GENETICS

INTRODUCTION

Humans have only about 30,000 genes

Genetics is study of single or few genes and their phenotypic effects.

Genomics is the study of all the genes in the genome and their phenotypic effects

Any 2 individuals share greater than 99.5% of their DNA sequences.

Remarkable diversity of humans is encoded in less than 0.5% of our DNA

DISEASES

time-honored classification of human diseases

(1) those that are genetically determined, (2) those that are almost entirely

environmentally determined, (3) those to which both nature and nurture

contribute.

MUTATIONSPERMANENT change in DNA

GENE MUTATION: (may, and often, result in a single base error)

CHROMOSOME MUTATION: (visible chromosome change)

GENOME MUTATION: (whole chromosome)

Those that affect germ cells are transmitted to the progeny and may give rise to inherited diseases.

Mutations in somatic cells are not transmitted to the progeny but are important in the causation of cancers and some congenital malformations.

Point mutations result from the substitution of a single nucleotide base by a different base, resulting in the replacement of one amino acid by another in the protein product.

EX: sickle cell anemia.

"nonsense" mutations interrupt translation, and the resultant truncated proteins are rapidly degraded.

POINT MUTATION

Frameshift mutations occur when the insertion or deletion of one or two base pairs alters the reading frame of the DNA strand

Trinucleotide repeat mutations mutations are characterized by amplification

of a sequence of 3 nucleotides.

MENDELIAN INHERITANCE PATTERNSAUTOSOMAL DOMINANTAUTOSOMAL RECESSIVESEX-LINKED (recessive), involving “X” chromosome

AUTOSOMAL DOMINANT Disease is in HETEROZYGOTES NEITHER parent may have the disease (NEW

mut.)

REDUCED PENETRANCE (environment?, other genes?)

VARIABLE EXPRESSIVITY (environment?, other genes?)

May have a DELAYED ONSET Usually result in a REDUCED PRODUCTION or INACTIVE protein

AUTOSOMAL DOMINANT•HUNTINGTON DISEASE•NEUROFIBROMATOSIS•MYOTONIC DYSTROPHY•TUBEROUS SCLEROSIS

•ACUTE INTERMITTENT PORPHYRIA•FAMILIAL HYPERCHOLESTEROLEMIA

•MARFAN SYNDROME•EHLERS-DANLOS SYNDROMES (some)•OSTEOGENESIS IMPERFECTA•ACHONDROPLASIA

•HEREDITARY SPHEROCYTOSIS•VON WILLEBRAND DISEASE

•POLYCYSTIC KIDNEY

AUTOSOMAL DOMINANT PEDIGREE

1) BOTH SEXES INVOLVED

2) GENERATIONS NOT SKIPPED

AUTOSOMAL RECESSIVE Disease is in HOMOZYGOTES More UNIFORM expression than AD

Often COMPLETE PENETRANCE Onset usually EARLY in life NEW mutations rarely detected clinically Proteins show LOSS of FUNCTION Include ALL inborn errors of metabolism MUCH more common that autosomal dominant

AUTOSOMAL RECESSIVE

CF PKU GALACTOSEMIA HOMOCYSTINURIA LYSOSOMAL

STORAGE Α-1 ANTITRYPSIN WILSON DISEASE HEMOCHROMATOSIS GLYCOGEN STORAGE

DISEASES

Hgb STHALASSEMIASCONG. ADRENAL HYPERPLASIAEHLERS-DANLOS (some)ALKAPTONURIANEUROGENIC MUSC. ATROPHIESFRIEDREICH ATAXIASPINAL MUSCULAR ATROPHY

AUTOSOMAL RECESSIVE PEDIGREE

1) BOTH SEXES INVOLVED

2) GENERATIONS

SKIPPED

SEX (“X”) LINKED

MALES ONLYHIS SONS are OK, right?ALL his DAUGHTERS are CARRIERSThe “Y” chromosome is NOT homologous to the “X”, i.e., the concept of dominant/recessive has no meaning here

HETEROZYGOUS FEMALES have no phenotypic expression (carriers)….usually, this means autosomal “recessive”, right?

