Medical Genetics 05 疾病的单基因遗传 Monogenic Inheritance

Medical Genetics single-gene disorder or monogenic disorder Some disorders result when a mutation causes the product of a single gene to be altered or missing. These disorders are inherited in simple patterns similar to or identical with those described by Mendel for certain discrete characteristics in garden peas. Therefore, it ’ s also called Mendelian diseases.

Medical Genetics Basic Pattern of Single Gene Inheritance Autosomal Dominant Autosomal Recessive X-linked Dominant X-linked Recessive Y-linked

Medical Genetics 1. Pedigree and Proband Humans are unique among organisms in many ways, but one way which is near and dear to a geneticist's heart is that humans are not susceptible to genetic experimentation.

Medical Genetics The study of inherited Mendelian traits in humans must rely on observations made while working with individual families.

Medical Genetics Classical cross fertilization breeding experiments as performed by Mendel are not allowed in humans! Human geneticists are not allowed to selectively breed for the traits they wish to study!

Medical Genetics One of most powerful tools in human genetic studies is pedigree analysis.

Medical Genetics pedigree They are graphic representations of a family tree which show the biological relationship of the index case, or proband or propositus to the rest of the individuals. A family tree diagram that shows how a particular genetic trait or disease has been inherited.

Medical Genetics When human geneticists first began to publish family studies, they used a variety of symbols and conventions. Now there are agreed upon standards for the construction of pedigrees.

Medical Genetics Symbols

Medical Genetics

2. autosomal dominant inheritance The pattern of autosomal dominant inheritance is perhaps the easiest type of Mendelian inheritance to recognize in a pedigree. One dose of the mutant gene, one mutant allele, is all that is required for the expression of the phenotype.

Medical Genetics There are three reasons why an individual with an autosomal dominant disease should always be considered as being a heterozygote until proven otherwise.

Medical Genetics A. The disease is usually rare, with only about 1/10,000 individuals affected as an order of magnitude. Affected individuals are most likely to come from affected by normal matings. The normal parent is homozygous recessive, thus assuring that each product of the mating has at least one normal gene.

Medical Genetics B. In the extremely rare instances where two affected individuals have mated, the homozygous affected individuals usually are so severely affected they are not compatible with life. The exceptions are the autosomal dominant diseases caused by the somatic expansion of trinucleotide repeat sequences (e.g., Huntington's disease) that we will study later.

Medical Genetics C. The mating of very closely related individuals, the most likely way for two affected individuals to know each other, is forbidden in our society.

Medical Genetics With the understanding that almost all affected individuals are heterozygotes, and that in most matings involving a person with an autosomal dominant trait the other partner will be homozygous normal, there are four hallmarks of autosomal dominant inheritance.

Medical Genetics There are four hallmarks of autosomal dominant inheritance: (1) Except for new mutations, which are rare in nature and extremely rare on examination pedigrees, and the complexities of incomplete penetrance to be discussed later, every affected individual has an affected biological parent. There is no skipping of generations. (2) Males and females have an equally likely chance of inheriting the mutant allele and being affected. The recurrence risk of each child of an affected parent is 1/2.

Medical Genetics (3) Normal siblings of affected individuals do not transmit the trait to their offspring. (4)The defective product of the gene is usually a structural protein, not an enzyme. Structural proteins are usually defective when one of the allelic products is nonfunctional; enzymes usually require both allelic products to be nonfunctional to produce a mutant phenotype.

Medical Genetics THE PUNNET SQUARE In 1910, Punnett developed a simple method of depicting the possible genotypes one could get from various matings. We call it the Punnett Square.

Medical Genetics Suppose a father is heterozygous for an autosomal dominant gene, with allele D, the mutant dominant allele, and allele d, the recessive normal allele. He can produce two types of gametes, D and d. Suppose also his wife is homozygous normal, having both d alleles. The Punnett Square is constructed as follows:

Medical Genetics One gamete comes from each parent to produce the genotype of the offspring. Two out of the four possible combinations are affected; two out of four are normal.

