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Define Karyotype

The number and visual appearance of the chromosomes in the cell nuclei of an organism or species


Define mutation

A pathogenic(heritable) alteration in the gene affecting the structure or the function of a protein.


What are the characteristics of autosomal dominant conditions

-Caused by a mutation in a single autosomal gene
-Affected individuals are heterozygous for the mutation
-They have a normal(wild) type and a mutant copy of the gene
-Transmitted from generation to generation( i.e vertical inheritance)
-Males and females are usually affected equally
-Affected parent of either sex can transmit the disorder to both sons and daughters
-1 in 2 (50%) risk of an affected parent transmitting the condition to his/her children
-Key feature= male-to-male transmission
-Variable (reduced) penetrance
-Variable expression


What is reduced penetrance?

-Penetrance is a statistic and is usually expressed as a %
-The proportion of carriers who manifest phenotypic signs of the condition
-Not all individuals who inherit a dominant disease mutation necessarily show signs of the condition
-There may be age-specific penetrance


What are some of the characteristics of cherubism and its inheritance?

-A genetic abnormality
-Occurs as an autosomal dominant disorder and with 100% pentrance in males and 50 to 75% penetrance in females with 2:1 male predominance
-Marked fullness of the jaws


What is variable expression/ expressivity?

-Extent of clinical manifestation
-Variable within and between families


What are the 4 defects in Tetralogy of Fallot?

-Thick right ventricle (hypertrophy)
-Ventricular septal defect (VSD)
-Pulmonary stenosis(narrow pulmonary valve)
-Large overriding aorta.
This leads to reduced pulmonary blood flow due to a narrow outlet


What is germline mosaicism?

A parent carries a small proportion of gametes(germline cells) that harbour the same mutation


What are the characteristics of autosomal recessive conditions?

-Males and females can be equally affected
-Generally only members of a single sibship, or cousins affected(unless multiple consanguinity in the family)
-The probability that a future sibling of an affected individual will also be affected is 1 in 4
-The probability that a future sibling will be a carrier is 1 in 2
-The probability that an existing unaffected sibling is a carrier is 2 in 3 (the denominator changes as we have excluded the affected individual from our calculation)


What is compound heterozygosity?

-Someone who has different allelic mutations at the same locus


What are the characteristics of X-linked recessive disorders?

-Only males related via the female line are usually affected
-Women are usually asymptomatic
-1 in 2 chance that each son born to a carrier female will be affected
-1 in 2 chance that each daughter will be a carrier
-All the daughters of an affected male will be carriers
-Sons of an affected male are not affected (no male-male transmission)


How can females be affected with X-linked recessive disorders?

-Non-random inactivation leading to chance expression in certain tissues e.g expression of mutant allele in: heart in Duchenne Muscular dystrophy carriers; Kidney in X-linked Alport's disease; brain in fragile X syndrome(learning disability)
-Turner's syndrome 45,X


What is X inactivation?

-Only one X used per cell in 46 XX or 47XXY
-Idea of dosage compensation
-One X in each cell is switched off before blastocyst implants in females
-All women are mosaics, expressing either their maternal or paternal X but not both in any one of their cells


Explain the idea of random X inactivation

-One X chromosome per cell is inactivated by methylation
-All of its daughter cells have the same X chromosome inactivated (i.e they are a clone of cells with the same pattern of inheritance)


What are the characteristics of X-linked dominant disorders?

-Males and females affected (males>females)
-Affected females can show a mosaic pattern of involvement in tissues such as skin
-The condition may be lethal in males
-50% offspring risk to males and females of affected mothers
-All daughters of affected males inherit the condition
-None of the sons of affected males inherit the condition.


What are lines of Blaschko

-represent territories of clonal cell populations: some using normal X chromosome, some using mutated X chromosome
-Can be manifest in X-linked dominant disorders e.g Incontinentia Pigmenti and Goltz focal dermal Hypoplasia.