SEX (“X”) LINKED

DUCHENNE MUSCULAR DYSTROPHY

HEMOPHILIA , A and BG6PD DEFICIENCYAGAMMAGLOBULINEMIAWISKOTT-ALDRICH SYNDROMEDIABETES INSIPIDUSLESCH-NYHAN SYNDROMEFRAGILE-X SYNDROME

SEX LINKED PEDIGREE

1) MALES ONLY, sons of affected males are OK

2) GENERATION SKIPPING DOESN’T MATTER

SINGLE GENE DISORDERSENZYME DEFECT (Most of them, e.g., PKU)

Accumulation of substrateLack of productFailure to inactivate a protein which causes

damageRECEPTOR/TRANSPORT PROTEIN DEFECT

(Familial Hypercholesterolemia)STRUCTURAL PROTEIN DEFECT (Marfan,

Ehl-Dan)StructureFunctionQuantity

ENZYME DEFECT WHICH INCREASES DRUG SUSCEPTIBILITY: G6PDPrimaquine

MARFAN SYNDROME

autosomal dominant disorder of connective tissues, the basic biochemical abnormality affects fibrillin 1. This glycoprotein, secreted by fibroblasts, is the

major component of microfibrils found in the extracellular matrix.

Microfibrils serve as scaffolding for the deposition of elastin and are considered integral components of elastic fibers.

Fibrillin 1 is encoded by the FBN1 gene, which maps to chromosome 15q21.

Mutations in the FBN1 gene are found in all patients with Marfan syndrome.

ABRAHAM LINCOLN

SKELETAL ABNORMALITIES

Patients have a slender, elongated habitus with abnormally long legs, arms, and fingers (arachnodactyly);

a high-arched palate; hyperextensibility of joints. A variety of spinal deformities, such as

severe kyphoscoliosis, may appear.

The chest is deformed, exhibiting either pectus excavatum (i.e., deeply depressed sternum) or a pigeon-breast deformity.

ocular change is bilateral dislocation, or subluxation, of the lens owing to weakness of its suspensory ligaments.

It should be noted that the ciliary zonules that support the lens are devoid of elastin and are made up exclusively of fibrillin

SUBLUXATION OF LENS

cardiovascular system. Fragmentation of the elastic fibers in the

tunica media of the aorta predisposes to aneurysmal dilation and aortic dissection

The cardiac valves, especially the mitral and, less commonly, the tricuspid valve, may be excessively distensible and regurgitant (floppy valve syndrome), giving rise to congestive cardiac failure

Death from aortic rupture may occur at any age and is the most common cause of death. Less commonly, cardiac failure is the terminal event.

EHLERS-DANLOS SYNDROMES

(EDSs) are characterized by defects in collagen synthesis or structure.

30 distinct types of collagen, and all of them have characteristic tissue distributions and are the products of different genes.

the clinical heterogeneity of EDS can be explained by mutations in different collagen genes.

tissues rich in collagen, such as skin, ligaments, and joints, are frequently involved in most variants of EDS.

Because the abnormal collagen fibers lack adequate tensile strength, skin is hyperextensible and joints are hypermobile.

These features permit grotesque contortions, such as bending the thumb backward to touch the forearm and bending the knee upward to create almost a right angle.

The skin is extraordinarily stretchable, extremely fragile, and vulnerable to trauma.

Minor injuries produce gaping defects, and surgical repair or any surgical intervention is accomplished only with great difficulty because of the lack of normal tensile strength.

