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Inheritance patterns: Monogenic (Mendelian) Inheritance Polygenic and Multifactorial Inheritance Mitochondrial Inheritance

Inheritance patterns: Monogenic (Mendelian) Inheritance Polygenic and Multifactorial Inheritance Mitochondrial Inheritance

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Page 1: Inheritance patterns: Monogenic (Mendelian) Inheritance Polygenic and Multifactorial Inheritance Mitochondrial Inheritance

Inheritance patterns:Monogenic (Mendelian) Inheritance

Polygenic and Multifactorial InheritanceMitochondrial Inheritance

Page 2: Inheritance patterns: Monogenic (Mendelian) Inheritance Polygenic and Multifactorial Inheritance Mitochondrial Inheritance

Inheritance patternsInheritance patterns trace the transmission of genetically encoded traits, conditions or diseases to the offsprings. 

There are several modes of inheritance:

Single Gene or MendelianPolygenic and MultifactorialMitochondrial

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Single Gene Inheritance Genetic conditions caused by a mutation in a single gene follow

predictable patterns of inheritance within families.  Single gene inheritance is also referred to as Mendelian inheritance as they follow transmission patterns he observed in his research on peas.

There are 3 types of Mendelian inheritance patterns:

1. Autosomal: the gene responsible for the phenotype is located on one of the 22 pairs of autosomes (non-sex determining chromosomes).

2. X-linked: the gene that encodes for the trait is located on the X chromosome.

3. Y-linked (holandric): the gene that encodes for the trait is located on the Y chromosome

Dominant: conditions that are manifest in heterozygotes (individuals with just one copy of the mutant allele).

Recessive: conditions are only manifest in individuals who have two copies of the mutant allele (are homozygous).

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Page 5: Inheritance patterns: Monogenic (Mendelian) Inheritance Polygenic and Multifactorial Inheritance Mitochondrial Inheritance

Autosomal dominant (AD) Dominant conditions are expressed in

individuals who have just one copy of the mutant allele. 

The pedigree on the right illustrates the transmission of an autosomal dominant trait. 

Affected males and females have an equal probability of passing on the trait to offspring. 

Affected individual’s have one normal copy of the gene and one mutant copy of the gene, thus each offspring has a 50% chance on inheriting the mutant allele. 

As shown in this pedigree, approximately half of the children of affected parents inherit the condition and half do not.

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AD – Incomplete penetranceA typical pedigree from

a family with a mutation in the BRCA1 gene. 

Fathers can be carriers and pass the mutation onto offspring. 

Not all people who inherit the mutation develop the disease, thus patterns of transmission are not always obvious.

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Autosomal dominant (AD) Huntington Disease   Myotonic muscular dystrophy Achondroplasia (short-limbed dwarfism)   Polycystic kidney disease (ADPKD) Brachydactyly Polydactily Syndactyly Adactyly Osteogenesis imperfecta Gout Familial hypercholesterolemia Hypercalcemia (familial) Marfan syndrome Familial Polycystic ovary syndrome (PCOS) Neurofibromatosis

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Huntington Disease Huntington's disease (HD) is a neurodegenerative genetic disorder that

affects muscle coordination and leads to cognitive decline and psychiatric problems. It typically becomes noticeable in mid-adult life. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea, which is why the disease used to be called Huntington's chorea.

The Huntingtin gene (HTT=HD=IT15) on 4p16.3 provides the genetic information for a protein that is also called "huntingtin". Expansion of a CAG triplet repeat stretch within the Huntingtin gene results in a different (mutant) form of the protein, which gradually damages cells in the brain, through mechanisms that are not fully understood. The genetic basis of HD was discovered in 1993 by an international collaborative effort spearheaded by the Hereditary Disease Foundation.

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Huntington Disease Increases in the number of repeats (and hence earlier age of onset and

severity of disease) in successive generations is known as genetic anticipation. Instability is greater in spermatogenesis than oogenesis;

Individuals with more than sixty repeats often develop the disease before age 20, while those with fewer than 40 repeats may not ever develop noticeable symptoms;

Life expectancy in HD is generally around 20 years following the onset of visible symptoms;

Most life-threatening complications result from muscle coordination and, to a lesser extent, behavioral changes induced by declining cognitive function.

