Outline the different patterns of inheritance associated with X linked genes.
This presentation is the property of its rightful owner.
Sponsored Links
1 / 18

6 th October 2008 PowerPoint PPT Presentation


  • 56 Views
  • Uploaded on
  • Presentation posted in: General

Outline the different patterns of inheritance associated with X linked genes. Where possible give a molecular explanation for the pattern. 6 th October 2008. X Linked Inheritance. Refers to the pattern of inheritance of a condition caused by a mutations in a gene located on the X chromosome.

Download Presentation

6 th October 2008

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


6 th october 2008

Outline the different patterns of inheritance associated with X linked genes. Where possible give a molecular explanation for the pattern.

6th October 2008


X linked inheritance

X Linked Inheritance

  • Refers to the pattern of inheritance of a condition caused by a mutations in a gene located on the X chromosome.

  • Males have one X chromosome and a Y chromosome and females have two X chromosomes.

  • Because of this fundamental genetic difference, diseases caused by genes located on the X chromosome affect males and females differently and thus present unusual inheritance patterns.

  • Mutations in X linked genes will always affect males.

  • If the mutation is recessive, females will generally be unaffected while in a dominant condition they will generally be affected.


X linked genes

X linked genes

  • The X chromosome spans about 155 million base pairs

  • It represents approximately 5 percent of the total DNA in cells.

  • It is estimated to contain approximately 1400 genes (including non-coding RNA)

  • About 308 "disease genes" have been found on the X chromosome


Conditions related to genes on the x chromosome

Allan-Herndon-Dudley Syndrome

Alport Syndrome

Amelogenesis Imperfecta

Androgenetic Alopecia

Androgen Insensitivity Syndrome

Aarskog-Scott syndrome

Charcot-Marie-Tooth Disease

Choroideremia

Coffin-Lowry Syndrome

Colour Vision Deficiency

Congenital Hemidysplasia With Ichthyosiform Erythroderma And Limb Defects (CHILD)

Cornelia De Lange Syndrome

Duchenne And Becker Muscular Dystrophy

Emery-Dreifuss Muscular Dystrophy

Fabry Disease

Fragile X Syndrome

Frontometaphyseal Dysplasia

Glucose-6-Phosphate Dehydrogenase Deficiency

Haemophilia

Paroxysmal Nocturnal Hemoglobinuria

Pelizaeus-Merzbacher Disease

Periventricular Heterotopia

Rett Syndrome

Simpson-Golabi-Behmel Syndrome

Spastic Paraplegia Type 2

Spinal And Bulbar Muscular Atrophy

Turner Syndrome

X-Linked Adrenal Hypoplasia Congenita

X-Linked Adrenoleukodystrophy

X-Linked Agammaglobulinemia

X-Linked Juvenile Retinoschisis

X-Linked Lissencephaly

X-Linked Severe Combined Immunodeficiency

X-Linked Sideroblastic Anemia

X-Linked Spondyloepiphyseal Dysplasia Tarda

Conditions Related To Genes On The X Chromosome

Hypohidrotic Ectodermal Dysplasia

Incontinentia Pigmenti

Kallmann Syndrome

L1 Syndrome

Lenz Microphthalmia Syndrome

Lesch-Nyhan Syndrome

Lowe Syndrome

Mcleod Neuroacanthocytosis Syndrome

Melnick-Needles Syndrome

Menkes Syndrome

3-Methylglutaconic Aciduria

Nonsyndromic Deafness

Norrie Disease

Ocular Albinism

Oculofaciocardiodental Syndrome

Opitz G/BBB Syndrome

Ornithine Transcarbamylase Deficiency

Otopalatodigital Syndrome Type 1

Otopalatodigital Syndrome Type 2


X chromosome inactivation

X Chromosome Inactivation

  • Restores equal dosage of expression from genes on the X chromosome between males and females.

