Single Gene Disorders & Mutations

• Single gene disorders stem from DNA alterations in a specific gene
• They often exhibit predictable inheritance patterns

Key Facts

• Over 10,000 human disorders are attributed to single-gene mutations
• Mutations of the gene responsible for a disorder is known as a mutant allele
• Single gene disorders are individually rare, but collectively affect about 1% of the population

Molecular Basis of Inherited Diseases

• Mutations involve changes in DNA nucleotide sequences
• These alterations range from single base-pair mutations to chromosomal aneuploidy

Classifications

• Not all mutations lead to disease
• Polymorphisms represent genotypes proportionally in a population
• A polymorphism is a DNA sequence variation with a frequency of 1% or higher in a population

Mutations

• Mutations in germ cells lead to heritable inherited diseases
• Somatic cell mutations can cause cancer and some congenital malformations

Congenital vs Inherited

• Congenital diseases have genetic components and are present at birth
• Congenital disorders aren't necessarily heritable
• Congenital disorders stem from factors like drugs, chemicals, infections, or injuries during development
• A baby can inherit a disease like hemophilia and pass it on to future generations
• Congenital conditions like spina bifida cannot be passed on

Spina Bifida

• Spina bifida, is an condition referring to a "cleft spine" characterized by incomplete development of the brain, spinal cord, and/or meninges

Spina Bifida Risk Factors

• Genetic, nutritional, and environmental factors are suspected to play a role
• Folic acid deficiency during pregnancy is a risk factor for spina bifida
• Diabetes in women elevates the risk of spina bifida in their children, possibly due to excess glucose interfering with fetal development
• Obesity in women increases spina bifida risk where a BMI of 30 or higher increases the risk

Patterns of Inheritance

• Most phenotypes result from genetic and environmental interactions
• Some phenotypes result from alteration of a single gene
• Mendelian genetics can predict inheritance patterns for some phenotypes

Pedigree Analysis

• Inheritance patterns (transmission patterns) are determined by examining family histories and involve pedigree analysis
• Pedigree is a diagram showing the inheritance pattern of a phenotype in a family and a diagram of family phenotype or genotype
• Squares represent males, circles females, and shaded symbols indicate individuals with the trait

Patterns in Pedigree Symbols

• A dominant trait, like widow's peak, doesn't skip generations
• A recessive trait may skip generations
• Pedigree analysis using Mendelian principles determines dominant or recessive inheritance patterns
• It also determines if the gene is on an X, Y chromosome, or an autosome
• This information can be used to predict risk

3 Main Transmission Patterns

• Autosomal-dominant
• Autosomal-recessive
• X-linked or sex-linked recessive
• These patterns refer to the disease phenotype

Autosomal-Dominant Traits

• Expression of a trait requires only one copy of a gene (one allele) for it to be considered dominant
• A child of an affected individual and an unaffected mate has a 50%-100% chance of expressing the disease, in autosomal-dominant transmission

How Autosomal-Dominant Traits are Inherited

• Only one abnormal allele of a gene is needed for expression
• Heterozygotes and homozygotes for the abnormal gene are affected
• Heterozygous individuals express the affected phenotype in an autosomal dominant transmission

Rules for inheritance

• An affected person has an affected parent
• A heterozygous affected parent and an unaffected parent have an equal number of affected and unaffected children on average
• There is a 50% risk of occurrence for each child of an affected parent
• Unaffected children of an affected parent do not transmit the trait to their descendants
• Males and females are equally likely to be affected

Autosomal Dominant Inheritance

• Lethal alleles are almost always recessive, expressed only in homozygotes
• One exception is the gene causing Huntington disease, also known as Huntington chorea

Huntington's Disease

• Persons with Huntington develop a progressive nerve disorder
• It causes involuntary muscle movement and loss of mental function
• Huntington is expressed mainly in adulthood and is always fatal
• There is no cure; treatment alleviates symptoms only

Traits

Achondroplasia

• Dwarfism linked to defects in long bone growth regions

Brachydactyly

• Malformed hands with shortened fingers

Camptodactyly

• Stiff, permanently bent little fingers

Crouzon Syndrome

• Defective midfacial development, protruding eyes, hook nose

Ehlers-Danlos Syndrome

• Connective tissue disorder, elastic skin, loose joints

Familial Hypercholesterolemia

• Elevated cholesterol, predisposes to plaque, cardiac disease; may be prevalent genetic disease

Adult Polycystic Kidney Disease

• Kidney cysts lead to hypertension, kidney failure

Huntington Disease

• Progressive nerve degeneration, dementia, early death

Marfan Syndrome

• Connective tissue defect; death by aortic rupture

Nail-Patella Syndrome

• Absence of nails, kneecaps

Single-gene disorders result from DNA alterations in a specific gene. These disorders often exhibit predictable inheritance patterns. Mutations in germ cells lead to heritable inherited diseases, while somatic cell mutations contribute to cancer.