Genetics Patterns of inheritance (Lectures 4, 5, 6, & 7)

How many blood type groups are there?

4 (or 8 if you count the +/- factor) A type B type O type AB type

Why are males said to be "hemizygous" and not females?

A chromosome in a diploid organism is hemizygous when only one copy is present. Only males have one copy of the X chromosome; every chromosome females have, they also have a copy of it. Because it refers to the X chromosome; and since males only have half the X chromosomes as compared to females. Males XY versus females XX. Humans have 24 chromosomes (22 autosomes and 2 sex chromosomes); but they have 23 pairs of chromosomes and 46 total number of chromosomes.

What is horizontal inheritance?

When a disease in a family is seen in only one generation of a pedigree then it is said that the disease exhibits horizontal inheritance!

What is meant by variable expressivity?

When not all patients with the disease have the same severity of the symptoms then that disease is said to exhibit variable expressivity.

What does "having the same mutant allele" imply?

When the parent is a carrier then "having the same mutant allele" means that you're finding the probability of the kids also being carriers, etc.

Xeroderma pigmentosum is autosomal recessive disorder AND has variable expression; what increases the risk of developing Xeroderma pigmentosum?

Xeroderma pigmentosum is more severe in individuals exposed more frequently to environmental UV radiation.

True or False: In all known cases a person who is homozygous for alleles causing autosomal dominant (AD) disease - the prognosis is worse.

Yes! This can be seen in Familial Hypercholesterolemia, Achondroplasia, and Huntington disease. However, note that in all of the autosomal dominant diseases, a patient who is homozygous for disease alleles (for an AD disorder) is EXTREMELY rare!!! Therefore, unless it is clearly indicated, always assume a person with an AD disorder is a heterozygote!!!

What is Allelic heterogeneity?

Allelic heterogeneity is when DIFFERENT mutations at the SAME locus cause the SAME disease phenotype! In other words, different mutations at the same locus cause the disease.

What should you assume about the mode of inheritance of Autosomal Dominant disorders?

Always assume that autosomal dominant disorders are in the heretozygote state, unless otherwise specified; because they can "rarely" be presented in the homozygous state as well. KEY FACT / ASSUMPTION: Autosomal dominant disorders manifest in the heterozygous state. It's an assumption because rarely it can a autosomal dominant disease can also manifest in an individual with homozygous state.

Define "pseudo dominant" mode of inheritance?

Apparent Autosomal Dominant inheritance when a heterozygote & homozygote for an autosomal recessive disorder have affected children.

Explain what are identical twins known as monozygotic twins?

Arise as result of fertilization of a single zygote. Possess identical genes

Explain what are identical twins known as dizygotic twins?

Arise as result of fertilization of two ova. Genetically share about 50% genes (Sibling)

What are the two major types of Mendelian Modes of Inheritance? What are the 5 different types of Mendelian Modes of Inheritance?

Autosomal (involving the 22 pairs of autosomal chromosomes) and Sex chromosomal (involving the 23rd pair of sex chromosome). Autosomal: 1) Autosomal Dominant 2) Autosomal Recessive Sex chromosomal: 3) X-linked Dominant 4) X-linked Recessive 5) Y-linked inheritance (rare)

What is the MODE OF INHERITANCE for familial hypercholesterolemia disorder?

Autosomal Dominant

What is the MODE OF INHERITANCE for • Alkaptonuria (delayed age of onset)

Autosomal Recessive Disease/Disorder (this is expressed only in a homologous state--when there are two mutant copies of the same gene, one from mom and one from dad).

What is the MODE OF INHERITANCE for • Galactosemia

Autosomal Recessive Disease/Disorder (this is expressed only in a homologous state--when there are two mutant copies of the same gene, one from mom and one from dad).

What is the MODE OF INHERITANCE for • Hemochromatosis (delayed age of onset)

Autosomal Recessive Disease/Disorder (this is expressed only in a homologous state--when there are two mutant copies of the same gene, one from mom and one from dad).

What is the MODE OF INHERITANCE for • Homocystinuria

Autosomal Recessive Disease/Disorder (this is expressed only in a homologous state--when there are two mutant copies of the same gene, one from mom and one from dad).

What is the MODE OF INHERITANCE for • Most enzyme deficiencies - Beware those that are X-linked, and IAP

Autosomal Recessive Disease/Disorder (this is expressed only in a homologous state--when there are two mutant copies of the same gene, one from mom and one from dad).

What is the MODE OF INHERITANCE for • Phenylketonuria

Autosomal Recessive Disease/Disorder (this is expressed only in a homologous state--when there are two mutant copies of the same gene, one from mom and one from dad).

What is the MODE OF INHERITANCE for • Sickle cell anemia

Autosomal Recessive Disease/Disorder (this is expressed only in a homologous state--when there are two mutant copies of the same gene, one from mom and one from dad).

What is the MODE OF INHERITANCE for • Tay-Sachs disease (Hexosaminidase A deficiency)

Autosomal Recessive Disease/Disorder (this is expressed only in a homologous state--when there are two mutant copies of the same gene, one from mom and one from dad).

What is the MODE OF INHERITANCE for • SCID due to adenosine deaminase deficiency - Severe combined immune deficiency

Autosomal Recessive Disease/Disorder (this is expressed only in a homologous state--when there are two mutant copies of the same gene, one from mom and one from dad). Autosomal recessive SCIDS is due to ADA (adenosine deaminase) enzyme deficiency; when ADA enzyme is deficient, there is build up of dATP, which is toxic to B-cell and T- cell development.

