Unit
- Single gene disorders: Conditions caused by mutations in a single gene, following predictable inheritance patterns. They affect about 1% of the population collectively and include well-known conditions such as cystic fibrosis and Huntington disease.
- Genetic vs. genomic: Single gene disorders involve one gene, while genomic disorders involve larger chromosomal segments. Understanding this distinction helps in selecting appropriate diagnostic tests.
- Mutation types: Point mutations, insertions, deletions, and duplications can alter gene function. Missense, nonsense, frameshift, and splice-site mutations each produce different molecular consequences.
- Penetrance and expressivity: Not all individuals with a mutation show symptoms (incomplete penetrance), and those who do may vary in severity (variable expressivity). These concepts explain why family members with the same mutation can have different presentations.
- De novo mutations: Some mutations arise spontaneously in the germline of a parent and are not inherited. This is important for genetic counseling, as recurrence risk may be low.
- Mosaicism: A mutation may be present in only a subset of cells. Somatic mosaicism can cause milder or segmental forms of a disorder, while germline mosaicism affects recurrence risk.
- Genetic heterogeneity: Mutations in different genes can produce similar clinical phenotypes (locus heterogeneity), and different mutations in the same gene can cause distinct disorders (allelic heterogeneity).
- Inheritance patterns: Autosomal dominant, autosomal recessive, and X-linked are the classic Mendelian patterns. Non-Mendelian patterns include mitochondrial inheritance, imprinting, and trinucleotide repeat expansion.
- Clinical relevance: Understanding single gene disorders is essential for accurate diagnosis, risk assessment, family planning, and management. Many rare diseases are single gene disorders, and their collective burden on healthcare is significant.
- Founder mutations: A mutation that occurs in a single individual and is then passed to many descendants in a population, often due to a genetic bottleneck. Founder mutations are common in isolated populations and can lead to high carrier frequencies for certain disorders, such as the delta F508 mutation in cystic fibrosis.
- Anticipation: In some disorders, symptoms appear at an earlier age or become more severe in successive generations. This phenomenon is often due to the expansion of trinucleotide repeats, as seen in Huntington disease and myotonic dystrophy. Anticipation has important implications for genetic counseling and risk prediction.
- Consanguinity and autosomal recessive disorders: When parents are blood relatives, the risk of autosomal recessive conditions increases because both parents are more likely to carry the same recessive mutation. Consanguinity is a significant factor in populations with high rates of cousin marriage and contributes to the prevalence of rare recessive disorders.
- Genetic testing for single gene disorders: Molecular testing methods such as Sanger sequencing, next generation sequencing, and targeted mutation analysis are used to identify pathogenic variants. Choice of test depends on the suspected disorder, mutation type, and clinical context. Results guide diagnosis, prognosis, and family planning decisions.
Terminology
- Allele
- Alternative form of a gene at a specific locus.
- Genotype
- The genetic constitution of an individual at a particular locus.
- Phenotype
- The observable physical or biochemical characteristics resulting from genotype and environment.
- Homozygous
- Having two identical alleles at a locus.
- Heterozygous
- Having two different alleles at a locus.
- Hemizygous
- Having only one copy of a gene, as in males for X-linked genes.
Quick Revision
- Single gene disorders result from mutations in one gene and follow predictable patterns.
- Mutation types include point mutations, insertions, deletions, and duplications.
- Penetrance and expressivity explain variations in symptom manifestation.
- De novo mutations and mosaicism are important for recurrence risk assessment.
- Genetic heterogeneity complicates genotype-phenotype correlations.