The largest risk is pneumonia, which causes death in one third of those with HD. As the ability to synchronize movements deteriorates, difficulty clearing the lungs and an increased risk of aspirating food or drink both increase the risk of contracting pneumonia. The second greatest risk is heart disease, which causes almost a quarter of fatalities of those with HD.[

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Huntington Disease Recommended (highly) to see what Huntington is all about

An excellent French documentary (subtitled in English) about a family carrying such a genetic “burden”, including aspects of their life and expectancies

As a reminder, the disease has a complete penetrance (100%) make the disease, usually after 35-40 years of age, and transmit it to their progenitors

http://www.youtube.com/watch?v=0qOdGvoOXI0 (it takes 1 hour and a half)

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Other AD conditions Myotonic muscular dystrophy (dystrophia myotonica, myotonia

atrophica) is a chronic, slowly progressing, highly variable, inherited multisystemic disease. It is characterized by wasting of the muscles (muscular dystrophy), cataracts, heart conduction defects, endocrine changes, and myotonia.

Achondroplasia is a common cause of dwarfism. It occurs as a sporadic mutation in approximately 75% of cases (associated with advanced paternal age) or may be inherited as an autosomal dominant genetic disorder. People with achondroplasia have short stature, with an average adult height of 131 centimeters for males and 123 centimeters for females. Achondroplastic adults are known to be as short as 62.8 cm.

Polycystic kidney disease (PKD or PCKD, also known as polycystic kidney syndrome) is a cystic genetic disorder of the kidneys. There are two types of PKD: autosomal dominant polycystic kidney disease (ADPKD) and the less-common autosomal recessive polycystic kidney disease (ARPKD). Polycystic kidney disease is one of the most common life-threatening genetic diseases, affecting an estimated 12.5 million people worldwide.

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Other AD conditionsBrachydactyly (short fingers/toes)Polydactily (extra fingers/toes)Syndactyly (two or more digits are fused together)Adactyly (congenital absence of fingers and/or toes)

Osteogenesis imperfecta types I-V (OI and sometimes known as brittle bone disease, or "Lobstein syndrome") is a congenital bone disorder. People with OI are born with defective connective tissue, or without the ability to make it, usually because of a deficiency of Type-I collagen. As a genetic disorder, OI has historically been viewed as an autosomal dominant disorder of type I collagen. In the past several years, there has been the identification of autosomal recessive forms. Most people with OI receive it from a parent but in 35% of cases it is an individual (de novo or "sporadic") mutation. There are eight different types of OI, Type I being the most common, though the symptoms vary from person to person.

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Osteogenesis imperfecta

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Other AD conditions Gout (also known as podagra when it involves the big toe). is a medical condition

usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected (approximately 50% of cases). However, it may also present as tophi, kidney stones, or urate nephropathy. It is caused by elevated levels of uric acid in the blood. The uric acid crystallizes, and the crystals deposit in joints, tendons, and surrounding tissues. The occurrence of gout is partly genetic, contributing to about 60% of variability in uric acid level.

Familial hypercholesterolemia (abbreviated FH) is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein (LDL, "bad cholesterol"), in the blood and early cardiovascular disease. Many patients have mutations in the LDLR gene that encodes the LDL receptor protein, which normally removes LDL from the circulation, or apolipoprotein B (ApoB), which is the part of LDL that binds with the receptor; mutations in other genes are rare. Patients who have one abnormal copy (are heterozygous) of the LDLR gene may have premature cardiovascular disease at the age of 30 to 40. Having two abnormal copies (being homozygous) may cause severe cardiovascular disease in childhood. Heterozygous FH is a common genetic disorder, inherited in an autosomal dominant pattern, occurring in 1:500 people in most countries; homozygous FH is much rarer, occurring in 1 in a million births.

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Other AD conditionsHypercalcemia - Familial hypocalciuric hypercalcemia is a condition

that can cause hypercalcemia, a serum calcium level typically above 10.2 mg/dL. It is also known as familial benign hypocalciuric hypercalcemia (FBHH) where there is usually a family history of hypercalcemia which is mild, a urine calcium to creatinine ratio <0.01, and urine calcium <200 mg/day.