How can you tell the difference between X-linked dominant and Autosomal dominant disorders (considering that both have no skipping of generations / vertical inheritance)?

Autosomal dominant disorders characteristically exhibit FATHER TO SON transmission; whereas X-linked dominant disordres characteristically DO NOT exhibit father to son transmission.

Recurrence Risk for Autosomal Recessive Inheritance with a carrier mother and a carrier father?

In autosomal recessive disorders A = normal allele a = disease allele aa = affected individual Aa = carrier individual AA = normal individual This is different from autosomal dominant disorders: A = disease allele a = normal allele Aa = affected individual aa = normal individual AA = lethal mutation

What is the concept of Germline mosaicism?

• A normal father had two infants affected with osteogenesis imperfecta with different partners. The father also has another child that is normal. The results of the genetic tests for osteogenesis imperfecta are normal in all the parents. • This may be due to germline (gonadal) mosaicism in the father • The mutation is present in a proportion of the germline cells • Presence of two affected children is in favor of germline mosaicism (compare to new mutation, where there is a single child with a disorder and no family history of the disorder) Germline mosaicism, also known as gonadal mosaicism, is a condition in which the precursor (germline) cells to ova and spermatazoa are a mixture (mosaic) of two or more genetically different cell lines. A study of semen samples from 100 men found low-level germline mosaicism in one third of infertile men, with increased incidence with advancing paternal age.

Describe autosomal recessive disorders?

• Autosomal recessive diseases are usually seen in only one generation of a pedigree (horizontal inheritance) • Autosomal recessive diseases are expressed only in the homozygous state. Parents are usually carriers of the disease causing allele. Siblings are more commonly affected • Males and females are affected in almost equal frequency

Mitochondrial Inheritance

• Mitochondria are inherited from the mother • All offspring of an affected female are affected • Only females transmit disease • Affected father does not transmit the disease to children • BOTH male and female children of an affected female are AFFECTED

What are three conditions / diseases that are examples of LOSS OF FUNCTION MUTATION (aka Haplo-insufficiency)?

- Examples include cell membrane receptors (familial hypercholesterolemia) - AIP (enzyme deficiency, heme can't be produced fast enough) - Consider OI type I

What are the two different ways of indicating carrier individuals in a pedigree diagram?

1) Half filled symbols may be used to indicate carriers. 2) A dot may also be used to indicate carrier status.

What are the two types of loss of function mutations?

1) Hypomorph and 2) Amorph Hypomorph loss of function mutation is when there is reduced activity of a gene. Amorph loss of function mutation is when there is complete loss of gene product.

Why do autosomal dominant mutations manifest in the heterozygous state?? Give three reasons!!!

1) Loss-of-function mutations (Haplo-insufficiency): in which half normal levels of the gene product result in phenotypic effects. 2) Gain-of-function mutations: result from increased levels of gene expression or the development of a new function of the gene product. 3) Dominant-negative mutations: a mutant gene product interferes with the function of the normal gene product.

What is the more common classic examples of diseases that demonstrate locus heterogeneity?

1) Osteogenesis imperfecta (collagen gene: chromosome 17's COL1A1 gene and chromosome 7's COL1A2 gene) 2) Charcot Marie Tooth disease (AD, AR, or X-linked) 3) BREAST CANCER: BRCA1 locus or BRCA2 locus (on same gene) 4) Congenital Deafness has 15 different loci that can cause deafness.

What are 7 examples of diseases that demonstrate locus heterogeneity?

1) Osteogenesis imperfecta: Defect in collagen - Mutations of chromosome 17 (COL1A1 gene) or chromosome 7 (COL1A2 gene)- lead to the disease manifestations (phenotype) of osteogenesis imperfecta • Other disorders that demonstrate locus heterogeneity: 2)- Sensorineural hearing impairment 3)- Retinitis pigmentosa 4)- Charcot Marie Tooth disease (AD, AR, or X-linked) 5)- SCID (AR and X-linked) 6)--BREAST CANCER: BRCA1 locus or BRCA2 locus. 7)--Congenital Deafness: in fact there are over 15 loci that have been shown to be involved in deafness.

Autosomal recessive SCIDS is due to which enzyme's deficiency?

ADA = adenosine deaminase

If it is known that a particular disorder has an autosomal dominant mode of inheritance and only one parent is affected (i.e. has the disease) then what is the probability that a couple's next child will be affected? For that same couple, what is the probability for the second pregnancy / child?

ALL autosomal dominant disorders ALWAYS have 50% recurrence risk (regardless of the sex/gender of the parents as well as regardless of the sex/gender of the kids)! For that same couple, the probability for the second pregnancy / child stays the same as the first pregnancy / child because this is not dependent on the number of previously affected children. It remains the same for every new child born to the couple.

Hemochromatosis is autosomal recessive disorder AND YET it is found to be more severe in males than females; why is that?

Autosomal recessive disorders affect males and females EQUALLY; however sometimes certain disorders can be "variable expression." Variable expression means that two individuals who have inherited the same mutant allele can have different severity due to the same disease--meaning some individuals are severely affected and others are mildly affected. Why does variable expression take place at all? There are three current hypothesis: Three reasons: - random chance - other genetic factors (modifier loci) - environmental exposure

It is important to be able to calculate the recurrence risk given the penetrance of a disease. If the penetrance of an autosomal dominant disease is 80%, then the recurrence risk for the couple would be?