The basic defect in connective tissue may lead to serious internal complications, including

rupture of the colon and large arteries (vascular EDS);

ocular fragility, with rupture of the cornea and retinal detachment (kyphoscoliosis EDS);

diaphragmatic hernias (classic EDS),

MOLECULAR BASE

Deficiency of the enzyme lysyl hydroxylase. Decreased hydroxylation of lysyl residues in

types I and III collagen interferes with the normal cross-links among collagen molecules.

Diseases Caused by Mutations in Receptor

Familial Hypercholesterolemia

FAMILIAL HYPERCHOLESTEROLEMIA is among the most common mendelian disorders;

the frequency of heterozygotes is one in 500 in the general population.

It is caused by a mutation in the gene that specifies the receptor for LDL, the form in which 70% of total plasma cholesterol is transported.

Dietary triglycerides and cholesterol are incorporated into chylomicrons in the intestinal mucosa, which drain via the gut lymphatics into the blood.

These chylomicrons are hydrolyzed by an endothelial lipoprotein lipase in the capillaries of muscle and fat.

The chylomicron remnants, rich in cholesterol, are then delivered to the liver

Some of the cholesterol enters the metabolic pool and some is excreted as free cholesterol or bile acids into the biliary tract.

The endogenous synthesis of cholesterol and LDL begins in the liver

The first step in the synthesis of LDL is the secretion of triglyceride-rich very-low-density lipoprotein (VLDL) by the liver into the blood.

In the capillaries of adipose tissue and muscle, the VLDL particle undergoes lipolysis and is converted to intermediate-density lipoprotein (IDL).

In familial hypercholesterolemia, mutations in the LDL receptor gene impair the intracellular transport and catabolism of LDL, resulting in accumulation of LDL cholesterol in the plasma.

In addition, the absence of LDL receptors on liver cells also impairs the transport of IDL into the liver, and hence a greater proportion of plasma IDL is converted into LDL.

Thus, patients with familial hypercholesterolemia develop excessive levels of serum cholesterol as a result of the combined effects of reduced catabolism and excessive biosynthesis

In the presence of such hypercholesterolemia, there is a marked increase of cholesterol traffic into the monocyte macrophages and vascular walls via the scavenger receptor.

This accounts for the appearance of skin xanthomas and premature atherosclerosis

Diseases Caused by Mutations in Enzyme Proteins

Phenylketonuria

affects 1 in 12,000 live-born Caucasian infants.

Homozygotes with this autosomal recessive disorder classically have a severe lack of phenylalanine hydroxylase, leading to hyperphenylalaninemia and PKU.

Affected infants are normal at birth but within a few weeks develop a rising plasma phenylalanine level, which in some way impairs brain development.

Usually by 6 months of life severe mental retardation becomes all too evident;

fewer than 4% of untreated phenylketonuric children have IQs greater than 50 or 60..

About one-third of these children are never able to walk, and two-thirds cannot talk.

Seizures, other neurologic abnormalities, decreased pigmentation of hair and skin, and eczema often accompany the mental retardation in untreated children.

Hyperphenylalaninemia and the resultant mental retardation can be avoided by restriction of phenylalanine intake early in life.

Hence, several screening procedures are routinely performed to detect PKU in the immediate postnatal period

Many female PKU patients, treated with diet early in life, reach childbearing age and are clinically normal.

Most of them have marked hyperphenylalaninemia, because dietary treatment is discontinued after they reach adulthood.

Children born to such women are profoundly mentally retarded and have multiple congenital anomalies, even though the infants themselves are heterozygotes.

This syndrome, termed maternal PKU, results from the teratogenic effects of phenylalanine that crosses the placenta and affects the developing fetus.

Hence, it is imperative that maternal phenylalanine levels be lowered by dietary means before conception.

Maternal hyperphenylalaninemia also increases the risk of spontaneous abortions.

The biochemical abnormality in PKU is an inability to convert phenylalanine into tyrosine.

In normal children, less than 50% of the dietary intake of phenylalanine is necessary for protein synthesis.

