal incontinence, and infections.

The term association is sometimes used in reference to anomalies which occur together in more than one individual but which cannot be identified as being the result of any known syndromal process nor do they appear to exhibit the causal relationship of a sequence. This term does not imply anything regarding the nature of the relationship between the anomalies, only that the traits may be seen together statistically.