Medical Genetics Sample Pedigree

Medical Genetics neurofibroma

Medical Genetics marfan ‘ s syndrome

Medical Genetics 3. AUTOSOMAL RECESSIVE INHERITANCE The first, and most important, thing to remember about autosomal recessive inheritance is that most, if not all, affected individuals have parents with normal phenotypes.

Medical Genetics Suppose the disease affects one in ten thousand live births, a good order of magnitude estimate for most autosomal recessive diseases. That would make the heterozygote frequency in the population one in fifty (see population genetics for calculations).

Medical Genetics The likelihood of two affected persons mating would be 1/10,000 x 1/10,000 or 1/100,000,000. By chance alone there might be two such matings in the Unites States, but no more than 2. The likelihood of an affected and a heterozygote mating would be 1/10,000 x 1/50 x 2(since either parent could be the affected) or 1/250,000. The likelihood of two heterozygotes (heterozygotes are usually called "carriers") mating is 1/50 x 1/50 or 1/2500, more than 99% of all possible matings.

Medical Genetics The Punnett Square for autosomal recessive diseases with an affected child in the family almost always looks like the following:

Medical Genetics Where the father and mother are both Dd (dd is the recessive affected individual, Dd the heterozygous carrier individual, and DD the homozygous normal individual). The Punnet Square shows the origin of the famous Mendelian ration of 3/4 normal to 1/4 affected.

Medical Genetics For most autosomal recessive diseases, but not all, the heterozygote cannot be distinguished from the normal homozygote. In the normal phenotype categories of offspring in the above Punnett Square (Dd and DD produce the same normal phenotype), please note that two of the three are heterozygotes (carriers); one of the three is homozygous normal.

Medical Genetics Within the normal siblings of an affected individual the probability of being a carrier is 2/3.

Medical Genetics There are five hallmarks of autosomal recessive inheritance: (1) Males and females are equally likely to be affected. (2) On average, the recurrence risk to the unborn sibling of an affected individual is 1/4. (3) The trait is characteristically found in siblings, not parents of affected or the offspring of affected. (4) Parents of affected children may be related. The rarer the trait in the general population, the more likely a consanguineous mating is involved. (5) The trait may appear as an isolated (sporadic) event in small sibships.

Medical Genetics Sample pedigree

Medical Genetics When consanguinity is involved, i.e., matings between related individuals, in the production of an affected child the assignment of probabilities changes, especially in the rarer autosomal recessive diseases.

Medical Genetics Sample pedigree

Medical Genetics amaurotic idilcy

Medical Genetics Wilson ’ s disease

Medical Genetics 4. X-LINKED DOMINANT INHERITANCE When an X-linked gene is said to express dominant inheritance, it means that a single dose of the mutant allele will affect the phenotype of the female. A recessive X-linked gene requires two doses of the mutant allele to affect the female phenotype.

Medical Genetics Affected father x normal mother. Affected mother x normal father.

Medical Genetics The following are the hallmarks of X- linked dominant inheritance: (1)The trait is never passed from father to son. (2)All daughters of an affected male and a normal female are affected. All sons of an affected male and a normal female are normal. (3)Matings of affected females and normal males produce 1/2 the sons affected and 1/2 the daughters affected. (4)Males are usually more severely affected than females. The trait may be lethal in males. (5)In the general population, females are more likely to be affected than males, even if the disease is not lethal in males.

Medical Genetics Sample pedigree

Medical Genetics incontinentia pigmenti

Medical Genetics vitamin D-resistant Rickets

Medical Genetics 5. X-LINKED RECESSIVE INHERITANCE Everyone has heard of some X-linked recessive disease even though they are, in general, rare. Hemophilia, Duchenne muscular dystrophy, Becker muscular dystrophy, and Lesch-Nyhan syndrome are relatively rare in most populations, but because of advances in molecular genetics they receive attention in the media.