Familial Polycystic ovary syndrome (PCOS) is one of the most common female endocrine disorders. PCOS is a complex, heterogeneous disorder of uncertain etiology, but there is strong evidence that it can to a large degree be classified as a genetic disease. PCOS produces symptoms in approximately 5% to 10% of women of reproductive age (12–45 years old). It is thought to be one of the leading causes of female subfertility and the most frequent endocrine problem in women of reproductive age. The genetic component appears to be inherited in an autosomal dominant fashion with high genetic penetrance but variable expressivity in females; this means that each child has a 50% chance of inheriting the predisposing genetic variant(s) from a parent, and if a daughter receives the variant(s), then the daughter will have the disease to some extent.

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Other AD conditionsMarfan syndrome (also called Marfan's syndrome) is a genetic

disorder of the connective tissue. People with Marfan tend to be unusually tall, with long limbs and long, thin fingers. The syndrome is inherited as a dominant trait, carried by the gene FBN1, which encodes the connective protein fibrillin-1. People have a pair of FBN1 genes. Because it is dominant, people who have inherited one affected FBN1 gene from either parent will have Marfan syndrome. Marfan syndrome has a range of expressions, from mild to severe. The most serious complications are defects of the heart valves and aorta. It may also affect the lungs, the eyes, the dural sac surrounding the spinal cord, the skeleton and the hard palate.

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Other AD conditionsNeurofibromatosis (commonly abbreviated NF;

neurofibromatosis type 1 is also known as von Recklinghausen disease) is a genetically-inherited disorder in which the nerve tissue grows tumors (neurofibromas) that may be benign and may cause serious damage by compressing nerves and other tissues. Neurofibromatosis is an autosomal dominant disorder, which means only one copy of the affected gene is needed for the disorder to develop. Therefore, if only one parent has neurofibromatosis, his or her children have a 50% chance of developing the condition as well. The severity in affected individuals can vary; this may be due to variable expressivity. Approximately half of cases are due to de novo mutations and no other affected family members are seen. It affects males and females equally.

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Autosomal Recessive (AR) Recessive conditions are clinically

manifest only when an individual has two copies of the mutant allele. 

When just one copy of the mutant allele is present, an individual is a carrier of the mutation, but does not develop the condition. 

Females and males are affected equally by traits transmitted by autosomal recessive inheritance. 

When two carriers mate, each child has a 25% chance of being homozygous wild-type (unaffected); a 25% chance of being homozygous mutant (affected); or a 50% chance of being heterozygous (unaffected carrier).

Note: Affected individuals are indicated by solid black symbols and unaffected carriers are indicated by the half black symbols.

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Autosomal Recessive (AR)Cystic fibrosis  Phenylketonuria (PKU)AlbinismGalactosemiaXeroderma pigmentosumFanconi anemiaBloom syndromeTay-Sachs  Hemochromatosis

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Cystic fibrosis (CF or mucoviscidosis) Affects most critically the lungs, and also the pancreas, liver, and intestine. It

is characterized by abnormal transport of chloride and sodium across an epithelium, leading to thick, viscous secretions.

The name cystic fibrosis refers to the characteristic scarring (fibrosis) and cyst formation within the pancreas, first recognized in the 1930s.

Difficulty breathing is the most serious symptom and results from frequent lung infections that are treated with antibiotics and other medications. Ultimately, lung transplantation is often necessary as CF worsens.

Other symptoms, including sinus infections, poor growth, and infertility affect other parts of the body.

GENETICS: CF is caused by a mutation in the gene for the protein cystic fibrosis

transmembrane conductance regulator (CFTR). This protein is required to regulate the components of sweat, digestive fluids, and mucus.

CF is most common among Caucasians; 4% of people of European descent carries one allele for CF (by far the most common mutation is ΔF508, but there are >1000)

Individuals with cystic fibrosis can be diagnosed before birth by genetic testing, or by a sweat test in early childhood.