Because every child with autosomal dominant has 50% chance of being affected and there is a given 80% penetrance then: 50%x80% ----------- = 40% is the answer. 100%

What is a common feature of both the autosomal dominant and autosomal recessive disorders?

Both, autosomal dominant and autosomal recessive disorders, affect males and females equally.

What is the probability that a couple who are both carriers for an autosomal recessive disorder is a carrier of the recessive allele?

CAUTION. If the child is going to be a carrier then it cannot be 'aa' or be affected. I know that all autosomal recessive disorders produce 25% homozygous affected, 75% phenotypically normal, 50% carriers, and 25% homozygeous normal. However, this question is asking for the probability of being a carrier excluding being affected; which means 2/3 can be carriers or 67%.

In which mode of inheritance does the blood type get transmitted?

Co-dominance

What is allelic heterogeneity?

Different mutations of the same gene resulting in the same phenotype (i.e. condition or disease) is called allelic heterogeneity.

What is a Mitochondrial mode of inheritance?

Disease due to a mutation in a gene encoded by mitochondrial DNA.

What are two conditions / diseases that are examples of GAIN OF FUNCTION MUTATION?

Examples include Huntington disease and achondroplasia

What are two conditions / diseases that are examples of DOMINANT NEGATIVE MUTATION?

Examples include collagenopathies such as OI Type II, III, or IV also Marfan syndrome (defect in fibrillin).

True or False: Vertical inheritance is exhibited in ALL autosomal recessive disorders, whereas Horizontal inheritance is exhibited in ALL autosomal dominant disorders.

FALSE. It is in fact that horizontal inheritance that is witnessed in ALL autosomal recessive disorders, whereas vertical inheritance (no skipping of generations) is witnessed in ALL autosomal dominant disorders. To recap: HORIZONTAL inheritance = autosomal RECESSIVE VERTICAL inheritance = autosomal DOMINANT

What is the MODE OF INHERITANCE for Huntington's disease?

Huntington's disease has autosomal dominant inheritance, meaning that an affected individual typically inherits one copy of the gene with an expanded trinucleotide repeat (the mutant allele) from an affected parent. Huntington's disease (HD) is a neurodegenerative genetic disorder that affects muscle coordination and leads to mental decline and behavioral symptoms. In the few documented examples, homozygotes have earlier and more severe disease onset

What is the MODE OF INHERITANCE for Acute intermittent porphyria?

Have autosomal dominant mode of inheritance.

What is the MODE OF INHERITANCE for Marfan syndrome?

Have autosomal dominant mode of inheritance.

What is the MODE OF INHERITANCE for Osteogenesis imperfecta?

Have autosomal dominant mode of inheritance.

What is the MODE OF INHERITANCE for Achondroplasia?

Have autosomal dominant mode of inheritance. Achondroplasia • FGFR3 mutations • FGFR3 codes for a transmembrane receptor that is involved in differentiation of cartilage to bone • Mutations in FGFR3 result in severe stunting of growth

What is the MODE OF INHERITANCE for Neurofibromatosis type I disease?

Have autosomal dominant mode of inheritance. • Mutations in neurofibromin (NF1) gene. • NF-1 is caused by different mutations in the NF-1 gene (allelic heterogeneity = different mutations of the same gene resulting in the same phenotype (condition/disease) is called allelic heterogeneity.) • Neurofibromin gene codes for a tumor suppressor protein • Café-au-lait spots (pronounced "Cafe aw lay" spots) • Neurofibromas: swellings on the skin • Lisch nodules in the iris of the eye • NF1 is a classic example of a disease that exhibits variable expressivity (not all patients with the disease have the same severity of the symptoms).

Delayed age of onset has to be kept in mind when reading the pedigrees for which disorders?

Huntington disease Hemochromatosis Familial breast cancer

What is skewed X - inactivation (asymmetric X inactivation) ?

If this asymmetric X-chromosome inactivation occurs, the carrier may have gene expression activity level that is BELOW NORMAL and thus will experience gene-mutation/disease-like problems. There is BELOW NORMAL gene expression activity in individual with skewed X-inactivation because the number of cells that contain the active mutant X are large compared to the cells that contain the active normal X. For example, some areas of tissue can be healthy while other areas may be badly affected--this happens in DMD mutations. Such symptoms are generally mild compared to the problems of the ACTUALLY affected individual.

What is vertical inheritance? Which type of mode of inheritance disorders exhibit vertical inheritance?

In vertical inheritance, affected children receive the disease causing gene from an affected parent. IN OTHER WORDS, the disease does not SKIP generations! Autosomal Dominant Disorders exhibit vertical inheritance (no skipping of generations because every affected parent necessarily affects / gives the disease to their children).

What is a Pseudo-Autosomal Dominant disease or disorder or condition?

Is actually an Autosomal Recessive disorder/disease but it appears like an autosomal dominant disease on the pedigree.

When a disease is pleiotropic disease; what does this describe about how the disease manifests itself in patients?

It means that the disease affects more than one organ system even though there is a mutation of a SINGLE gene that is causing the disease.

What is the MODE OF INHERITANCE for LDL receptor deficiency disorder?

LDL receptor deficiency is the same as familial hypercholesterolemia disorder! Mode of Inheritance is Autosomal Dominant. Details about Familial Hypercholesterolemia: Patients have high levels of LDL with normal VLDL. The heterozygous form occurs in a lot more frequently (1:500) than the homozygous form (which occurs in 1:1 million). Heterozygous form has adult onset, with risk of coronary heart disease. Homozygous form has childhood onset, risk of MI and death in childhood. Characteristics: xanthoma over tendon and xanthelasmas.