Medical Genetics More common traits, such as glucose-6-phosphate dehydrogenase deficience or color blindness, may occur frequently enough in some populations to produce a few affected females. However, their effect on individuals is rarely life threatening and medical intervention is not needed. Pedigree 7 shows one typical inheritance pattern for a rare X-linked recessive disease.

Medical Genetics

the hallmarks of X-linked recessive inheritance (1) As with any X-linked trait, the disease is never passed from father to son. (2) Males are much more likely to be affected than females. If affected males cannot reproduce, only males will be affected. (3) All affected males in a family are related through their mothers. (4) Trait or disease is typically passed from an affected grandfather, through his carrier daughters, to half of his grandsons.

Medical Genetics Sample pedigree

Medical Genetics hemophilia

Medical Genetics

6. Y-linked A gene on the Y chromosome. A Y-linked gene is by necessity passed from father to son, since the Y chromosome can only be transmitted by a man to his male progeny.

Medical Genetics It has often been said that little is known about whether specific genes are or are not Y-linked.

Medical Genetics a number of genes were known to be Y-linked including: ASMTY (acetylserotonin methyltransferase), TSPY (testis-specific protein), IL3RAY (interleukin-3 receptor), SRY (sex-determining region), TDF (testis determining factor), ZFY (zinc finger protein), PRKY (protein kinase, Y- linked), AMGL (amelogenin), CSF2RY (granulocyte- macrophage colony-stimulating factor receptor, alpha subunit on the Y chromosome), ANT3Y (adenine nucleotide translocator-3 on the Y), AZF2 (azoospermia factor 2), BPY2 (basic protein on the Y chromosome), AZF1 (azoospermia factor 1), DAZ (deleted in azoospermia), RBM1 (RNA binding motif protein, Y chromosome, family 1, member A1), RBM2 (RNA binding motif protein 2) and UTY (ubiquitously transcribed TPR gene on Y chromosome).

Medical Genetics Sample pedigree

Medical Genetics

7. SPECIAL FEATURES Penetrance The likelihood a given gene will result in disease. For example, if half (50%) of the people with the neurofibromatosis (NF) gene have the disease NF, the penetrance of the NF gene is 0.5.

Medical Genetics Expressivity The consistency of a genetic disease. For example, Marfan disease shows variable expressivity. Some persons with Marfan's merely have long fingers and toes while others have the full-blown disease with dislocation of the lens and dissecting aneurysm of the aorta.

Medical Genetics Phenocopy (1) An environmental condition that imitates (copies) one produced by a gene. (2) The person who has an environmentally-produced condition that mimics one produced by a gene.

Medical Genetics Genetic heterogeneity Here a similar clinical picture may be produced by different mutations at the same locus or at different loci. Retinitis pigmentosa may be caused by both autosomal dominant or recessive inheritance.

Medical Genetics Anticipation A remarkable phenomenon in which a genetic disease appears earlier appearance and with increased from with each succeeding generation. Anticipation was once thought not to exist in genetics. It was chalked off as a meaningless statistical artifact. However, anticipation has now been proven to occur in a large number of important genetic disorders, including Huntington disease and myotonic dystrophy. In molecular terms, anticipation is due to the expansion of a trinucleotide repeat sequence in the DNA. This phenomenon also occurs in the fragile X syndrome, the most common inherited form of mental retardation.

Medical Genetics Genomic imprinting The phenomenon of parent-of-origin gene expression. The expression of a gene depends upon the parent who passed on the gene.

Medical Genetics For instance, two different disorders - Prader-Willi syndrome and Angelman syndrome - - are due to deletion of the same part of chromosome 15. When the deletion involves the chromosome 15 that came from the father, the child has Prader-Willi syndrome, but when the deletion involves the chromosome 15 that came from the mother, the child has Angelman syndrome. Genomic imprinting plays a critical role in fetal growth and development. Imprinting is regulated by DNA methylation and chromatin structure.

Medical Genetics New mutations Seen as isolated cases. Increased paternal age may be associated with new mutations. Majority of Achondroplasics are new mutations.