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Other AR conditions Phenylketonuria (PKU) is a metabolic genetic disorder characterized by a

mutation in the gene for the hepatic enzyme phenylalanine hydroxylase (PAH), rendering it nonfunctional. This enzyme is necessary to metabolize the amino acid phenylalanine (Phe) to the amino acid tyrosine. When PAH activity is reduced, phenylalanine accumulates and is converted into phenylpyruvate (also known as phenylketone), which is detected in the urine. Untreated PKU can lead to mental retardation, seizures and other serious medical problems. The mainstream treatment for classic PKU patients is a strict PHE-restricted diet (requires severely restricting or eliminating foods high in Phe, such as meat, chicken, fish, eggs, nuts, cheese, legumes, milk and other dairy products) supplemented by a medical formula containing aminoacids and other nutrients. The current recommendation is that the PKU diet should be maintained for life. Patients who are diagnosed early and maintain a strict diet can have a normal life span with normal mental development.

Albinism also called achromia, achromasia, or achromatosis) is a congenital disorder characterized by the complete or partial absence of pigment in the skin, hair and eyes. While an organism with complete absence of melanin is called an albino an organism with only a diminished amount of melanin is described as albinoid.

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Other AR conditions Galactosemia is a rare genetic metabolic disorder that affects an

individual's ability to metabolize the sugar galactose properly. Although the sugar, lactose, metabolizes to galactose, galactosemia is not related to and should not be confused with lactose intolerance. The only treatment for classic galactosemia is eliminating lactose and galactose from the diet. Even with an early diagnosis and a restricted diet, however, some individuals with galactosemia experience long-term complications such as speech difficulties, learning disabilities, neurological impairment (tremor).

Xeroderma pigmentosum (XP) is a disorder in which the ability to repair damage caused by ultraviolet (UV) light is deficient. In extreme cases, all exposure to sunlight must be forbidden, no matter how small; as such, individuals with the disease are often colloquially referred to as Children of the Night. Patients with XP are at a high risk for developing skin cancers, such as basal cell carcinoma.

Page 24: Inheritance patterns: Monogenic (Mendelian) Inheritance Polygenic and Multifactorial Inheritance Mitochondrial Inheritance

Other AR conditions Fanconi anemia is a genetic disease with an incidence of 1 per 350,000 births,

with a higher frequency in Ashkenazi Jews and Afrikaners in South Africa. FA is the result of a genetic defect in a cluster of proteins responsible for DNA repair. As a result, the majority of FA patients develop cancer, most often acute myelogenous leukemia, and 90% develop bone marrow failure (the inability to produce blood cells) by age 40. About 60-75% of FA patients have congenital defects, commonly short stature, abnormalities of the skin, arms, head, eyes, kidneys, and ears, and developmental disabilities. Around 75% of FA patients have some form of endocrine problem, with varying degrees of severity. Median age of death was 30 years in 2000. Treatment with androgens and hematopoietic (blood cell) growth factors can help bone marrow failure temporarily, but the long-term treatment is bone marrow transplant if a donor is available. Because of the genetic defect in DNA repair, cells from people with FA are sensitive to drugs that treat cancer by DNA crosslinking, such as mitomycin C.

Bloom syndrome is characterized by short stature and predisposition to the development of cancer. Cells from a person with Bloom syndrome exhibit a striking genomic instability that includes excessive homologous recombination.

Tay-Sachs (I gave you a separate ppt for it)

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Other AR conditions Hemochromatosis (iron overload) indicates accumulation of iron in the body

from any cause. The most important causes are hereditary hemochromatosis (HHC), the most common genetic disease in Europe (1:200-300). The gene responsible for HHC (known as HFE gene) is located on chromosome 6; the majority of HHC patients have mutations in this HFE gene (other genes involved C283Y and H63D). HHC is characterized by an accelerated rate of intestinal iron absorption and progressive iron deposition in various tissues that typically begins to be expressed in the 3rd to 5th decades of life, but may occur in children. Hemochromatosis can be asymptomatic (75%) and be discovered by routine blood tests or may present with the following clinical features:

Cirrhosis of the liver Diabetes due to pancreatic islet cell failure Cardiomyopathy Arthritis (iron deposition in joints) Testicular failure Tanning of the skin (bronze diabetes) Joint pain and bone pain

Routine treatment consists of regularly scheduled bloodletting (500ml). For those unable to tolerate routine blood draws, there is a chelating agent available for use (Deferoxamine).

A third of those untreated develop hepatocellular carcinoma.

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X-linked DominantBecause the gene is located on the

X chromosome, there is no transmission from father to son, but there can be transmission from father to daughter (all daughters of an affected male will be affected since the father has only one X chromosome to transmit). 