The remainder is converted to tyrosine by the phenylalanine hydroxylase system

When phenylalanine metabolism is blocked

because of a lack of phenylalanine hydroxylase, minor shunt pathways come into play, yielding several intermediates that are excreted in large amounts in the urine and in the sweat.

These impart a strong musty or mousy odor to affected infants.

It is believed that excess phenylalanine or its metabolites contribute to the brain damage in PKU.

Concomitant lack of tyrosine ,a precursor of melanin, is responsible for the light color of hair and skin

GALACTOSEMIA is an autosomal recessive disorder of galactose

metabolism that affects one in 30,000 live-born infants.

Normally, lactase splits lactose, the major carbohydrate of mammalian milk, into glucose and galactose in the intestinal microvilli.

Galactose is then converted to glucose in several steps, in one of which the enzyme galactose-1-phosphate uridyltransferase is required. Lack of this enzyme is responsible for galactosemia.

As a result of this lack of transferase, galactose 1-phosphate and other metabolites, including galactitol, accumulate in many tissues, including the liver, spleen, lens of the eye, kidney, and cerebral cortex.

The liver, eyes, and brain bear the brunt of the damage.

The early-developing hepatomegaly is due largely to fatty change,

Opacification of the lens (cataracts) develops, probably because the lens absorbs water and swells as galactitol, produced by alternative metabolic pathways, accumulates and increases its tonicity.

Nonspecific alterations appear in the central nervous system (CNS), including loss of nerve cells, gliosis, and edema.

Almost from birth, these infants fail to thrive. Vomiting and diarrhea appear within a few days

of milk ingestion. Jaundice and hepatomegaly usually become

evident during the first week of life. Accumulation of galactose and galactose 1-

phosphate in the kidney impairs amino acid transport, resulting in aminoaciduria.

There is an increased frequency of fulminant Escherichia coli septicemia.

Without appropriate dietary therapy, long-term complications such as cataracts, speech defects, neurologic deficits, and ovarian failure may occur in older children and adults.

Most of the clinical and morphologic changes can be prevented by early removal of galactose from the diet for at least the first 2 years of life.

The diagnosis is established by assay of the transferase in leukocytes and erythrocytes.

Antenatal diagnosis is possible by enzyme assays or DNA-based testing of cultured amniocytes or chorionic villi.

ENZYME DEFICIENCIESBY FAR, THE LARGEST KNOWN CATEGORYSUBSTRATE BUILDUPPRODUCT LACKSUBSTRATE could be HARMFUL

LYSOSOMAL STORAGE DISEASES comprise MOST of them

LYSOSOMAL STORAGE DISEASES GLYCOGEN STORAGE DISEASES SPHINGOLIPIDOSES (Gangliosides) SULFATIDOSES MUCOPOLYSACCHARIDOSES MUCOLIPIDOSES OTHER

Fucosidosis, Mannosidosis, Aspartylglycosaminuria WOLMAN, Acid phosphate deficiency

LYSOSOMAL STORAGE DISEASES

Lysosomes contain a variety of hydrolytic enzymes that are involved in the breakdown of complex substrates, such as sphingolipids and mucopolysaccharides, into soluble end products.

These large molecules may be derived from the turnover of intracellular organelles that enter the lysosomes by autophagocytosis, or they may be acquired from outside the cells by phagocytosis.

With an inherited lack of a lysosomal enzyme, catabolism of its substrate remains incomplete, leading to accumulation of the partially degraded insoluble metabolites within the lysosomes

They are divided into broad categories based on the biochemical nature of the substrates and the accumulated metabolites, but a more mechanistic classification is based on the underlying molecular defect

PATHOGENESIS

TAY-SACHS DISEASE (GM2 GANGLIOSIDOSIS)

Gangliosidoses are characterized by accumulation of gangliosides, principally in the brain, as a result of a deficiency of a catabolic lysosomal enzyme.