  • Early in embryonic development in females, one of the two X chromosomes is randomly and permanently inactivated in somatic cells.

  • Females are mosaics for two cell populations, one with the maternal and one with the paternal X as the active chromosome.

  • In a female heterozygous for an X linked condition -each cell will express either the normal or abnormal allele but not both.

  • X inactivation “blurs” the distinction between dominant and recessive X linked conditions.


Skewed x chromosome inactivation

Skewed X Chromosome Inactivation

  • X-linked disorders are generally rare in females and are usually attributable to advantageous silencing of the X chromosome that carries the mutant allele.

  • Initial X-inactivation choice is presumed to be random.

  • During proliferation, cells that have chosen the mutant X chromosome to be active can have a significant or total selective growth disadvantage - underrepresented in the adult carrier (negative cell selection).

  • Postinactivation cell selection has been documented in carriers for a number of X-linked diseases e.g. Aarskog-Scott syndrome, X linked SCID

  • In contrast, the positive growth advantage of cells in which the mutant X is primarily active has been reported in a few conditions.


Female carriers of x linked conditions

Female Carriers of X linked conditions

  • In general the boundaries between X linked dominant and recessive diseases might not be well defined for a number of cases displaying intermediate disease penetrance in heterozygous females.

  • When the phenotype depends on a circulating product e.g. in haemophilia, there is an averaging effect between the normal and the abnormal cells.

  • And so female carriers may have an intermediate phenotype and are usually clinically unaffected but biochemically abnormal

    • Increased CK levels and muscle weakness in carriers of DMD.

    • Many “carrier” females can display classical disease symptoms of Fabry disease.


X linked recessive inheritance

X linked recessive inheritance


X linked recessive inheritance1

X linked recessive inheritance

  • The vast majority of affected individuals are male (no back-up copy).

  • No male-to-male transmission.

  • All daughters of affected males are obligate carriers.

  • Female carriers pass the defective X chromosome to half their sons (affected) and half their daughters (carriers).

  • All affected males in a family are related through their mothers.

  • Trait or disease is typically passed from an affected grandfather, through his carrier daughters, to half of his grandsons.

  • The trait can “skip” generations (only carrier females and unaffected males are born).

  • e.g. Duchenne/Becker Muscular Dystrophy, Alport, Haemophilia A and B, Menkes disease, Norrie disease


Manifesting carriers

Manifesting Carriers

Reasons that a female may be affected with an X-linked recessive disorder

  • The affected female is homozygous for the mutant allele (has an affected father and carrier mother).

  • Cells with the normal X inactivated could be present in disproportionate numbers (skewed X inactivation).

  • The affected female has a 45,X karyotype or have an X chromosome with deletion of a normal gene.

  • Genetic defect in the X-inactivation process itself (reported female affected with Wiskott-Aldrich syndrome).

  • Caused by mutations in autosomal genes (genocopies) that have the same clinical effect as a mutation in an X-chromosome gene in males.


X linked dominant inheritance

X linked dominant Inheritance


X linked dominant inheritance1

X-linked dominant Inheritance

  • Dominant X-linked mutations are rare.

  • Affects either sex, but more females than males

  • Inheritance of mutant X – will get the disease

  • Females are more mildly and more variably affected than males

  • The child of an affected female regardless of its sex has a 50% chance of being affected

  • For an affected male, all of his daughters but none of his sons will be affected.

  • Examples include Chondrodysplasia Punctata, Rett Syndrome, Incontinentia Pigmenti, X-linked hypophosphatemia, CHILD.


X linked dominant inheritance with male lethality

Affected males are rarely or never seen because of a lethal effect of the mutant allele in the hemizygous male.

Only females (and boys with Klinefelter Syndrome) are affected The pedigree may appear to have several spontaneous abortions in the offspring of affected females.

As a result the sex ratio of their live offspring is often skewed.