Children of an affected woman have a 50% chance of inheriting the X chromosome with the mutant allele. 

X-linked dominant disorders are clinically manifest when only one copy of the mutant allele is present.

Page 27: Inheritance patterns: Monogenic (Mendelian) Inheritance Polygenic and Multifactorial Inheritance Mitochondrial Inheritance

X-linked Dominant Some forms of Retinitis Pigmentosa

Chondrodysplasia Punctata  

Hypophosphatemic rickets = X-linked hypophosphatemia (XLH)=Hypophosphatemic vitamin D-resistant

rickets (HPDR)

Amelogenesis imperfecta

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X-linked Dominant Some forms of Retinitis Pigmentosa (RP)

is an inherited, degenerative eye disease that causes severe vision impairment and often blindness. The progress of RP is not consistent. Some people will exhibit symptoms from infancy, others may not notice symptoms until later in life. Generally, the later the onset, the more rapid is the deterioration in sight.Fundus of patient with retinitis pigmentosa, mid

stage (Bone spicule-shaped pigment deposits are present in the mid periphery along with retinal atrophy, while the macula is preserved although with a peripheral ring of depigmentation. Retinal vessels are attenuated.) From a review by Christian Hamel, 2006.

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X-linked DominantChondrodysplasia Punctata is a clinically and genetically

diverse group of rare diseases, first described by Conradi, that share the features of stippled (presenting small dots) epiphyses and skeletal changes.

Amelogenesis imperfecta presents with abnormal formation of the enamel or external layer of teeth. Enamel is composed mostly of mineral, that is formed and regulated by the proteins in it. People afflicted with amelogenesis imperfecta have teeth with abnormal color: yellow, brown or grey. The teeth have a higher risk for dental cavities and are hypersensitive to temperature changes. This disorder can afflict any number of teeth.

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X-linked Dominant Hypophosphatemic rickets = X-linked hypophosphatemia (XLH)

=Hypophosphatemic vitamin D-resistant rickets (HPDR) is an X-linked dominant form of rickets (or osteomalacia) that differs from most cases of rickets in that ingestion of vitamin D is relatively ineffective. It can cause bone deformity including short stature and genu varum (bow leggedness). It is associated with a mutation in the PHEX gene sequence (Xp.22) and subsequent inactivity of the PHEX protein. The prevalence of the disease is 1:20000

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X-linked Recessive X-linked recessive traits are not clinically

manifest when there is a normal copy of the gene. 

All X-linked recessive traits are fully evident in males because they only have one copy of the X chromosome, thus do not have a normal copy of the gene to compensate for the mutant copy. 

For that same reason, women are rarely affected by X-linked recessive diseases, however they are affected when they have two copies of the mutant allele. 

Because the gene is on the X chromosome there is no father to son transmission, but there is father to daughter and mother to daughter and son transmission. 

If a man is affected with an X-linked recessive condition, all his daughter will inherit one copy of the mutant allele from him.

•  Duchenne muscular dystrophy (DMD)  •  Hemophilia A  

•  X-linked severe combined immune disorder (SCID)  

•  Some forms of congenital deafness

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Duchenne muscular dystrophy (DMD)

Is affecting around 1 in 3,600 boys, which results in muscle degeneration and eventual death. The disorder is caused by a mutation in the dystrophin gene, located on the human X chromosome, which codes for the protein dystrophin, an important structural component within muscle tissue that provides structural stability to the dystroglycan complex (DGC) of the cell membrane. While both sexes can carry the mutation, females rarely exhibit signs of the disease. Symptoms usually appear in male children before age 6 and may be visible in early infancy. Even though symptoms do not appear until early infancy, laboratory testing can identify children who carry the active mutation at birth. Progressive proximal muscle weakness of the legs and pelvis associated with a loss of muscle mass is observed first. Eventually this weakness spreads to the arms, neck, and other areas. Early signs may include pseudohypertrophy (enlargement of calf and deltoid muscles), low endurance, and difficulties in standing unaided or inability to ascend staircases. As the condition progresses, muscle tissue experiences wasting and is eventually replaced by fat and fibrotic tissue (fibrosis). By age 10, braces may be required to aid in walking but most patients are wheelchair dependent by age 12. Later symptoms may include abnormal bone development that lead to skeletal deformities, including curvature of the spine. Due to progressive deterioration of muscle, loss of movement occurs, eventually leading to paralysis. Intellectual impairment may or may not be present but if present, does not progressively worsen as the child ages. The average life expectancy for patients afflicted with DMD is around 25.

