Clinical Genetics Flashcards
Important chromosomal abnormalities with cytogenetics
the RB1 gene on chromosome arm 13q and the PAX6 gene on chromosome arm 11p, defects in which result in retinoblastoma and aniridia, respectively.
What is a dominant gene?
a dominant gene is always expressed with similar phenotype, whether the mutant gene is present in a homozygous or heterozygous state
What is a recessive gene?
A gene is called recessive if its expression is masked by a normal allele or, more precisely, if it is expressed only in the homozygote (or compound heterozygote) state when both alleles at a specific locus are mutant.
What is codominance?
If the alleles are different and yet are both manifested in the phenotype, they are said to be codominant. Examples of phenotypes with codominant inheritance patterns include the ABO blood types, HLA types, and hemoglobin variants (as involved in sickle cell disease).
Autosomal recessive inheritance?
An autosomal recessive disease is expressed fully only in the presence of a mutant gene at the same locus on both homologous chromosomes (ie, homozygosity for a mutant gene) or of 2 different mutant alleles at the same locus (compound heterozygosity)
What do autosomal recessive conditions normally have?
Autosomal recessive diseases often result from defects in enzymatic proteins. Most of the so-called inborn errors of metabolism that result from enzyme defects are autosomal recessive traits, although a few are X-linked recessive disorders (eg, Lesch-Nyhan syndrome).
How to detect galactokinase deficiency?
identification of abnormal metabolites by electrophoresis
How to detect oculocutaneous albinism and Fabry disease?
hair bulb assay
How to detect galactose-1-phosphate uridyl-
transferase in galactosemia?
monitoring of enzyme activity in leukocytes
How to detect ornithine aminotransferase deficiency in gyrate atrophy of the retina and choroid?
skin culture for analysis of enzyme activity in fibroblasts
How to detect hexosaminidase A in Tay-Sachs disease?
assay of serum and tears
What do autosomal dominant conditions usually have?
Autosomal dominant traits often represent defects in structural nonenzymatic proteins, such as in fibrillin in Marfan syndrome or collagen in Stickler syndrome. In addition, a dominant mode of inheritance has been observed for some malignant neoplastic syndromes, such as retinoblastoma, von Hippel–Lindau disease, tuberous sclerosis, and Gardner syndrome. Although the neoplasias in these diseases are inherited as autosomal dominant traits, the defect is recessive at the cellular level, with the tumors arising from loss of function of both alleles
Aniridia- which gene involved
loss of 1 of the 2 alleles for the developmental transcription factors PAX6
Waardenburg syndrome- which gene involved?
loss of 1 of the 2 alleles for the developmental transcription factors
PAX3
Complete Penetrance?
Conclusive evidence of autosomal dominant inheritance with complete penetrance requires demonstration of the disease in at least 3 successive generations.
Incomplete Penetrance?
In some instances, dominantly inherited traits are not clinically expressed. In other instances—such as in some families with autosomal dominant RP—pedigree analysis can sometimes show a defective gene in individuals who do not manifest any discernible clinical or functional impairment. This situation is called incomplete penetrance or skipped generation.
Important feature of X-linked recessive inheritance
The distinctive feature of X-linked inheritance, both dominant and recessive, is the absence of father-to-son transmission. Because the male X chromosome passes only to daughters, all daughters of an affected male will inherit the mutant gene.
Define hereditary
Hereditary indicates that a disease or trait under consideration results directly from an individual’s particular genetic composition (or genome) and that it can be passed from one generation to another.
Define genetic
Genetic denotes that the disorder is caused by a defect of genes, whether acquired or inherited
Isolated genetic disease
A condition known to be genetic and hereditary (eg, RP) may appear in only 1 indi- vidual of a family. Such an individual is said to have a simplex, or isolated, form of a genetic disease. A genetically determined trait may be isolated in the pedigree for several reasons:
* The pedigree is small.
* The full expression of the disease has not been sought or has not manifested in
other relatives.
* The disorder represents a new genetic mutation or chromosomal change.
* The disorder is recessive, and the investigation to determine whether the parents
are carriers has been inadequate.
* There is nonpaternity.
What is an allele?
The alternative forms of a particular gene at the same locus on each of an identical pair of chromosomes are called alleles. If both members of a pair of alleles for a given autosomal locus are identical (ie, the DNA sequence is the same), the individual is homozygous (a homozygote). If the allelic genes are distinct from each other (ie, the DNA sequence differs), the individual is heterozygous (a heterozygote)
Genes involved in Oculocutaneous albinism
Defects in separate gene loci (the tyrosinase gene and the P gene) are now known to cause oculocutaneous albinism
Define mutation
Change in the structure or sequence of a gene is called a mutation. A mutation can occur randomly anywhere along the DNA sequence of a gene and may result when one nucleotide is substituted for another (point mutation)
Define polymorphism
Many base changes have little or no deleterious effect on the organism. A polymorphism is defined as the occurrence of 2 or more alleles at a specific locus with a frequency greater than 1% each in a given population. Single nucleotide polymorphisms (SNPs) are important for gene mapping in genome-wide association studies (GWAS)
Define phenocopy
A clinical picture produced entirely by environmental factors that nevertheless closely resembles, or is even identical to, a phenotype is known as a phenocopy. Thus, for example, the pigmentary retinopathy of congenital rubella has occasionally been confused with a hereditary dystrophic disorder of the retina, RP. Similarly, amiodarone-induced changes in the corneal epithelium resemble those observed as cornea verticillata in the X-linked dystrophic disorder Fabry disease.
Features of myotonic dystrophy
motor myotonia, cataracts, gonadal atrophy, and presenile baldness
