Clinical Genetics deals with the diagnosis of genetic diseases, care and counseling of patients with genetic disorders. Cytogenetics is the study of number & structure of chromosomes.

Common Terminologies:

• Genome: complete set of genes of a species
• Proband/Index case: an individual of family who draws an attention to physician for being genetic disorders
• Genotype: genetic constitution of an individual
• Phenotype: observable characteristic of an individual
• Dominant: a trait expressed in heterogygotes
• Recessive: trait is expressed only in homozygous and not in heterozygous
• Mutation: a permanent and heritable change in genetic material
• Expressivity: variation in the severity of a genetic trait
• Exon: coding region of a gene
• Introns: noncoding part of a gene
• Gene:  DNA sequence which produces a functional polypeptide Or RNA.
• Allele: Alternative forms a gene at the same locus on a homologous chromosome.
• Pedigree: diagrammatic representation of a family history important for the diagnosis of genetic diseases.

Classification of Genetic Disorders:

A) Single Gene Disorders (Mendelian)

• These are caused by mutant genes
• Single critical error in genetic information
• Exhibit obvious and characteristic pedigree pattern

B) Chromosomal Disorders

C) Multifactorial disorders

• Combined effect of various genes and environment can produce or predispose to a serious defect.  e.g.: Glaucoma, cleft lip, neural tube defect, CHD, cancer and diabetes mellitus.

Mendelian Law of Inheritance:

• Law of Segregation: Each of the two inherited factors (alleles) possessed by the parent will segregate and pass into separate gametes (eggs or sperm) during meiosis, which will each carry only one of the factors.
• Law of Independent Assortment: In the gametes, alleles of one gene separate independently of those of another gene, and thus all possible combinations of alleles are equally probable.
• Law of Dominance: Each trait is determined by two factors (alleles), inherited one from each parent. These factors each exhibit a characteristic dominant; co-dominant, or recessive expression, and those that are dominant will mask the expression of those that are recessive.

Inheritance:

• To receive body traits and genetic makeup as a result of genetic transmission is inheritance
• Variation that influence gene function are usually referred to as mutation.
• Variation not affecting health is polymorphism (an allelic variation within a species).
• Mutation can take place in Somatic and Germ cells.

Unifactorial Inheritance

Defect in a single gene.

Follows Mendelian’s law.

Types:

1. Autosomal Dominant and Recessive
2. Sex linked Dominant and Recessive

Autosomal dominant inheritance:

• Inheritance of dominant gene on autosome
• Appears in each generation.
• Male and female offspring are equally affected (not influenced by sex).
• Dominant trait is manifested in Heterozygote.
• Normal and abnormal genes (alleles) are present.
• One mutant gene is sufficient to produce the character.
• An affected parent is always present or is due to new mutation. Unaffected person do not transmit the trait.
• Severe case is either infertile or die on childhood.
• Severity is variable. The variability is referred to as expressivity. In osteogenesis imperfecta the severity varies from blue sclera to blue sclera + deafness + multiple fractures+abnormal dentitions.
• Sometimes the mutant gene can’t produce effect, in such condition the gene is termed non-penetrant. The mutant gene is modified by other genes and environment.
• Example: Hutington’s disease, Neurofibromatosis

Autosomal recessive inheritance

• Both the genes on autosomes are affected.
• Low incidence.
• Recurrence risk: 1 in 4
• Both sexes are equally affected.
• Appear suddenly in the family.
• Consanguinity increases the rate of incidence.
• Affected offspring may or may not have an affected parent.
• Enzyme proteins are affected in many cases.
• In 4 children, 1 is normal; 2 are born with a normal and abnormal gene (carriers) and 1 with 2 abnormal genes (at risk for disease)
• Examples: Sickle cell anaemia, Beta-Thalassemia, Cystic fibrosis

Sex linked inheritance

• Genes are on sex chromosome.
• There are 2 functions of sex chromosomes: sex determination and control of some metabolic activities.
• In females, only 1 X chromosome remains active and other remains inactive and is seen as condensed dark body (Barr body)

Types :

Y-linked

• Only males are affected.
• Sons of affected male inherit the trait. e.g. Hairy ear

X-linked

• Defect in genes of X chromosome.
• Female can be heterozygous or homozygous for mutant gene.
• Absence of father to son transmission.

X-linked Dominant Disorders:

• abnormal gene dominates the gene pair
• Both sexes are affected.
• Males are severely affected.
• If father carries abnormal X gene, all daughters will inherit the disease and sons are normal.
• Affected heterozygous females transmit these disorders to male and female children equally; half of their children will inherit the disease tendency.
• Examples : Vitamin D-resistant rickets

X-Linked Recessive disorders:

• Males are mostly affected.
• Both matching genes be abnormal for disease
• Rarely in females e.g. Turner syndrome
• May skip a generation
• Trait may be transmitted through a series of female carriers
• Examples: Deuchenne muscular dystrophy, Hemophilia

Inborn Errors of Metabolism:

• Genetically determined biochemical disorder in which a specific enzyme defect causes a metabolism block
• Expressed only in homozygotes while heterozygotes are carriers
• Errors of amino acids, carbohydrate, lipid and mineral metabolism
• May be able to treat if diagnosed early
• Eg. : phenylketone-urea, albinism, mucoplysaccharidosis

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Last updated: June 15, 2011

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