Sex Linked Inheritance  

Introduction

• A human female, has 23 pair of chromosomes

• A human male, has 22 similar pairs and one pair consisting of two chromosomes that are dissimilar in size and structure.

• The 23 rd pair in both the sexes is called sex chromosomes

• the female, XX. the male, XY

X-linked diseases

• X-linked diseases are those for which the gene is present on the X chromosome.

• X-linked diseases show inheritance patterns that differ from autosomal diseases.

• This occurs because males only have one copy of the X chromosome (plus their Y chromosome) and females have two X chromosomes.

• Because of this, males and females show different patterns of inheritance and severity of manifestation. While there are both dominant and recessive X-linked diseases, there are some characteristics that are common to X-linked disorders in general

• X-linked genes are never passed from father to son.

• The Y chromosome is the only sex chromosome that passes from father to son.

• Males are never carriers – if they have a mutated gene on the X chromosome, it will be expressed.

• Males are termed hemizygous for genes on the X chromosome.

 

X-linked dominant

• hereditary pattern in which a dominant gene on the X chromosome causes a characteristic to be manifested in the offspring.

• X-linked dominant diseases are those that are expressed in females when only a single copy of the mutated gene is present.

• Very few X-linked dominant diseases have been identified (e.g. hypophosphatemic rickets, Alport syndrome, diabetes insipidus)

hypophosphatemic rickets or vitamin D resistant rickets >>>low serum phosphorus, skeletal abnormalities

• Alport syndrome, which involves progressive hearing loss and progressive kidney problems.

Characteristics of X-linked dominant diseases include:

• Never passed from father to son.

• Affected males produce only affected females. An affected male only has one X chromosome to pass on to his daughters

• Affected females produce 50% normal and 50% affected offspring.. >>>> heterozygous

• Males are usually more severely affected than females. Some X-linked dominant traits may even be lethal to males.

• Females are more likely to be affected. Since females have 2 X chromosomes, they have 2 “chances” to inherit the mutated allele.

The pattern for the pedigree of X-linked dominant inheritance

Alport syndrome

Pattern for inheritance• Mating A Mating B

Pattern for inheritance

• Mating A Mating B

X-linked recessive

• hereditary pattern in which a recessive gene on the X chromosome results in the manifestation of characteristics in male offspring and a carrier state in female offspring

• X-linked recessive diseases are those in which a female must have two copies of the mutant allele in order for the mutant phenotype to develop.

• Many X-linked recessive disorders are well-known, including color blindness, hemophilia, and Duchenne muscular dystrophy.

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• www.tylermedicalclinic.com/ pgd-presentation18...

 

 

                                                                                                                                                        

                                                                                                                                                         

Pattern of x linked recessive inheritance

Hemophilia

• The blood fails to clot normally• Lacking a blood clotting factor

VIII(antihemophilic globulin, AHG),IX• bleeding from even minor cuts• in 1,500 newborn males. Most (75%) have he

mophilia A, a lack of clotting factor VIII. • Hemophilia B- "Christmas Disease" is a defect in

clotting factor IX.• Transfusions of fresh whole blood or plasma or f

actor concentrates control bleeding

Hemophilia A and B. Coagulation system

Inheritance of hemophilia

A Pedigree of Hemophilia in the Royal Families of Europe

Hemophilia

Duchene muscular dystrophy

www.rehabinfo.net/.../ mcdonald2/ppt/Slide5.JPG

Typical features of X-linked recessive inheritance

• Never passed from father to son.

• Males are much more likely to be affected because they only need one copy of the mutant allele to express the phenotype.

• • Affected males get the disease from their mothers and all of the

ir daughters are obligate carriers.

• Sons of heterozygous females have a 50% chance of receiving the mutant allele.

• These disorders are typically passed from an affected grandfather to 50% of his grandsons.

The Marker X syndrome

• Fragile X syndrome (Marker X syndrome ) is a genetic condition involving changes in the long arm of the X chromosome. It is characterized by mental retardation.

Alternative Names Martin-Bell syndrome; Marker X syndrome

Causes, & Risk Factors

• Fragile X syndrome is the most common form of inherited mental retardation in males and a significant cause in females.

