Genetics

Anticipation

The signs and symptoms of some genetic conditions tend to become more severe and appear at an earlier age as the disorder is passed from one generation to the next. Most often seen with certain genetic disorders of the nervous system, such as Huntington disease, myotonic dystrophy, and fragile X syndrome. Typically occurs with disorders that are caused by an unusual type of mutation called a trinucleotide repeat expansion.

Tuberous sclerosis

a. Characteristics include the presence of glial nodules and distorted neurons in the cerebral cortex. Seizures, mental retardation, and adenoma sebaceum (a facial skin lesion consisting of malformed blood vessels and connective tissue) also occur. b. Other associated tumors include rhabdomyomas of the heart, subependymal giant cell astrocytomas (SEGAs), and renal angiomyolipomas. c. Caused by mutations in the TSC1 or TSC genes which encode the hamartin and tuberin proteins, respectively.

Cri du chat (5p-, cry of the cat) syndrome cause and characteristics

a. The cause is the deletion of the short arm of chromosome 5. b. Characteristics are severe mental retardation, microcephaly, and an unusual catlike cry. Additional manifestations include low birth weight, round face, hypertelorism (wideset eyes), low-set ears, and epicanthal folds.

Translocation

a. This is an exchange of chromosomal segments between nonhomologous chromosomes. It is denoted by a t followed by the involved chromosomes in numeric order. For example, the translocation form of Down syndrome is designated as t(14q;21q). b. Reciprocal or balanced translocation is a break in two chromosomes leading to an exchange of chromosomal material. Because no genetic material is lost, balanced translocation is often clinically silent. c. Robertsonian translocation is a variant in which the long arms of two acrocentric chromosomes, chromosomes in which the short arm is very short, are joined with a common centromere, and the short arms are lost. One important example leads to a hereditable form of Down syndrome. Chromosome 21 is joined to a second acrocentric chromosome, commonly chromosome 14 or 22. The union of a gamete with this translocation with a gamete from an unaffected person can result in trisomy 21 (1 in 3 theoretic chance).

Hurler syndrome

(1) This mucopolysaccharidosis is caused by deficiency of α-L-iduronidase, with consequent accumulations of the mucopolysaccharides heparan sulfate and dermatan sulfate in the heart, brain, liver, and other organs. (2) Characteristics include progressive deterioration, hepatosplenomegaly, dwarfism, gargoyle-like facies, stubby fingers, corneal clouding, progressive mental retardation, and death by 10 years of age. (3) The syndrome is clinically similar to, but should not be confused with, Hunter syndrome, which is an X-linked recessive disorder.

List Autosomal Dominate disorders

Adult polycystic kidney disease, Familial hypercholesterolemia, Hereditary hemorrhage telangiectasia, Hereditary spherocytosis, Marfan, Neurofibromatosis type I, Tuberous sclerosis, von Hippel-Lindau disease

Mendelian Modes of Inheritance

Autosomal Dominant, Autosomal recessive, X-linked recessive

List the sex chromosomal disorders

Klinefelter (XXY), XYY, Turner (XO), XXX

Inversion

is a reunion of a chromosome broken at two points, in which the internal fragment is reinserted in an inverted position.

Uniparental disomy (UPD)

occurs when a person receives two copies of a chromosome, or part of a chromosome, from one parent and no copies from the other parent. In some genes, this is not a big deal and has no effect, but in other genes (if one is silenced) this can lead to problems- Angelman and Prader-Willi.

Sex chromosomes: X inactivation and Barr body formation

Extreme karyotype deviations in the sex chromosomes are compatible with life; this is believed to be due to X inactivation (lyonization) and the relatively scanty genetic information carried by the Y chromosome.

Familial Hypercholesterolemia

is a genetic defect characterized by anomalies of receptors for low-density lipoprotein (LDL) receptors. a. The disease results in decreased transport of LDL cholesterol into cells, which causes hypercholesterolemia and a striking increase in incidence and in earlier onset of atherosclerosis and its complications. b. Additional manifestations include xanthomas, raised yellow lesions filled with lipidladen macrophages, in the skin and tendons.

Isochromosome formation

is the result of transverse rather than longitudinal division of a chromosome, forming two new chromosomes, each consisting of either two long arms or two short arms. One of the two isochromosomes, usually the short-arm isochromosome, often is lost.