Locus

Location of gene on chromosome

What is the difference between locus heterogeneity versus allelic heterogeneity?

Locus heterogeneity is when 2 or more DIFFERENT loci (aka 2 or more different genes may be mutated here) mutations cause the SAME disease phenotype, whereas allelic heterogeneity is when 2 or more mutations at the SAME locus (aka in the SAME gene) cause the SAME disease phenotype. Breast cancer, congenital deafness, osteogenesis imperfecta, and charcot marie tooth disease are all famous examples of LOCI HETEROGENEITY. Whereas hemochromatosis (iron-overload), neurofibromatosis type 1, and cystic fibrosis.

What is locus heterogeneity?

Locus heterogeneity refers to mutations at different loci that cause the same disease phenotype. Many loci can cause the same disease.

What is the difference between locus and allele?

Locus is the location of the gene on a chromosome, whereas allele is the different versions of the same gene at occurs AT A SPECIFIC LOCUS on a chromosome.

Consanguinity

Medical term for "in-breeding." Sexual relationship or marriage between second cousins or closer than second cousins.

What are the two major categories of Modes of Inheritance?

Mendelian Mode of Inheritance and Non-Mendelian (or also known as Mitochondrial Mode of Inheritance).

Polymorphism

Multiple forms (alleles) of a gene in population (>1% of population).

What are 2 examples of triplet repeat expansion disorders?

Myotonic dystrophy and Huntington's disease are examples of triplet repeat expansion disorders, both of which have autosomal dominant mode of inheritance.

What are two example diseases which exhibit a pleiotropic nature?

Pleiotropy is when "a disease causing mutation affects multiple organ systems." Two pleiotropic diseases are: 1) Marfan syndrome (mutation in fibrillin gene) 2) Osteogenesis imperfecta (mutation in collagen gene) 1) The disease causing mutation in Marfan syndrome affects multiple organ systems (i.e. skeletal abnormalities, ocular abnormalities (myopia, lens dislocation), and cardiovascular diseases). 2) The disease causing mutation in Osteogenesis imperfecta affects multiple organ systems (i.e. bone as well as sclera). Pleiotropy is when "a disease causing mutation affects multiple organ systems."

Heterozygote

Possess different alleles at a locus

Homozygote

Possess the same alleles at a locus

What are the FOUR diseases/disorders/conditions that we learned in our genetics course which exhibit "Allelic Heterogeneity"?

Neurofibromatosis-1 Hemochromatosis Hemophilia A Cystic Fibrosis 1) NF-1 is caused by different mutations in the NF-1 gene. 2) Hemochromatosis can either have mutations in the HFE gene at two different locations (C282Y versus H63D loci of the same gene) where cysteine becomes tyrosine or have mutations in the same gene where histidine becomes aspartic acid. 3) Hemophilia A is caused by a mutated clotting factor 8; where most of the severe mutations in factor VIII gene involve inversions of an intron sequence; but there are many other types of mutations of the Factor VIII gene that also result in Hemophilia A. 4) The most common mutation in cystic fibrosis is a deletion of Phe at the codon 508 (ΔF508). However, missense, frameshift, nonsense mutations in the CFTR gene have also been reported.

What affects the penetrance (ability of the disease to actually fully express the manifestations of the disease) of a disease?

Penetrance may be dependent on AGE!!! ---> Especially in adult onset diseases like Huntington disease.

What is Pleiotropy?

Pleiotropy is when "a disease causing mutation affects multiple organ systems."

Charcot-Marie-Tooth (CMT) Neuropathy

Pronounced Shahrr-co Mahree Tooth disease or Shahrr-co Mahree Tooth Neuropathy. CMT is a group of genetically inherited disorders of the peripheral nervous system characterized by progressive loss of muscle tissue and touch sensation across various parts of the body. Currently incurable, this disease is one of the most common inherited neurological disorders affecting approximately 1 in 2,500 people. CMT was previously classified as a subtype of muscular dystrophy. The foot of a person with Charcot-Marie-Tooth disease has lack of muscle, a high arch, and claw toes, which are signs of this genetic disease.

How is pseudo-autosomal dominant mode of inheritance (which is actually autosomal recessive mode of inheritance) different from the actual autosomal dominant mode of inheritance? How do we know that a pseudo-autosomal dominant is in fact an autosomal recessive? What assumptions are we not to make about pesudo-autosomal dominant diseases?

Pseudo-autosomal dominant is BEHAVES LIKE the autosomal dominant in that it: 1) presents in two or more generations in a pedigree vertically 2) an affected parent may have an affected child 3) This is also known simply as "PSEUDO-DOMINANCE of an autosomal recessive disorder;" because it is an autosomal recessive disorder which is appearing to be dominant in every generation.. this is happening due to 2 reasons: 1) higher carrier and affected individuals mating with each other, 2) close cousins mating with each other (discussed below). Then how do we know that a pseudo-autosomal dominant is in fact an autosomal recessive disease? We know because of two reasons: 1) The disease being described in the pedigree will be one of the commonly known autosomal recessive diseases (such as Sickle cell anemia, etc) 2) It is autosomal recessive disease because a heterozygous "Aa" (recessive carrier) is mating with "aa" (recessive affected individual); this cross causes the couple's children to also be affected and give the false appearance of an autosomal dominant disorder. We should not NEVER assume based only on the pedigree that a disease that looks like an autosomal dominant is an pseudo-autosomal dominant UNLESS we are told by the question stem that there is 1. High carrier frequency of the disorder - sickle cell anemia in Africa 2. Higher incidence of consanguinity - geographical, social or religious isolation

What is Pseudoautosomal region?