• The inheritance is different from common dominant or rece

ssive inheritance patterns.

• A fragile area on the X chromosome tends to repeat bits of the genetic code.

• The more repeats, the more likely there is to be a problem.

• Boys and girls can both be affected, but because boys have only one X chromosome, a single fragile X is more likely to affect them more severely.

Mental retardation

• Mental retardation is described as below-average general intellectual function with associated deficits in adaptive behavior that occurs before age 18.

• Causes of mental retardation are numerous, but a specific reason for mental retardation is determined in only 25% of the cases.

Mental retardation

• Failure to adapt normally and grow intellectually may become apparent early in life or, in the case of mild retardation, not become recognizable until school age or later.

• An assessment of age-appropriate adaptive behaviors can be made by the use of developmental screening tests.

• The failure to achieve developmental milestones is suggestive of mental retardation.

Fragile X Syndrome Symptoms & Signs

• Family history of fragile X syndrome, especially a male relative

• Mental retardation • Large testicles (macro-orchidism) • Large size • Tendency to avoid eye contact • Hyperactive behavior • Large forehead and/or ears with a prominent jaw

Fragile X Syndrome Symptoms

www.fragilexohio.org/ images/366_littleguy.gif

Origin of Fragile-X Syndrome through slipped-mispair recombination

• In the F1 generation, a man hemizygous for an X-chromosome with a 40-fold CGG repeat marries a woman heterozygous for X-chromosomes with 10- and 30-fold CGG repeats. Their daughter inherits the 40 CGG repeat from her father, and the 30 CGG repeat from her mother. In her germline, slipped-mispair recombination results in production of eggs with 10- or 60-fold CGG repeats. Although the threshold for expression of Fragile-X syndrome is ~55CGG repeats, because the event occurs only in her germline and not in the somatic tissues, she does not show the syndrome.

   • In the F2 generation, the daughter marries a man with a 20-fold CG

G repeat. One-half of their sons will inherit the 60 CGG chromosome and will likely show the syndrome, and one-half of their daughters will be carriers.  Further slippage of the repeat region may occur in the F3 daughter's germlines. These daughters may or may not show the syndrome themselves: the phenotype is sex-influenced, with higher penetrance in males (80%) than females (30%), which may be due the presence of a 'standard' X-chromosome in heterozygous females.

Inheritance of Fragile-X syndrome.

www.sciencemuseum.org.uk/. ../genes/218.asp

An altered gene on the X-chromosome causes Fragile-X syndrome. A girl will normally have a working gene on her other X-chromosome, which partially makes up for the altered gene, so girls are usually less severely affected than boys. The genetic change in Fragile-X is very unusual; it tends to change between parent and child, so predi

cting the exact risk of having an affected child is complicated.

Inheritance of Fragile-X syndrome

• This picture shows affected men and women  in a fragile x pedigree.  Solid colored shapes are those that are affected and dotted shapes are those that may have mild symptoms, and carry the disease.  The percentages on the pedigree show the disease rate as the generations progress.  The picture was borrowed from Medical Genetics by Carey, John C., Jorde, Lynn B., and White, Raymond L.

www.ikm.jmu.edu/.../ shermananticipation.gifwww.ikm.jmu.edu/.../ shermananticipation.gif

Sex limited traits

• sex linked traits are generally expressed much more often in males than in females.

• some traits which affect one sex more than another are not necessarily sex linked.

• Examples are cases of sex limited expression which might include genes affecting beard growth or breast size, and (in cattle), horn growth and milk yield.

• These genes have no visible affect in one sex because the necessary machinery to express them is not present.

• Sex-limited inheritance:• A trait that appears in only one sex is called sex-limited inh

eritance. • Sex hormones and other physiologic differences between m

ales and females may alter the expressivity of a gene.

• For example, premature baldness is an autosomal dominant trait, but presumably as a result of female sex hormones, the condition is rarely expressed in the female, and then usually only after menopause.

• Thus, sex-limited inheritance, perhaps more correctly called sex-influenced inheritance, is a special case of limited expressivity and penetrance