Depending on the ganglioside involved, these disorders are subclassified into

GM1 and GM2 categories. Tay-Sachs disease is characterized by a

mutation in and consequent deficiency of the α subunit of the enzyme hexosaminidase A, which is necessary for the degradation of GM2.

most affect protein folding or intracellular transport.

The brain is principally affected, because it is most involved in ganglioside metabolism.

The storage of GM2 occurs within neurons, axon cylinders of nerves, and glial cells throughout the CNS.

Affected cells appear swollen, possibly foamy Electron microscopy reveals a whorled configuration within lysosomes

These anatomic changes are found throughout the CNS (including the spinal cord), peripheral nerves, and autonomic nervous system

infants appear normal at birth, but motor weakness begins at 3 to 6 months

of age, followed by mental retardation, blindness,

and severe neurologic dysfunctions. Death occurs within 2 or 3 years

SPHINGOLIPIDOSES• MANY types, Tay-Sachs most often referred to

– GANGLIOSIDES are ACCUMULATED– Ashkenazi Jews (1/30 are carriers)– CNS neurons a site of accumulation– CHERRY RED spot in Macula

NIEMANN-PICK DISEASE, TYPES A AND B

characterized by a primary deficiency of acid sphingomyelinase and the resultant accumulation of sphingomyelin.

In type A, characterized by a severe deficiency of sphingomyelinase, the breakdown of sphingomyelin into ceramide and phosphorylcholine is impaired, and excess sphingomyelin accumulates in all phagocytic cells and in the neurons..

The macrophages become stuffed with droplets or particles of the complex lipid, imparting a fine vacuolation or foaminess to the cytoplasm

Because of their high content of phagocytic cells, the organs most severely affected are the spleen, liver, bone marrow, lymph nodes, and lungs

The splenic enlargement may be striking. CNS: The affected neurons are enlarged and

vacuolated as a result of the storage of lipids. This variant manifests itself in infancy with

massive visceromegaly and severe neurologic deterioration.

Death usually occurs within the first 3 years of life.

patients with the type B variant have organomegaly but no neurologic symptoms.

Niemann-Pick Disease Type C primary defect in lipid transport. Affected cells accumulate cholesterol as well

as gangliosides such as GM1 and GM2.

NPC is clinically marked by ataxia, vertical supranuclear gaze palsy, dystonia, dysarthria, and psychomotor regression

NIEMANN-PICK• TYPES A, B, C• SPHINGOMYELIN BUILDUP• Sphingomyelinase (ASM), is the missing enzyme• MASSIVE SPLENOMEGALY• ALSO in ASHKANAZI JEWS• OFTEN FATAL in EARLY LIFE, CNS, ORGANOMEGALY

GAUCHER DISEASE

This disease results from mutation in the gene that encodes glucosylceramidase.

deficient activity of a glucosylceramidase that normally cleaves the glucose residue from ceramide.

This leads to an accumulation of glucosylceramide in the mononuclear phagocytic cells and their transformation into so-called Gaucher cells.

Normally the glycolipids derived from the breakdown of senescent blood cells, particularly erythrocytes, are sequentially degraded.

In Gaucher disease, the degradation stops at the level of glucosylceramides, which, in transit through the blood as macromolecules, are engulfed by the phagocytic cells of the body, especially in the liver, spleen, and bone marrow.

These phagocytes (Gaucher cells) become

enlarged, with some becoming as large as 100 μm, because of the accumulation of distended lysosomes, and develop a pathognomonic cytoplasmic appearance characterized as "wrinkled tissue paper"

High levels of macrophage-derived cytokines, such as interleukins (IL-2, IL-6) and tumor necrosis factor (TNF) are found in affected tissues.

type I :-- the chronic non-neuronopathic form,

accounts for 99% of cases of Gaucher disease.

It is characterized by clinical or radiographic bone involvement (osteopenia, focal lytic lesions, and osteonecrosis) in 70% to 100% of cases.