Region of chromosomes that match. It is necessary to line up chromosomes correctly during meiosis recombination.

Dominant

Require only one copy of the mutation to produce disease

Proband

The affected individual in the family who gains the attention of the physician due to a genetic condition.

What is the MODE OF INHERITANCE for Myotonic dystrophy disease?

The disease display an autosomal dominant pattern of inheritance. Myotonic 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. There are two main types of myotonic dystrophy. Myotonic dystrophy type 1 (DM1), also called Steinert disease, has a severe congenital form and an adult-onset form. Myotonic dystrophy type 2 (DM2), also called proximal myotonic myopathy (PROMM) is rarer than DM1 and generally manifests with milder signs and symptoms. Myotonic dystrophy can occur in patients of any age. Both forms of the disease display an autosomal dominant pattern of inheritance. Details: • Mutation in the DMPK gene • Most pleiotropic phenotype of all unstable triplet repeat disorders • Characterized by wasting of the muscles, cataracts, heart conduction defects, endocrine changes, and myotonia.

Consultand

The person who approaches a physician or geneticist for a consultation. - this person may, or may not, be affected.

What is the the phenomenon of incomplete or reduced penetrance?

This phenomenon usually / commonly occurs with "autosomal dominant" mode of inheritance. This happens when the pedigree fits the description of the autosomal dominant inheritance except for an individual who most probably has the disease genotype but does not display the disease phenotype. "INCOMPLETE" or "REDUCED" refers to the fact that even though the person is carrying an autosomal dominant mutant allele, he or she does NOT have the disease; the mutant allele is incomplete or reduced in its ability to affect this individual. Whereas a disorder that is said to be FULLY penetrant would cause all the people carrying the mutation to express the manifestations of the disease! Most autosomal dominant diseases ARE fully penetrant but some can have incomplete or reduced penetrance.

What is a compound heterozygote?

This term only refers to allelic heterogeneity demonstrating disorders such as cystic fibrosis, hemochromatosis, or neurofibromatosis. A compound heterozygote is the affected child who inherits BOTH the paternal as well as the maternal mutations; such an individual is known as a compound heterozygote.

True or False: All humans carry recessive mutations.

True! It is predicted that each of us have 7 to 10 recessive mutations; only when we mate with someone else with the same mutations will we find out that we are carrier of a disease.

True or False: All Dominant disorders (whether autosomal dominant or X-linked dominant) do NOT skip generations.

True! No skipping of generations is a key stone feature of dominant disorders!

True or False: Siblings are more commonly affected in autosomal recessive disorders.

True.

True or False: Autosomal recessive diseases are expressed only in "homozygous" state; this is unlike autosomal dominant disease which are only expressed in "heterozygous" state.

True. Autosomal recessive diseases are usually seen in only one generation of a pedigree (horizontal inheritance). Autosomal recessive diseases are expressed only in the homozygous state. Parents are usually carriers of the disease causing allele. Siblings are more commonly affected. Males and females are affected in almost equal frequency.

Tell me about X-linked recessive disorders?

X linked disorders are diseases caused by mutations on the sex chromosome called X. Males have XY sex chromosomes, whereas females have XX. Females (XX) 1) one X having the mutation WILL NOT affect them 2) two Xs having the mutation is VERY RARE but will affect Males (XY) 1) X having mutation WILL cause disease.

What are the four triplet repeat disorders?

"Hunt My Fragile Friedrich" mnemonic. Huntington disease (CAG) Myotonic dystrophy (CTG) Fragile X syndrome (CGG) Friedrich ataxia (GAA) All of these are caused by expansion of triplet repeats! Repeats are unstable, and repeat size of influences disease severity - which explains phenomena called "anticipation" seen with these four disorders over time.

What are the FOUR locations where the triplet repeats can pop up?

1) At the promoter. 2) In an intron (which is NOT part of the encoded DNA and is excised OUT). 3) In the actual coding region of the gene itself 4) At the 3' end of the gene

What are the two causes of Prader Willi Syndrome (major and minor)? Which diagnostic test can detect it either of these?

1) Prader Willi Syndrome DUE TO a "microdeletion of father's (paternal) chromosome," which causes absence of SNRPN. 2) Prader Willi Syndrome DUE TO a condition known as "uniparental disomy" in which the child has two of mother's (maternal) chromosomes 15 (and an absence of father's chromosome 15). Such children have two active copies of UBE3A and again "NO active copies of SNRPN gene." Therefore, it is very clear that no SNRPN gene =s Prader Willi Syndrome. For the microdeletion of father's chromosome type of Prader Willi Syndrome, FISH can be used to detect it. Remember FISH is used when you are FISHing for a specific region to see if it is present or not within the chromosomes of the individual (whole genome). Detection by FISH is done by using specific probes against the region of interest. For the uniparental disomy type of Prader Willi Syndrome, methylation analysis can be done to detect the two methylated copies of chromosome 15.

What are the two key/prominent features/symptoms of Huntington disease (autosomal dominant)?