Cystic fibrosis

in which there is an apparent protective effect against cholera. It is thought that the enterotoxin of cholera facilitates the egress of chloride and water from intestinal mucosa by enhanced activity of chloride channels. Both heterozygous carriers and homozygous affected subjects with cystic fibrosis are relatively resistant to this effect, because insufficient chloride channels are available.

Tay-Sachs disease

in which there may be a protective effect against tuberculosis.

Polyploidy

is a chromosome number that is a multiple greater than two of the haploid number. a. Triploidy is three times the haploid number; tetraploidy is four times the haploid number. b. Polyploidy is rarely compatible with life and usually results in spontaneous abortion.

Aneuploidy

is a chromosome number that is not a multiple of 23, the normal haploid number. It is caused most often by an addition or loss of one or two chromosomes; this change may result from nondisjunction or anaphase lag. a. Nondisjunction (1) Nondisjunction is the failure of chromosomes to separate during meiosis or mitosis. Meiotic nondisjunction is the most common cause of aneuploidy. (2) This process is responsible for disorders such as trisomy 21, the most common form of Down syndrome. b. Anaphase lag (1) Anaphase lag results in the loss of a chromosome during meiotic or mitotic division. (2) In early embryonic life, this can result in mosaicism, in which an individual develops two lines of cells, one with a normal chromosome complement and another with monosomy, a single residual chromosome, for the affected chromosome pair.

Phenylketonuria

Unaffected heterozygotes have a lower incidence of spontaneous abortion. It is thought that modestly increased concentrations of phenylalanine exert a protective effect on pregnancy. This should not be confused with maternal PKU, which is discussed elsewhere in this chapter.

Complications of Down syndrome

(1) Congenital heart disease, especially defects of the endocardial cushion, including atrioventricular valve malformations and atrial and ventricular septal defects (2) Acute leukemia (20-fold increase), most often lymphoblastic (3) Increased susceptibility to infection (4) In patients surviving into middle age, morphologic changes in the brain similar to those of Alzheimer disease

Characteristics of Down syndrome

(1) Mental retardation is always present but is highly variable in degree. (2) Changes in appearance include: (a) Large forehead, broad nasal bridge, wide-spaced eyes, epicanthal folds, large protruding tongue, and small low-set ears (b) Brushfield spots, small white spots on the periphery of the iris (c) Short, broad hands with curvature of the fifth finger; simian crease, a single palmar crease; and an unusually wide space between the first and second toes

Maternal screening for Down syndrome

(1) α-Fetoprotein—low (2) Human chorionic gonadotropin (hCG)—high (3) Unconjugated estriol—low (4) The foregoing assays are referred to as the "triple screen." When assay for elevated serum inhibin A is also performed, it is referred to as the "quadruple screen." Expansion of this panel to include other substances such as pregnancy associated plasma protein-A (reduced in Down syndrome) and ultrasound studies for physical defects such as increased nuchal fold has shown promise.

XXX syndrome

(47,XXX) and other multi-X chromosome anomalies. These syndromes are usually unaccompanied by any clinical abnormalities, although they may be marked by menstrual irregularities. Additional X chromosomes beyond XXX are marked by progressively increasing mental deficiency, depending on the number of additional X chromosomes.

Glucose-6-phosphate dehydrogenase

(G6PD) deficiency. In this X-linked disorder, hemizygotes manifest drug-related (classically primaquine, an antimalarial) or oxidant-related hemolytic anemia and are also resistant to malaria. In this instance, selection working both positively and negatively clearly represents a manifestation of the balance implied by the term balanced polymorphism.

Hereditary hemorrhagic telangiectasia

(Osler-Weber-Rendu syndrome) is a rare disorder seen with increased frequency in certain populations, such as in Mormon families of Utah. Characteristics include localized telangiectases of the skin and mucous membranes and by recurrent hemorrhage from these lesions.

Fabry disease

(angiokeratoma corporis diffusum universale) is a lysosomal storage disease caused by deficiency of α-galactosidase A, with resultant accumulation of ceramide trihexoside in body tissues. a. Characteristics include skin lesions (angiokeratomas) over the lower trunk, febrile episodes, severe burning pain in the extremities, and cardiovascular and cerebrovascular involvement. b. Patients typically die of renal failure in early adult life.