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X-linked RecessiveHemophilia A is the most common type of hemophilia. It

is also known as factor VIII deficiency or classic hemophilia. It is largely an inherited disorder in which one of the proteins needed to form blood clots is missing or reduced. In about 30% of cases, there is no family history of the disorder and the condition is the result of a spontaneous gene mutation.

Approximately one in 5,000 males born in the United States has hemophilia. All races and economic groups are affected equally. When a person with hemophilia is injured, he does not bleed harder or faster than a person without hemophilia, he bleeds longer. Small cuts or surface bruises are usually not a problem, but more traumatic injuries may result in serious problems and potential disability (called "bleeding episodes").

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Hemophilia A Normal plasma levels of FVIII range from 50% to 150%. There are different levels

of hemophilia: mild, moderate, and severe, depending on the amount of clotting factor in the blood:

1. People with mild hemophilia have 6% up to 49% of the normal clotting factor in their blood.   Most patients usually have problems with bleeding only after serious injury, trauma or surgery. In many cases, mild hemophilia is not diagnosed until an injury,  surgery or tooth extraction results in prolonged bleeding. The first episode may not occur until adulthood. Women with mild hemophilia often experience menorrhagia, heavy menstrual periods, and can hemorrhage after childbirth.

2. People with moderate hemophilia about, 15% of the hemophilia population, have 1% up to 5% of the normal clotting factor in their blood. They tend to have bleeding episodes after injuries and some without obvious cause. These are called spontaneous bleeding episodes.

3. People with severe hemophilia about 60% of the hemophilia population, have <1% of the normal clotting factor in their blood. They have bleeding following an injury and may have frequent spontaneous bleeding episodes, often into their joints and muscles.

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Hemophilia AEveryone inherits two sex chromosomes, X and Y, from his or her parents. A female inherits one X chromosome from her mother and one X chromosome from her father (XX). A male inherits one X chromosome from his mother and one Y chromosome from his father (XY). The gene that causes hemophilia is located on the X chromosome.

A woman who gives birth to a child with hemophilia often has other male relatives who also have hemophilia. Sometimes, a baby will be born with hemophilia when there is no known family history. This means either that the gene has been "hidden" (that is, passed down through several generations of female carriers without affecting any male members of the family) or the change in the X chromosome is new (a "spontaneous mutation").

There are four possible outcomes for the baby of a woman who is a carrier. These four possibilities are repeated for each and every pregnancy: 1. A girl who is not a carrier 2. A girl who is a carrier 3. A boy without hemophilia 4. A boy with hemophilia

With each pregnancy, a woman who is a carrier has a 25% chance of having a son with hemophilia. Since the father's X chromosome determines the baby will be a girl, all the daughters of a man with hemophilia will be carriers. None of his sons, which is determined by the father through his Y chromosome, will have hemophilia.

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Hemophilia A

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Hemophilia AIn general, small cuts and scrapes are treated with regular first-aid: clean the cut, then apply pressure and a band-aid. Individuals with mild hemophilia can use a non-blood product called desmopressin acetate (DDAVP) to treat small bleeds. Deep cuts or internal bleeding, such as bleeding into the joints or muscles, require more complex treatment. The clotting factor missing (VIII or IX) must be replaced so the child can form a clot to stop the bleeding.

Some factor products are made from human blood products such as donated plasma. Others, called "recombinant factor," are made in a laboratory and do not use human blood products. The Medical and Scientific Advisory Council of the National Hemophilia Foundation encourages the use of recombinant clotting factor products because they are safer. Your doctor or your HTC will help you decide which is right for you. All factor treatments are injected or infused directly into the veins.

In cases of severe hemophilia, doctors sometimes recommend giving a regimen of regular factor replacement treatments (a therapy called prophylaxis) to prevent bleeding episodes before they happen. The Medical and Scientific Advisory Council of the National Hemophilia Foundation recommends prophylaxis as optimal therapy for children with severe hemophilia A and B.