1) Progressive dementia, 2) Loss of motor control

Helene is a carrier for Duchenne muscular dystrophy. She marries Gary, who has Becker muscular dystrophy. Helene has just given birth to a daughter. What is the probability that this child will be affected with a disease associated with a defect of the dystrophin protein?

25% or 1/4

A study of the CFTR mutation in two separate families, revealed a codon deletion in one family and a missense mutation in the second family. This illustrates the concept of

Allelic heterogeneity

Allelic Heterogeneity

Allelic heterogeneity is when DIFFERENT mutations at the SAME locus cause the SAME disease phenotype! In other words, different mutations at the same locus cause the disease. Locus heterogeneity is when 2 or more DIFFERENT loci (aka 2 or more different genes may be mutated here) mutations cause the SAME disease phenotype, whereas allelic heterogeneity is when 2 or more mutations at the SAME locus (aka in the SAME gene) cause the SAME disease phenotype. Breast cancer, congenital deafness, osteogenesis imperfecta, and charcot marie tooth disease are all famous examples of LOCI HETEROGENEITY. Whereas hemochromatosis (iron-overload), neurofibromatosis type 1, and cystic fibrosis.

What is another name for the happy puppet syndrome?

Angelmann Syndrome

What is are different features between autosomal dominant and autosomal recessive disorders?

Autosomal Dominant Mode of Inheritance: 1) Father to son transmission is seen. 2) No generations are skipped (more than one generation has the condition on the pedigree); vertical inheritance. 3) Only one mutant allele is needed for the disease phenotype to affect the patient.

Autosomal Dominant disorders have 1) what type of mode of inheritance? 2) do diseases skip generations? 3) do such diseases affect males and females equally? 4) do such diseases have male to male transmission? 5) do such diseases have affected parents affecting children directly?

Autosomal Dominant disorders have 1) what type of mode of inheritance? VERTICAL 2) do such diseases skip generations? NO 3) do such diseases affect males and females equally? YES 4) do such diseases have male to male transmission? YESSS 5) do such diseases have affected parents affecting children directly? YES

What is the MODE OF INHERITANCE for • Congenital deafness (autosomal recessive)

Autosomal Recessive Disease/Disorder (this is expressed only in a homologous state--when there are two mutant copies of the same gene, one from mom and one from dad).

What is the MODE OF INHERITANCE for • Cystic fibrosis

Autosomal Recessive Disease/Disorder (this is expressed only in a homologous state--when there are two mutant copies of the same gene, one from mom and one from dad).

What does the codon CAG encode for? Why is it clinically relevant to know about this codon?

CAG encodes for "glutamine." An expansion of triplet repeats (of above 40 repeats) is said to put an individual at direct risk of developing Huntington disease later on in life (and the higher the number of triplet repeats the sooner the age of onset there will be).

A study of the CFTR mutation in two separate families, revealed a codon deletion in one family and a missense mutation in the second family. A marriage occurred between members of these two families, and a child was born with CF. Which term describes this patient?

Compound heterozygote

How is detection by FISH molecular diagnostic test done and for what purpose?

Detection by FISH is done by using specific probes against the region of interest. Remember FISH is used whenever you are FISHing for a specific region to see if it is present or not within the chromosomes of the individual (whole genome).

Digenic inheritance

Digenic disorders are newly recognized and were first noted in retinitis pigmentosa in children of parents who each carried a mutation in different RP-associated genes. Both parents had normal vision. With digenic inheritance, normal parents, one of whom carries a "gene A' mutation and the other a "gene B" mutation, will ave a one in four risk of having a child who inherits both gene A and gene B mutations (be homozygous for the mutated alleles) and will express the mutant phenotype. The affected child will havea one in four chance of passing on both alleles (gene A and B mutations). This appears like an autosomal recessive trait (affected sibs, unaffected parents, and one in four recurrence risk) but transmission will appear as vertical (dominant) if it is a digenic disorder like retinitis pigmentosa (RP).

Give an example of digenic disorder and explain this mode of inheritance!

Digenic disorders are newly recognized and were first noted in retinitis pigmentosa in children of parents who each carried a mutation in different RP-associated genes. Both parents had normal vision. With digenic inheritance, normal parents, one of whom carries a "gene A' mutation and the other a "gene B" mutation, will ave a one in four risk of having a child who inherits both gene A and gene B mutations (be homozygous for the mutated alleles) and will express the mutant phenotype. The affected child will havea one in four chance of passing on both alleles (gene A and B mutations). This appears like an autosomal recessive trait (affected sibs, unaffected parents, and one in four recurrence risk) but transmission will appear as vertical (dominant) if it is a digenic disorder like retinitis pigmentosa (RP).

If there is a mutation that causes polyglutamine expansion; then which disease / disorder does this point to?

Huntington disease!

What are the mode of inheritance of Prader Willi syndrome and Angelman syndrome?

Imprinting.

Mutation of the splice DONOR site of exon or intron would would the mature mRNA transcript to be what? LONGER? or SHORTER? And yes donor and acceptor sites DO exist in both exon and introns (though they are commonly referred to as being in the introns because these get excised out).

LONGER.

Locus heterogeneity

Locus heterogeneity refers to mutations at different loci that cause the same disease phenotype. Many loci can cause the same disease. 1) Osteogenesis imperfecta (collagen gene: chromosome 17's COL1A1 gene and chromosome 7's COL1A2 gene) 2) Charcot Marie Tooth disease (AD, AR, or X-linked) 3) BREAST CANCER: BRCA1 locus or BRCA2 locus (on same gene) 4) Congenital Deafness has 15 different loci that can cause deafness.

what happens in the mito disease called Leber hereditary optic neuropathy?