Neurofibromatosis type I

(von Recklinghausen disease) a. Distinguishing features include multiple neurofibromas in skin and other locations, café-au-lait spots, and pigmented iris hamartomas (Lisch nodules). The benign neurofibromas can become malignant. b. Skeletal disorders, such as scoliosis and bone cysts, and increased incidence of other tumors, especially pheochromocytoma, and malignancies, such as Wilms tumor, rhabdomyosarcoma, and leukemia, also occur. c. The cause is mutations in the NF1 gene, a tumor suppressor gene that normally codes for a GTPase-activating protein (GAP) that facilitates the conversion of active ras-GTP to inactive ras-GDP.

Polygenic and multifactorial disorders

A. These disorders are more common than monogenic disorders. B. The causes are abnormalities of complex processes that are regulated by the protein products of two or more genes. Environmental factors also play an important role in the modulation of the genetic defects. C. Common polygenic disorders include ischemic heart disease, diabetes mellitus, hypertension, gout, schizophrenia, bipolar disorder, and neural tube defects.

Balanced Polymorphism

1. Balanced polymorphism refers to the increased incidence of deleterious (usually in homozygotes) alleles among certain populations in environments in which the same allele is associated with a potential survival advantage (usually in heterozygotes). 2. This condition has been observed in both autosomal and X-linked disorders. 3. Hemoglobin S, G6PD, Phenylketonuria, Tay-Sachs, Cystic fibrosis.

True hermaphrodite

1. This rare condition is characterized by both ovarian and testicular tissue, with ambiguous external genitalia and both X and Y chromosomes. 2. One possible mechanism is the parthenogenetic division of a haploid ova into two haploid ova, followed by double fertilization and then fusion of the two zygotes in early embryonic development.

Marfan syndrome

A defect of connective tissue characterized by faulty scaffolding. a. The apparent cause is a deficiency of fibrillin, a glycoprotein constituent of microfibrils. b. Characteristics include defects in skeletal, visual, and cardiovascular structures. (1) Patients are tall and thin with abnormally long legs and arms, spider-like fingers (arachnodactyly), and hyperextensible joints. (2) Dislocation of the ocular lens (ectopia lentis) is frequent. (3) Cystic medial necrosis can lead to aortic dilation with resultant aneurysm of the proximal aorta, aortic valvular insufficiency, and dissecting aneurysm of the aorta. Loss of connective tissue support may lead to mitral valve prolapse.

Disorders of sexual differentiation

A. These disorders are more common than monogenic disorders. B. The causes are abnormalities of complex processes that are regulated by the protein products of two or more genes. Environmental factors also play an important role in the modulation of the genetic defects. C. Common polygenic disorders include ischemic heart disease, diabetes mellitus, hypertension, gout, schizophrenia, bipolar disorder, and neural tube defects.

Barr bodies

Also known as sex chromatin, these are clumps of chromatin in the interphase nuclei of all somatic cells in females. a. According to the Lyon hypothesis, each Barr body represents one inactivated X chromosome. Thus, normal female cells (XX) have one Barr body; normal male cells (XY) have no Barr bodies; and XXXY cells have two Barr bodies. The number of Barr bodies is always one less than the number of X chromosomes. b. Assessment of the presence or absence of Barr bodies and their number was once an important diagnostic tool, but it has now been supplanted by more definitive and sophisticated analytic procedures.

Variable expressivity

Although some genetic disorders exhibit little variation, most have signs and symptoms that differ among affected individuals. Variable expressivity refers to the range of signs and symptoms that can occur in different people with the same genetic condition.

DiGeorge/velocardiofacial syndrome (microdeletion of 22q11, CATCH 22 syndrome) characteristics

Characteristics include a set of findings summed up in the acronym CATCH 22, which denotes Cardiac abnormalities, Abnormal facies, T-cell deficit because of thymic hypoplasia, Cleft palate, Hypocalcemia because of hypoparathyroidism, and microdeletion 22q11. In about 30% of cases, this syndrome is also associated with behavior disorders and psychosis (bipolar disorder and schizophrenia) that develop during adolescence.