Additional features are hepatosplenomegaly and the absence of CNS involvement.

The spleen often enlarges massively, filling the entire abdomen.

Gaucher cells are found in the liver, spleen, lymph nodes, and bone marrow.

Marrow replacement and cortical erosion may produce radiographically visible skeletal lesions, as well as a reduction in the formed elements of blood.

Bone changes are believed to be caused by macrophage-derived cytokines

Types II and III variants are characterized by neurologic signs and symptoms.

In type II, the symptoms start before 2 years of age and are more severe, whereas in type III, the symptoms appear later and are milder.

Although the liver and spleen are also involved, the clinical features are dominated by neurologic disturbances.

In addition to these, there is a perinatal-lethal form characterized by hepatosplenomegaly, skin lesions, and non-immune hydrops . In the so-called cardiovascular form, there is involvement and calcification of mitral and aortic valves.

MUCOPOLYSACCHARIDOSES (MPSS)

characterized by defective degradation (and therefore excessive storage) of mucopolysaccharides in various tissues.

Recall that mucopolysaccharides form a part of ground substance and are synthesized by connective tissue fibroblasts.

Most of the mucopolysaccharide is secreted into the ground substance, but a certain fraction is degraded within lysosomes.

Several enzymes are involved in this catabolic pathway; it is the lack of these enzymes that leads to accumulation of mucopolysaccharides within the lysosomes.

Several clinical variants of MPS, classified numerically from MPS I to MPS VII, have been described, each resulting from the deficiency of one specific enzyme.

The mucopolysaccharides that accumulate within the tissues include

dermatan sulfate, heparan sulfate, keratan sulfate, chondroitin sulfate

Most are associated with coarse facial features, clouding of the cornea, joint stiffness, and mental retardation.

Urinary excretion of the accumulated mucopolysaccharides is often increased.

All of these disorders except one are inherited as autosomal recessive conditions; the exception, Hunter syndrome, is an X-linked recessive disease.

Mucopolysaccharidosis type I caused by a deficiency of α-L-iduronidase.

In Hurler syndrome, affected children have a life expectancy of 6 to 10 years.

they develop coarse facial features associated with skeletal deformities.

Death is often due to cardiac complications resulting from the formation of raised endothelial and endocardial lesions by the deposition of mucopolysaccharides in the coronary arteries and heart valves.

type II, or Hunter syndrome, (X-linked), results from a deficiency of L-iduronate

sulfatase.

GLYCOGEN STORAGE DISEASES (GLYCOGENOSES)

An inherited deficiency of any one of the enzymes involved in glycogen synthesis or degradation can result in excessive accumulation of glycogen or some abnormal form of glycogen in various tissues.

Regardless of the tissue or cells affected, the glycogen is most often stored within the cytoplasm, or sometimes within nuclei.

Most glycogenoses are inherited as autosomal recessive diseases, as is common with "missing enzyme" syndromes.

Hepatic type. Liver contains several enzymes that

synthesize glycogen for storage and also break it down into free glucose.

Hence, a deficiency of the hepatic enzymes involved in glycogen metabolism is associated with two major clinical effects:

enlargement of the liver due to storage of glycogen and hypoglycemia due to a failure of glucose production

Von Gierke disease (type I glycogenosis), resulting from a lack of glucose-6-phosphatase, is the most important example of the hepatic form of glycogenosis

Myopathic type. In striated muscle, glycogen is an important

source of energy. When enzymes that are involved in glycolysis

are deficient, glycogen storage occurs in muscles and there is an associated muscle weakness due to impaired energy production.

Typically, the myopathic forms of glycogen storage diseases are marked by muscle cramps after exercise, myoglobinuria, and failure of exercise to induce an elevation in blood lactate levels because of a block in glycolysis

McArdle disease (type V glycogenosis), resulting from a deficiency of muscle phosphorylase, is the prototype of myopathic glycogenoses.