Manifests as progressive blindness around 20-30 years of age. Blindness and cardiac conduction defects are present.

What abnormal event during cell cycle takes place when Prader Willi syndrome is caused by uniparental disomy?

Meiotic I nondisjunction causes uniparental disomy (aka two maternal copies of the chromosome 15 are in the child because when these chromosomes were "homologous chromosomes" during metaphase of meiosis I they failed to separate!

What does the mito disease MELAS stand for?

Mitochondrial Encephalomyopathy, Lactic Acidosis, & Stroke-like episodes

What does the mito disease MERRF stand for?

Myoclonic Epilepsy w/ Ragged Red muscle Fibres

Pleiotropic effect

Pleiotropy is when "a disease causing mutation affects multiple organ systems." Two pleiotropic diseases are: 1) Marfan syndrome (mutation in fibrillin gene) 2) Osteogenesis imperfecta (mutation in collagen gene) 1) The disease causing mutation in Marfan syndrome affects multiple organ systems (i.e. skeletal abnormalities, ocular abnormalities (myopia, lens dislocation), and cardiovascular diseases). 2) The disease causing mutation in Osteogenesis imperfecta affects multiple organ systems (i.e. bone as well as sclera). Pleiotropy is when "a disease causing mutation affects multiple organ systems."

What is your mnemonic for all the autosomal dominant diseases/disorders/syndromes that you have to know for SGU Genetics course?

Possible mnemonic for all the autosomal dominant diseases' mode of inheritance is: F! HAM MOAN!! F = familial hypercholesterolemia / LDL receptor def. H = Huntington disease A = Anchondroplasia M = Myotonic dystrophy M = Marfan syndrome O = Osteogenesis imperfecta A = Acute intermitten porphyria N = Neurofibrotoma (Neurofibromatosis type 1)

Recurrence risk

Probability that the offspring of a couple will express the genetic disease. For single gene disorders, it does not depend on the number of previously affected/unaffected offspring. Depends on mode of inheritance of a disease.

Recessive

Requires two copies of the mutation to produce disease

What are the symptoms of Retinitis pigmentosa?

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.[citation needed] Those who do not have RP have 90 degree peripheral vision, while some people who have RP have less than 90 degrees. A form of retinal dystrophy, RP is caused by abnormalities of the photoreceptors (rods and cones) or the retinal pigment epithelium (RPE) of the retina leading to progressive sight loss.

Mutation of the splice acceptor site of exon or intron would would the mature mRNA transcript to be what? LONGER? or SHORTER? And yes donor and acceptor sites DO exist in both exon and introns (though they are commonly referred to as being in the introns because these get excised out).

SHORTER.

How do you find the probability of the grandchildren?

Simply multiply the two probabilities with each other. (1/2 x 1/2 = 1/4 or 25%)

What is the Recurrence Risk for Autosomal Dominant Inheritance?

Since in autosomal dominant disorder only one mutant allele is sufficient to cause the disease phenotype in affected individuals; capital A represents the disease allele and lower-case 'a' represents normal allele. A punnet square between Aa (affected parent) and aa (normal parent); yields two 'Aa's and two 'aa,' meaning that there is 50% recurrence risk (in other words 50% of kids can be affected if one of the parent has a autosomal dominant disorder; with will be regardless of the sex/gender of the child.

True or False: The sex/gender of the parent is not important in autosomal dominant disorders.

TRUE!

Two individuals who each have the same adult-onset autosomal dominantly inherited disorder meet, fall in love, and have children. Their first-born child inherits the disease allele from both parents. What can be expected in this child?

The disease phenotype is likely to be more severe in the child. It is NOT necessarily true that the child will die in utero (embryonic or perinatal lethality).

Anticipation

The four triplet repeat disorders (Huntington diease, Myotonic dystrophy, Fragile X syndrome, and Friedrich ataxia) all demonstrate anticipation. Triplet repeat size influences disease severity; individuals in the recent (newer) generations of a pedigree develop disease at an earlier age and with greater severity. Greater the number of repeats, earlier is the age of onset of symptoms and more severe is the disorder. The larger the repeat, the greater is the chance for it to be unstable and it tends to expand from one generation to the next.

Explain the phenomena called "anticipation" and which disorders demonstrates it?

The four triplet repeat disorders (Huntington diease, Myotonic dystrophy, Fragile X syndrome, and Friedrich ataxia) all demonstrate anticipation. Triplet repeat size influences disease severity; individuals in the recent (newer) generations of a pedigree develop disease at an earlier age and with greater severity. Greater the number of repeats, earlier is the age of onset of symptoms and more severe is the disorder. The larger the repeat, the greater is the chance for it to be unstable and it tends to expand from one generation to the next.

Heteroplasmy

The variable expression / severity of mitochondrial diseases is due to the phenomena of heteroplasmy. The term heteroplasmy is ONLY associated with mitochondrial diseases! Some mitochondrias carry disease and some do not... Therefore, the severity of the mito disease depends on how many diseased mitos are picked up by the child from the mother. If the oocyte w/ more mutant mito gets fertilized then the severity of the disease would be high and vice versa. •Unequal distribution of mutant and non-mutant mitochondrial DNA , results in the phenomenon of heteroplasmy in mitochondrial disorders.

What is heteroplasmy?