Patau syndrome (trisomy 13) characteristics

Characteristics include mental retardation, microcephaly, microphthalmia, brain abnormalities, cleft lip and palate, polydactyly, rocker-bottom feet, and congenital heart disease.

Hemophilia A

Classic hemophilia is a relatively common X-linked disorder caused by mutations affecting the factor VIII gene, which has been localized to the tip of the long arm of the X chromosome. The disease is manifest as a deficiency of coagulation factor VIII. a. Symptoms and signs include hemorrhage from minor wounds and trauma, bleeding from oral mucosa, hematuria, and hemarthroses. b. Recurrent hemarthroses can lead to progressive crippling deformities.

What is genomic imprinting?

Disorders associated with genomic imprinting. In these hereditary disorders, different phenotypes occur depending on whether an abnormal gene is of maternal or paternal origin. 1. It is thought that epigenetic changes occurring during gametogenesis mark at least some genes as of either maternal or paternal origin and can modify the later expression of these genes when they are passed to the next generation. Such marking is referred to as genomic imprinting. The most likely explanation for this phenomenon is differing levels of DNA methylation in the female and male gonads, making certain genes nonactive (i.e., not able to be transcribed).

Down Syndrome Cause

Down syndrome is the most frequently occurring chromosomal disorder. (1) Trisomy 21 (a) The vast majority of cases (95%) are caused by trisomy 21, and the incidence increases with maternal age. (b) Maternal meiotic nondisjunction is the usual cause. When the cause is paternal nondisjunction, there is no relation to paternal age. (2) Translocation (a) Translocation leads to a familial form of Down syndrome, with significant risk of the syndrome in subsequent children. (b) From 3% to 5% of cases result from translocation, and there is no relation to maternal age. (c) The cause is parental meiotic translocation between chromosome 21 and another chromosome. The fertilized ovum has three chromosomes bearing the chromosome 21 material, the functional equivalent of trisomy 21.

Fragile X syndrome characteristics

Fragile X syndrome is an important cause of hereditary mental retardation, second in frequency only to Down syndrome. (a) Sons with full mutations exhibit mental retardation and often bilateral macroorchidism (enlarged testes). The genetic defect can be further transmitted to all of their daughters. (b) Daughters with full mutations may or may not (∼50%) exhibit mental retardation. This unexplained phenomenon is possibly due to selective X inactivation, in which affected females have a greater number of somatic cells with full mutations than do unaffected females.

Hemoglobin S.

Heterozygotes are thought to be relatively resistant to Plasmodium falciparum malaria, and homozygotes have sickle cell anemia.

List X-linked recessive disorders

Hunter, Fabry, Hemophilia A, Lesch-Nyhan

Abnormalities due to increased numbers of trinucleotide repeats

Several disorders have been found to be associated with the expansion of the number of tandem trinucleotide repeats in certain critical genes. a. The number of repeats often increases from generation to generation and is associated with earlier onset and more severe manifestations in successive generations. This phenomenon is referred to as anticipation. b. fragile X syndrome

Genomic Imprinting

People inherit two copies of their genes—one from their mother and one from their father. Usually both copies of each gene are active, or "turned on," in cells. In some cases, however, only one of the two copies is normally turned on. Which copy is active depends on the parent of origin: some genes are normally active only when they are inherited from a person's father; others are active only when inherited from a person's mother. In genes that undergo genomic imprinting, the parent of origin is often methylated. These molecules identify which copy of a gene was inherited from the mother and which was inherited from the father. The addition and removal of methyl groups can be used to control the activity of genes.

Pseudohermaphrodite

This organism has gonads of only one sex, but the appearance of the external genitalia does not correspond to the gonads present. 1. Male pseudohermaphrodite. The gonads are testes, but the external genitalia are not clearly male. The cause may be tissue resistance to androgens (testicular feminization), defects in testosterone synthesis, or hormones administered to the mother during pregnancy. The condition has also been linked to chromosomal anomalies, such as 46,XY/45,X mosaicism. 2. Female pseudohermaphrodite. The gonads are ovaries, but the external genitalia are not clearly female. The condition is most often caused by increased androgenic hormones from congenital adrenal hyperplasia, an androgen-secreting adrenal or ovarian tumor in the mother, or hormones administered to the mother during pregnancy

Two disorders associated with genomic imprinting?