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X-linked RecessiveX-linked severe combined immune disorder

(X-SCID) is an immunodeficiency disorder in which the body produces very little T cells and NK cells. In the absence of T cell help, B cells become defective.

It is an x-linked recessive trait, stemming from a mutated (abnormal) version of the IL2-RG gene located at xq13.1 on the X-chromosome, which is shared between receptors for IL-2, IL-4, IL-7, and IL-15.

Persons afflicted with X-SCID often have infections very early in life, before three months of age. This occurs due to the decreased amount of immunoglobulin G (IgG) levels in the infant during the three-month stage.

This is followed by viral infections such as pneumonitis, an inflammation of the lung which produces common symptoms such as cough, fever, chills, and shortness of breath.

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X-linked RecessiveSome forms of congenital deafness:X-linked recessive inheritance causes hearing loss in only a small number

(about 3%) of people with hearing loss.

With X-linked recessive inheritance, only boys are affected. Girls can be carriers of the gene. That means they could pass it on to their sons in the

future.

If a mother is a carrier of the hearing loss gene, her sons will have a 50% chance of having hearing loss.

If a mother is a carrier of the hearing loss gene, none of her daughters will have hearing loss. But half of them will be carriers.

X-linked types of hearing loss can be a mix of conductive and sensorineural hearing loss.

If there is a recessive gene for hearing loss on only one of the mother’s X chromosomes, she will have normal hearing. She would be called a “carrier.” Half of her children will get the hearing loss gene. Her daughters will get the normal gene on the X chromosome from their father. Sons won’t have a second X chromosome because they will have gotten the Y chromosome from their father. So they will have hearing loss even though they have only one copy.

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X-linked recessive congenital deafness

In this picture the mother is a carrier of an X-linked hearing loss gene called Xd. Only her sons who get the Xd from her and the Y from their father will have hearing loss.

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Y-linked (holandric) traits

Hypertrichosis of the ears

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Polygenic and Multifactorial Inheritance

Most diseases have multifactorial inheritance patterns. 

As the name implies, multifactorial conditions are not caused by a single gene, but rather are a result of interplay between genetic factors and environmental factors. 

Diseases with multifactorial inheritance are not genetically determined, but rather a genetic mutation may predispose an individual to a disease.  Other genetic and environmental factors contribute to whether or not the disease develops.

Numerous genetic alterations may predispose individuals to the same disease (genetic heterogeneity).

For instance coronary heart disease risk factors include high blood pressure, diabetes, and hyperlipidemia.  All of those risk factors have their own genetic and environmental components. Thus multifactorial inheritance is far more complex than Mendelian inheritance and is more difficult to trace through pedigrees.

DISEASES:•  Alzheimers disease •  Heart disease  •  Some cancers  •  Neural tube defects  •  Schizophrenia  •  Insulin-dependent Diabetes mellitus

CHARACTERS:· Height, weight• Intelligence · Skin, eyes and hair color· Dermatoglyphics· Blood pressure

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Mitochondrial Inheritance (1)Mitochondria are organelles found in the cytoplasm of

cells.   

Mitochondria are only inherited from the mother’s egg, thus only females can transmit the trait to offspring, however they pass it on to all of their offspring. 

The primary function of mitochondria is conversion of molecule into usable energy. 

Thus many diseases transmitted by mitochondrial inheritance affect multiple organs with high-energy use such as the heart, blood, skeletal muscle, liver, and kidneys, becoming a complex texture of diseases, usually lethal in early childhood.

The difficulty arises when no mtDNA defect can be found or when the clinical abnormalities are complex and not easily matched to those of more common mitochondrial disorders.

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Mitochondrial Inheritance (2)Mitochondria are unique in that they have

multiple copies of a circular chromosome = mtDNA Each human cell contains

thousands of copies of mtDNA. At birth these are usually all identical (homoplasmy).

By contrast, individuals with mitochondrial disorders resulting from mtDNA mutations may harbor a mixture of mutant and wild-type mtDNA within each cell (heteroplasmy)

The percentage level of mutant mtDNA may vary among individuals within the same family, and also among organs and tissues within the same individual. This is one explanation for the varied clinical phenotype seen in individuals with pathogenic mtDNA disorders.

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