Wk8 Genetics In Clinical Practice Flashcards
What is autosomal dominant inheritance?
A dominant trait is one which manifests in a heterozygote (a person possessing both the altered and usual alleles) and is usually transmitted from one generation to the next - “vertical transmission”. Isolated cases within a family may arise as a result of a new mutation. Each offspring of a parent with an autosomal dominant trait has a 1 in 2 chance of inheriting the condition.
What autosomal dominant inheritance traits can be exhibited?
variable expressivity (variation in the presence/severity of clinical features of the condition from person to
person)
reduced penetrance (resulting in someone who is a heterozygote showing no clinical signs of the
condition - a “skipped generation”)
sex limitation (the appearance of certain features of the condition in only one sex).
Examples: familial hypercholesterolaemia, adult polycystic kidney disease, Huntington disease, neurofibromatosis, polyposis coli.
What is autosomal recessive inheritance?
Autosomal recessive disorders are manifest only in the homozygous state. Each child of parents who are heterozygous for the same autosomal recessive condition has a 1 in 4 chance of inheriting the condition. If a person with an AR condition is able to reproduce, children will be at risk only if the partner is a carrier. Certain AR conditions are more common in particular population groups (eg cystic fibrosis in Caucasians).
What is X-linked inheritance?
X-linked recessive conditions are normally manifest only in males. Each child of a female who is heterozygous for an X-linked recessive allele (a carrier) has a 1 in 2 chance of inheriting the allele, and so being a carrier if a girl, and having the condition if a boy.
All daughters of males with an X-linked recessive condition are obligate heterozygotes.
Why is it rare that a female shows signs of an X-linked recessive disease?
is homozygous for the allele (e.g. colour blindness),
has a single X chromosome (Turner syndrome),
has a structural rearrangement of an X chromosome,
is heterozygous but has skewed or non-random X-inactivation.
Very rarely, male to male transmission of an X-linked recessive condition can appear to occur – when the father has the condition and the mother is a carrier.
What is X-linked dominant inheritance?
Only a few disorders are known to be inherited in an X-linked dominant manner.
In some of these disorders (eg Vitamin D resistant rickets). hemizygous males are more severely affected than heterozygous females.
In a few XLD conditions (eg incontinentia pigmenti) males who inherit the altered allele are so severely affected that spontaneous abortion is usual. Only affected females are seen in such families.
What are unusual patterns of inheritance?
anticipation. A phenomenon in which a disorder manifests at an earlier age and/or increases in severity in successive generations. Characteristic of dynamic mutations (trinucleotide repeat expansions). Examples are myotonic dystrophy (CTG), fragile X syndrome (CGG), Huntington disease (CAG)
mitochondrial mutations. Mitochondria possess their own genetic material, coding for enzymes in energy-yielding reactions, mutations of which cause certain human diseases, particularly involving the neuromuscular system. As mitochondria are inherited only from the mother, the transmission of such a disease is exclusively through female relatives. Affected men cannot pass on the disease to sons.
genetic heterogeneity The phenomenon that a disorder can be caused by mutations at different loci. Example: autosomal dominant adult polycystic kidney disease can be caused by mutations in genes on either chromosome 16 or chromosome 4.
mosaicism Mosaicism is caused by an error in mitotic cell division, resulting in two cell lines with different genetic constitutions. This can be due to DNA replication errors resulting in a new mutation in a single gene, or aberrant cell division resulting in structural or numerical chromosome anomalies. Mosaicism occurring only in the gonads can explain how an apparently normal parent can transmit a genetic disorder to more than one offspring (eg two children with autosomal dominant achondroplasia born to normal parents). Somatic mosaicism occurs more frequently: the effect on the phenotype depends on its timing during development and consequently the relative proportions of the two cell lines.
What are other genetic mechanisms?
imprinting. The phenomenon of a gene or area of chromosome showing different expression depending on the parent of origin. For example, if the normal pattern of imprinting on 15q11-13 has failed this can cause Prader-Willi or Angelman syndromes depending from which parent the 15q with altered expression has been inherited. Imprinting problems can be inherited – the clinical effect (if any) in the offspring depends on the sex of the parent passing it on.
uniparental disomy This is when an individual inherits both chromosomes of a homologous pair from one parent. Thought most usually to occur when one homologous chromosome is lost from a conception that was initially trisomic for that chromosome.
How to establish autosomal dominant inheritance?
1 Males and females affected in equal proportions
2 Transmitted from one generation to next (“vertical transmission”)
3 All forms of transmission are observed (ie male to male, female to female and male to female)
How to establish autosomal recessive inheritance?
1 Males and females affected in equal proportions
2 Individuals affected in a single sibship in one generation
3 Consanguinity in the parents provides further support
How to establish X-linked recessive inheritance?
1 Males affected almost exclusively
2 Transmitted through carrier females to their sons (“knight’s move” pattern)
3 Affected males cannot transmit the disorder to their sons
How to establish X-linked dominant inheritance?
1 Males and females are affected but affected females occur more frequently than affected males.
2 Females are usually less severely affected than males because of lyonisation (some X-linked
dominant conditions cause embryonic lethality in males so no affected males are seen in the family))
3 While affected females can transmit the disorder to male and female children, affected males transmit
the disorder only to their daughters, all of whom are affected
What are other points to consider when inspecting a pedigree?
If all children of affected mothers are affected, but no children of affected fathers, consider the possibility of mitochondrial inheritance. If there are children with multiple malformations and stillbirths in several generations consider the possibility of the family having a chromosomal translocation.
What is key information needed for drawing a genetic family history?
For each key person, record under the pedigree symbol the following information as appropriate:
• Name
• Date of birth (DOBs are preferable to current ages or estimates)
• Relevant symptoms and/or diagnoses and age at diagnosis (if known)
• Cause of death and age at death (if known)
Depending on the medical condition in the family, it might also be appropriate to ask about:
• Pregnancy and birth history
• Developmental delay and learning disabilities
• Dysmorphic features/congenital anomalies
• Occupational/environmental exposures
• Operations and hospitalisations
• Medications
What is hypercholesterolemia familial?
- Most common Mendelian disorder
- As heterozygote frequency so high, expect to see people who are homozygotes (who have more severe manifestations)
- Diagnosis often made initially on clinical features/family history
- confirmed by blood test
- problem is getting cholesterol out of blood stream into cells
- no common mutation: each family unique
- a hétérozygote has half the normal number of active receptors
- important to find families: treatment can prevent complications