Type II glycogenosis (Pompe disease) is caused by a deficiency of lysosomal acid maltase and so is associated with deposition of glycogen in virtually every organ, but cardiomegaly is most prominent.

Brancher glycogenosis (type IV) is caused by deposition of an abnormal form of glycogen, with detrimental effects on the liver, heart, and muscles.

Accumulation of dermatan sulfate and heparan sulfate is seen in cells of the mononuclear phagocyte system, in fibroblasts, and within endothelium and smooth muscle cells of the vascular wall.

The affected cells are swollen and have clear cytoplasm, resulting from the accumulation of material positive for periodic acid-Schiff stain within engorged, vacuolated lysosomes.

Lysosomal inclusions are also found in neurons, accounting for the mental retardation

MULTIFACTORIAL INHERITANCE Multi-”FACTORIAL”, not just multi-GENIC “SOIL” theory Common phenotypic expressions governed by

“multifactorial” inheritance Hair color Eye color Skin color Height Intelligence Diabetes, type II

FEATURES OFMULTIFACTORIAL INHERITANCE

Expression determined by NUMBER of genes Overall 5% chance of 1st degree relatives having

it Identical twins >>>5%, but WAY less than 100% This 5% is increased if more children have it

Expression of CONTINUOUS traits (e.g., height) vs. DISCONTINUOUS traits (e.g., diabetes)

“MULTIFACTORIAL” DISORDERSCleft lip, palateCongenital heart diseaseCoronary heart diseaseHypertensionGoutDiabetesPyloric stenosisMANY, MANY, MANY, MANY MORE

KARYOTYPINGDefined as the study of CHROMOSOMES

46 = (22x2) + X + YConventional notation is “46,XY” or “46,XX”

G(iemsa)-banding, 500 bands per haploid recognizable

Short (“p”-etit) arm = p, other (long) arm = q

MORE KARYOTYPING INFO

A,B,C,D,E,F,G depends on chromosome length A longest G shortest

Groups within these letters depend on the p/q ratio

ARMREGIONBANDSub-BAND, numbering from the centromere progressing distad

F.I.S.H. (GENE “PROBES”)

GREATLY ENHANCES G-BANDING

Fluorescent In-Situ Hybridization

Uses fluorescent labelled DNA fragments, ~10,000 base pairs, to bind (or not bind) to its complement

FISHSUBTLE MICRODELETIONSCOMPLEX TRANSLOCATIONSAND TELOMERE ALTERATIONS

TRIPLE CHROMOSOME #20 A DELETION in CHROMOSOME #22

SPECTRAL KARYOTYPING

CYTOGENETIC DISORDERS

DEFINITIONS:EUPLOIDANEUPLOID (NOT AN EXACT MULTIPLE OF 23)

MONOSOMY, AUTOSOME OR SEXTRISOMY, AUTOSOME OR SEXDELETIONBREAKAGE

MORE DEFINITIONS

COMMON CYTOGENETIC DISEASES

AUTOSOMESTRISOMY-21 (DOWN SYNDROME)8, 9, 13 (Patau), 18 (Edwards), 2222q.11.2 deletion

SEX CHROMOSOMESKLINEFELTER: XXY, XXXY, etc.

TURNER: XO

TRISOMY-21

TRISOMY-21 Most trisomies (monosomies, aneuploidy) are

from maternal non-disjunction (non-disjunction or anaphase lag are BOTH

possible)

#1 cause of mental retardation

Maternal age related Congenital Heart Defects, risk for acute

leukemias, GI atresias Most LOVABLE of all God’s children

CHROMOSOME 22Q11.2 DELETION SYNDROME

Because of a DELETION, this cannot be detected by standard karyotyping and needs FISH