This phenomenon is illustrated by two rare syndromes in which the same cytogenetic deletion, del(15)(q11q13), results in differing phenotypes in progeny depending on whether the deletions were transmitted by the mother or the father. a. Paternal transmission results in the Prader-Willi syndrome, characterized by hypogonadism, hypotonia, mental retardation, behavior problems, and uncontrolled appetite leading to obesity and diabetes. b. Maternal transmission results in the Angelman syndrome, sometimes referred to as the "happy puppet" syndrome, which is also characterized by mental retardation but is additionally characterized by ataxia, seizures, and inappropriate laughter. In some instances, this condition is associated with alterations in a gene involved in the ubiquitin-proteosome system.

List the autosomal chromosomal Disorders

Trisomy 21(Downs), 18(Edwards), 13(Patau), Cri Cu Chat, 22q11.2

Hunter syndrome

a lysosomal storage disease, a form of mucopolysaccharidosis clinically similar to, but less severe than, Hurler syndrome. a. This disorder is caused by deficiency of L-iduronosulfate sulfatase, resulting in accumulations of heparan sulfate and dermatan sulfate. b. Characteristics include hepatosplenomegaly, micrognathia, retinal degeneration, joint stiffness, mild mental retardation, and cardiac lesions.

A trinucleotide repeat is

a sequence of three DNA building blocks (nucleotides) that is repeated a number of times in a row. DNA segments with an abnormal number of these repeats are unstable and prone to errors during cell division. The number of repeats can change as the gene is passed from parent to child. If the number of repeats increases, it is known as a trinucleotide repeat expansion. In some cases, the trinucleotide repeat may expand until the gene stops functioning normally. This expansion causes the features of some disorders to become more severe with each successive generation.

Neurofibromatosis type II

a. Characteristics include bilateral vestibular nerve schwannomas with an increased risk for schwannomas of other nerves, meningiomas, ependymomas, and astrocytomas as well as posterior subcapsular lens opacities. b. Attributable to mutations in the NF2 gene on chromosome 22q, which encodes merlin. c. The nomenclature is confusing for several reasons: First, it has little relationship to neurofibromatosis type I and neurofibromas do not typically occur. Second, it has historically been referred to as the syndrome of "bialateral acoustic neuromas," which is inappropriate because tumors are schwannomas rather than neuromas and because they affect the vestibular, rather than acoustic, nerves.

von Hippel-Lindau disease

a. Characteristics include hemangioblastoma or cavernous hemangioma of the cerebellum, brain stem, or retina; adenomas; and cysts of the liver, kidney, pancreas, and other organs. b. A remarkably increased incidence of renal cell carcinoma is associated with von Hippel-Lindau disease. The gene for von Hippel-Lindau disease has been localized to the short arm of chromosome 3, deletion of which has been noted in many cases of sporadic renal cell carcinoma.

Adult polycystic kidney disease characteristics

a. Characteristics include numerous bilateral cysts that replace and ultimately destroy the renal parenchyma. b. The disease becomes clinically manifest between 20 and 40 years of age even though the genetic defect is present at birth; death usually occurs at about 50 years of age. (Similarly, Huntington disease, a condition associated with multiple trinucleotide repeats, does not become manifest until adult life.)

Deletion

a. Deletion is most often an absence of a portion of a chromosome, although it can be a loss of an entire chromosome. b. This change is denoted by a minus sign following the number of the chromosome and the sign for the chromosomal arm involved, p for the short arm and q for the long arm. For example, cri du chat syndrome, characterized by partial loss of the short arm of chromosome 5, is designated as 46,XY,5p- in males or 46,XX,5p- in females.

Klinefelter syndrome cause

a. Klinefelter syndrome occurs when there are at least two X chromosomes and one or more Y chromosomes. The most striking clinical changes are male hypogonadism and its secondary effects. Most often, the karyotype 47, XXY is characteristic. Variants include additional X chromosomes (e.g., XXXY) and rare mosaic forms. b. Most often, the cause is maternal meiotic nondisjunction, and incidence increases with maternal age. f. Usually, Klinefelter syndrome is undiagnosed before puberty

Edwards syndrome (trisomy 18) cause and characteristics

a. Most frequently, trisomy 18 results from nondisjunction. b. Characteristics include mental retardation, prominent occiput, micrognathia (small lower jaw), low-set ears, rocker-bottom feet, flexion deformities of the fingers (index overlapping third and fourth), and congenital heart disease.