Examples include Incontinentia Pigmenti and Aicardi Syndrome

X linked dominant inheritance with male lethality


X linked dominant with male sparing

X linked dominant with male sparing

  • Epilepsy and mental retardation limited to females (EFMR) is a disorder with an X-linked mode of inheritance and an unusual expression pattern.

  • Disorders arising from mutations on the X chromosome are typically characterized by affected males and unaffected carrier females.

  • In contrast, EFMR spares transmitting males and affects only carrier females.

  • All daughters of males are affected, whereas none of their sons are affected.

  • Another example of a condition with this unusual mode of inheritance is Craniofrontonasal syndrome (CFNS).


Possible explanations for this paradoxical phenotypic pattern

Possible explanations for this paradoxical phenotypic pattern

In contrast to most other known X-linked recessive or dominant disorders, the milder phenotype of the males is unexplained. Possible explanations:

  • ‘Metabolic interference’ - the interaction of a normal and a mutant allele in a multimeric protein produces more severe dysfunction than the mutant allele alone

  • A functional homologue on the Y chromosome may ameliorate the effect of the X chromosome mutation.

  • A disturbance in the process of X inactivation of the mutant gene could create a condition of functional disomy in females (Males would be unaffected by this).

  • It might be a sex-limited disorder, in which the greater severity in females is explained by different interaction of the mutant gene with sex-specific developmental pathways.


Pseudoautosomal region

Pseudoautosomal region.

  • Some genes on the X chromosome escape X-inactivation.

  • These genes are located at the tip of the short (p) arm of the X chromosome - the pseudoautosomal region.

  • Genes in the pseudoautosomal region are present on both chromosomes - men and women each have two functional copies of these genes.

  • Many genes in the pseudoautosomal region are essential for normal development.

  • one gene called SHOX -important for bone development and growth.

  • Short stature homeobox (SHOX)-related haploinsufficiency disorders

  • Inherited in a pseudoautosomal dominant manner


Complications to x linked inheritance patterns

Complications to X linked inheritance patterns

  • Skewed X inactivation (affected females e.g Fabry)

  • High rate of new mutations (DMD)

  • Germinal Mosaicism (DMD)

  • Non-penetrance (FraX described as X-linked dominant with incomplete penetrance)

  • Anticipation (Sherman paradox)

  • Variable Expression (Lesch Nyhan)

  • Consanquinity (affected females and apparent male-to male inheritance)


References

References

  • http://www.genecards.org/cgi-bin/listdiseasecards.pl?type=chrom&search=X

  • www.genereviews.org

  • Human Molecular Genetics 3 (Strachan and Read)

  • Dobyns WB The pattern of inheritance of X-linked traits is not dominant or recessive, just X-linked, Acta Pædiatrica, 2006; Suppl 451: 11_/15

  • Dibbens LM et al., X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment. Nat Genet. 2008 Jun;40(6):776-81.

  • Jakub Minkset al., A skewed view of X chromosome inactivation Clin. Invest. 118:20–23 (2008).

  • Morleo and Franco.Dosage compensation of the mammalian X of X-linked dominant male-lethal disorders chromosome influences the phenotypic variability J. Med. Genet. 2008;45;401-408;

  • Parolini 0, Ressmann G, Haas OA, et at. X-linked Wiskott-Aldrich syndrome in a girl. N Engl J Med 1998;338:291-5.

  • Plenge RM et al., Skewed X-Chromosome Inactivation Is a Common Feature of X-Linked Mental Retardation Disorders. Am J Hum Genet. 2006 Sep;79(3):493-9.

  • Puck and Willard. Editorial: X inactivation in females with X-linked disease NEJM

  • 1998. 338 (5) 325-

  • Am J Hum Genet. 2002 July; 71(1): 168–173.

  • Hladnik U et al., Variable Expression of HPRT Deficiency in 5 Members of a Family With the Same Mutation Arch Neurol. 2008;65(9):1240-1243.


  • Login