The variable expression / severity of mitochondrial diseases is due to the phenomena of heteroplasmy. The term heteroplasmy is ONLY associated with mitochondrial diseases! Some mitochondrias carry disease and some do not... Therefore, the severity of the mito disease depends on how many diseased mitos are picked up by the child from the mother. If the oocyte w/ more mutant mito gets fertilized then the severity of the disease would be high and vice versa. •Unequal distribution of mutant and non-mutant mitochondrial DNA , results in the phenomenon of heteroplasmy in mitochondrial disorders.

What is the difference between Angelmann Syndrome and Prader Willi Syndrome?

They both involve chromosome 15th; however these two diseases are quite different in their manifestations/symptoms (i.e. eating too much versus smiling too much). Trisomy rescue is involved in both conditions. Angelmann syndrome happens if there were three copies of the chromosomes 15 but two were from dad and only one was from mom; then mom's chromosome would have been thrown out--this would cause Angelmann Syndrome. Prader Willi syndrome happens if there were three copies of the chromosomes 15 but two were from MOM and only one was from DAD; then DAD's chromosome would have been thrown out--this would cause Prader Willi syndrome.

Incomplete penetrance

This phenomenon usually / commonly occurs with "autosomal dominant" mode of inheritance. This happens when the pedigree fits the description of the autosomal dominant inheritance except for an individual who most probably has the disease genotype but does not display the disease phenotype. "INCOMPLETE" or "REDUCED" refers to the fact that even though the person is carrying an autosomal dominant mutant allele, he or she does NOT have the disease; the mutant allele is incomplete or reduced in its ability to affect this individual. Whereas a disorder that is said to be FULLY penetrant would cause all the people carrying the mutation to express the manifestations of the disease! Most autosomal dominant diseases ARE fully penetrant but some can have incomplete or reduced penetrance. Penetrance may be dependent on AGE!!! ---> Especially in adult onset diseases like Huntington disease.

Compound heterozygote

This term only refers to allelic heterogeneity demonstrating disorders such as cystic fibrosis, hemochromatosis, or neurofibromatosis. A compound heterozygote is the affected child who inherits BOTH the paternal as well as the maternal mutations; such an individual is known as a compound heterozygote.

True or False: Autosomal recessive disorders are expressed in the homozygous state, whereas autosomal dominant disorders are expressed in the heterozygous state.

True. Generally, both parents are carriers of a disease causing mutant allele. Carriers are phenotypically normal - all humans carry recessive mutations

Give an explanation for the uniparental disomy observed in Prader Willi Syndrome!

Uniparental disomy of Prader Willi syndrome is simply the condition in which the child has two copies of the chromosome 15 (both from the mother and no copy at all from the father of chromosome 15). A good explanation for why this phenomenon of uniparental disomy occurs in Prader Willi syndrome is known as Trisomy Rescue. According to the concept of trisomy rescue an infant cannot survive with three copies of chromosome 15...so a phenomenon known as trisomy rescue throws out the dad's chromosome 15 when there are two copies of maternal chromosome 15. Similarly, if there were three copies of the chromosomes 15 but two from dad and one from mom; then mom's chromosome would have been thrown out--this would cause Angelmann Syndrome.

If there was an expansion of triplet repeats "at the 3' end (3' UTR) of the gene" then which SPECIFIC disorder that we learned about would be caused?

We only learned about one example of a triplet repeat disorder that occurs AT THE 3' END OF THE GENE and that is the myotonic dystrophy disease. --See Slide 129/140.

If there was an expansion of triplet repeats "at the promoter" then which SPECIFIC disorder that we learned about would be caused?

We only learned about one example of a triplet repeat disorder that occurs AT THE PROMOTER and that is the Fragile X syndrome! See Slide 129/140. Note: this results in reduced expression of the gene.

If there was an expansion of triplet repeats "in an intron" then which SPECIFIC disorder that we learned about would be caused?

We only learned about one example of a triplet repeat disorder that occurs IN AN INTRON and that is the Friedrich ataxia! See Slide 129/140. Note: this results in formation of heterochromatin.

If there was an expansion of triplet repeats "in the coding region of the gene" then which SPECIFIC disorder that we learned about would be caused?

We only learned about one example of a triplet repeat disorder that occurs IN THE CODING REGION OF THE GENE and that is the Huntington disease with its CAG repeats increased (which code for glutamine--so there is polyglutamine expansion)! See Slide 129/140.

What are the two common explanations for why we observe pseudo-autosomal dominant disorder?

We should not NEVER assume based only on the pedigree that a disease that looks like an autosomal dominant is an pseudo-autosomal dominant UNLESS we are told by the question stem that there is 1. High carrier frequency of the disorder - sickle cell anemia in Africa 2. Higher incidence of consanguinity - geographical, social or religious isolation

Fragile X syndrome • General Info? • Symptoms? • Diagnostic Test?

• General Info 1) Triplet repeat expansion (CGG repeat) on the X chromosome. 2) Results in increased methylation of this region and silencing of the FMR1 gene. 3) Females are less severely affected than males. 4) Shows anticipation in successive generations (higher the number of repeats, greater is the severity of the disease). • Symptoms? Mental retardation, learning difficulties, prominent ears, elongated face, macro orchidism (enlarged testis) Diagnostic tests: • Southern blot analysis of the triplet repeats gives an indication of the number of triplet repeat sequences

Imprinting

• Some genes are active ONLY when transmitted by mother or father. • For some genes, the maternal loci are active • And for some genes, the paternal loci are active