Cardiac defects, DiGeorge syndrome, velocardiofacial, CATCH*

SEX CHROMOSOME DISORDERS Problems related to sexual development

and fertility Discovered at time of puberty Retardation related to the number of X

chromosomes If you have at least ONE “Y”

chromosome, you are male

KLINEFELTER (XXY, XXXY, ETC.)Hypogonadism found at puberty

#1 cause of male infertility

NO retardation unless more X’s

47, XXY 82% of the timeL----O----N----G legs, atrophic testes, small penis

TURNER (XO)45, X is the “proper” designation

Mosaics commonOften, the WHOLE chromosome is not missing, but just part

NECK “WEBBING”EDEMA of HAND DORSUMCONGENITAL HEART DEFECTS most FEARED

HERMAPHRODITESGENETIC SEX is determined by the

PRESENCE or ABSENCE of a “Y” chromosome, but there is also, GONADAL (phenotypic), and DUCTAL sex

TRUE HERMAPHRODITE: OVARIES AND TESTES, often on opposite sides (VERY RARE)

PSEUDO-HERMAPHRODITE: MALE: TESTES with female characteristics (Y-)FEMALE: OVARIES with male characteristics

(XX)

SINGLE GENE, NON-MENDELIAN

Triplet repeatsFragile X (CGG)Others: ataxias, myotonic dystrophy

Mitochondrial Mutations: (maternal)

(LEBER HEREDITARY OPTIC NEUROPATHY)Genomic “IMPRINTING”:

(Inactivation of maternal or paternal allele, contradicts Mendel)

Gonadal “MOSAICISM”: (only gametes have mutated cells)

MOLECULAR DX BY DNA PROBES

BIRTH DEFECTS, PRE- or POST- NATAL

TUMOR CELLSCLASSIFICATIONS of TUMORSIDENTIFICATION of PATHOGENS

DONOR COMPATIBILITYPATERNITYFORENSIC

H&E tissue structures

Immuno- Antigen Proteins

GENES thatMAKE thosePROTEINS

TRIPLET-REPEAT MUTATIONS: FRAGILE X SYNDROME

Fragile X syndrome is the prototype of diseases in which the mutation is characterized by a long repeating sequence of 3 nucleotides.

Other examples of diseases associated with trinucleotide repeat mutations include Huntington disease and myotonic dystrophy.

amplification of specific sets of 3 nucleotides within the gene disrupts its function

Fragile X syndrome is characterized by mental retardation and an abnormality in the X chromosome.

It is one of the most common causes of familial mental retardation.

Clinically affected males have moderate to severe mental retardation.

They express a characteristic physical phenotype that includes a long face with a large mandible, large everted ears, and large testicles (macro-orchidism).

Fragile X syndrome results from a mutation in the FMR1 gene, which maps to Xq27.3. Like all X-linked recessive disorders, this disease affects males

GENOMIC IMPRINTING: PRADER-WILLI AND ANGELMAN SYNDROMES

All humans inherit two copies of each gene, carried on homologous maternal and paternal chromosomes.

genomic imprinting certain genes are differentially "inactivated"

during paternal and maternal gametogenesis. Thus, maternal imprinting refers to

transcriptional silencing of the maternal allele, whereas paternal imprinting implies that the paternal allele is inactivated.

Imprinting occurs in ovum or sperm and is then stably transmitted to all somatic cells derived from the zygote

GENOMIC IMPRINTING

PRADER-WILLI SYNDROME

characterized by mental retardation, short stature, hypotonia, obesity, small hands and feet, and hypogonadism.

In 60% to 75% of cases, an interstitial deletion of band q12 in the long arm of chromosome 15 can be detected.

It is striking that in all cases the deletion affects the paternally derived chromosome 15.

.

Angelman syndrome are born with a deletion of the same chromosomal region derived from their mothers

Patients with Angelman syndrome are also mentally retarded, but in addition they present with ataxic gait, seizures, and inappropriate laughter.

Because of the laughter and ataxia, this syndrome is also called the happy puppet syndrome.