Lesch-Nyhan syndrome

a. The cause is a deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT), with resultant impaired purine metabolism and excess production of uric acid. b. Characteristics include gout, mental retardation, choreoathetosis, spasticity, selfmutilation, and aggressive behavior.

Hereditary spherocytosis cause and characteristics

a. The cause is a variety of inherited defects of erythrocyte membrane-associated skeletal proteins. b. Characteristics include spheroidal erythrocytes that are sequestered and destroyed in the spleen, producing hemolytic anemia.

Turner Syndrome characteristics

a. The most striking clinical changes are female hypogonadism and its secondary effects. Turner syndrome is also often associated with autoantibody-mediated hypothyroidism. b. Other characteristics of Turner syndrome include the following: (1) Replacement of the ovaries by fibrous streaks (2) Decreased estrogen production and increased pituitary gonadotropins from loss of feedback inhibition (3) Infantile genitalia and poor breast development (4) Short stature, webbed neck, shield-like chest with widely spaced nipples, and wide carrying angle of the arms (5) Lymphedema of the extremities and neck (6) Coarctation of the aorta and other congenital malformations e. Turner syndrome, the most common cause of primary amenorrhea, is generally not considered to be a cause of mental retardation.

X inactivation

a. This is the process by which all X chromosomes except one are randomly inactivated at an early stage of embryonic development. It results in all normal females being mosaics, with two distinct cell lines, one with an active maternal X, another with an active paternal X. b. It can be demonstrated if the female is heterozygous for an X-linked gene; if individuals demonstrate inheritable differences that distinguish the protein products of one X chromosome from the other, then members of the two cell lines can be identified. c. The X-inactive-specific transcript (XIST) is a large untranslated RNA molecule that is associated with "coating" and inactivating of one of the two X chromosomes. All except a single remaining X chromosome are inactivated. d. The phenotypic differences between XO, XX, and multiple X genotypes are thought to be caused by residual genes on the X chromosome that escape inactivation.

Turner syndrome cause

a. Turner syndrome is a disorder that occurs when there is complete or partial monosomy of the X chromosome. b. An XO karyotype (45, X) is characteristic.

XYY syndrome characteristics

a. XYY syndrome occurs with increased frequency among criminals demonstrating violent behavior; the significance of this association is unknown, because only about 2% of XYY individuals display such behavioral abnormalities. b. Characteristics include tallness, severe acne, and only rarely mild mental retardation.

Fragile X syndrome cause

b. The cause is a cytogenetically demonstrable defect on the long arm of the X chromosome that leads to chromosome breakage in vitro. Fragile X syndrome is considered to be an X-linked disorder; however, the pattern of inheritance has a number of unusual features. (1) Both males and females can be asymptomatic carriers. Such carriers have an increased number of CGG tandem repeats in the 5' untranslated region of the familial mental retardation (FMR-1) gene. This increased number of repeats is referred to as a premutation. In carrier females (but not carrier males), premutations can expand in the germline to even greater increases in the number of tandem repeats. These increased numbers are referred to as full mutations. (2) Carrier males (transmitting males) can transmit premutations through their daughters, who remain clinically unaffected but who can become carriers of X chromosomes with full mutations due to germline expansion of the repeats. (3) Carrier females can transmit the affected X chromosome to both sons and daughters.

Klinefelter syndrome characteristics and complications

b. The disorder is always manifested by a male phenotype with testes. Affected individuals have atrophic testes; tall stature, because fusion of the epiphyses is delayed; and a eunuchoid appearance with gynecomastia. In addition, they have decreased testosterone production and increased pituitary gonadotropins from loss of feedback inhibition. 50 BRS Pathology c. The disorder is a frequent cause of male infertility. d. Usually, there is no association with mental retardation. If present, mental retardation is usually mild, and the extent of retardation increases with increased number of X chromosomes.

Penetrance

refers to the proportion of people with a particular genetic change (such as a mutation in a specific gene) who exhibit signs and symptoms of a genetic disorder. If some people with the mutation do not develop features of the disorder, the condition is said to have reduced (or incomplete) penetrance.