HBG 24 ( Single Gene Disorder)

• Mendel's Law of Segregation:

  • Alternative versions of genes account for variations in inherited characters
  • For each character, an organism inherits two genes, one from each parent
  • If the two alleles differ, then one, the dominant allele, is fully expressed in the organism's appearance; the other, the recessive allele, has no noticeable effect on the organism's appearance
  • The two genes of each character segregate during gamete production
• Terminology:

  • Allele: An alternative form of a gene that is located at a specific position on a specific chromosome
  • Gene: A hereditary unit consisting of a sequence of DNA that occupies a specific location on a chromosome and determines a particular characteristic in an organism
  • Trait: Distinct variant of a phenotypic character of an organism that may be inherited
  • Single Gene Trait: Mendelian or monogenic trait; involving only one gene
  • Polygenic Trait: A phenotypic character of an organism caused by activities of more than one gene/multiple genes
• • Quantitative Trait: Polygenic trait with continuous phenotypic characteristics
  • Qualitative Trait: Single gene trait with discrete or 'all-or-none' phenotype
  • Dominant Allele: An allele that is almost always expressed, even if only one copy is present
  • Recessive Allele: An allele that is phenotypically manifest in the homozygous state but masked in the presence of a dominant allele
• Patterns of Inheritance:

  • Autosomal Dominant Inheritance
  • Autosomal Recessive Inheritance
  • X-linked Recessive Inheritance
  • X-linked Dominant Inheritance
  • Y-linked Inheritance
  • Mitochondrial Inheritance
• Autosomal Dominant Inheritance:

  • Males and females are equally affected
  • Affected males and females are equally capable of transmitting the trait
  • An affected person usually has at least one affected parent
  • An affected person has a 50% probability of transmitting the trait to any offspring
  • The gene product is commonly a nonenzymatic protein
  • Examples include Huntington's disease, neurofibromatosis type 1, neurofibromatosis type 2, Marfan syndrome, hereditary nonpolyposis colorectal cancer, and hereditary multiple exostoses
• Huntington's Disease:

  • Slow progressive selective cell death in the central nervous system
  • Worldwide prevalence of 1 in 15,000
  • Symptoms include chorea, unclear speech, unsteady gait, memory impairment, psychiatric disturbances, and dementia
  • Genetics: Caused by polymorphic CAG repeat expansion in the HTT gene that encodes for the Huntingtin protein
• Autosomal Recessive Inheritance:

  • Both parents of an affected child are usually asymptomatic carriers
  • Males and females are equally affected
  • Consanguineous partners have an increased risk of sharing the same genetic mutation
  • Examples include Cystic fibrosis, sickle-cell disease, Tay-Sachs disease, Phenylketonuria, Niemann-Pick disease, and spinal muscular atrophy
• Cystic Fibrosis:

  • Inherited disease of the secretory glands
  • Caused by a defective CFTR protein
  • Complications include thick and sticky fluid buildup in the lungs and pancreas
  • Genetics: Located at 7q31, with the most common mutation being ΔF508
• 1. linked Recessive Inheritance:

  • Males are mostly affected
  • Carrier females have a 50% risk of transmitting the trait to their sons
  • Examples include Haemophilia A, Duchenne muscular dystrophy, and Lesch-Nyhan syndrome
• Duchenne Muscular Dystrophy:

  • The commonest and most severe form of muscular dystrophy
  • Prevalence of 1 in 3500 males
  • Onset age 3-5 years
• Duchenne Muscular Dystrophy (DMD):

  • Prevalence: 1 in 3500 males, onset age 3-5 years
  • Characterized by pseudohypertrophy and rapid progression of muscle degeneration early in life
  • One third of DMD males show moderate intellectual impairment
  • Slightly reduced life expectancy
  • Patients with proven mutations in DMD gene can be asymptomatic in their fifth or sixth decade
• Becker Muscular Dystrophy (BMD):

  • Milder form of DMD
  • Prevalence: 1 in 20,000 males, onset age 10-11 years
• Dystrophin protein:

  • Important structural/large complex in muscle fiber membranes
  • When missing or non-functional, leads to degeneration of muscle tissue
  • Muscle wasting occurs when ability to regenerate muscle is exhausted
• 1. linked Dominant Inheritance:

  • Both males and females may be affected
  • Females are usually less severely affected due to random X inactivation and mosaicism
  • Pedigree may appear similar to autosomal dominant pedigree but without male-to-male transmission
• Fragile X Syndrome:

  • X-linked disorder
  • Affects 1:1500 males, 1:2500 females
  • Most common single cause of severe mental retardation after Down Syndrome
  • Clinical features include prominent forehead, large jaw and ears, macroorchidism, halting and repetitive speech
  • Females with full mutation are mildly or moderately mentally retarded
  • Autistic behaviors
• Incontinentia Pigmenti Type 2:

  • More than 30 mutations in IKBKG gene identified
  • Most common mutation is 11.7kb common deletion of genetic material from IKBKG gene
  • Mutated gene leads to abnormally small, nonfunctional IKBKG protein
  • No IKBKG protein leads to abnormal cell death
• 1. linked Inheritance:

  • Only male-to-male transmission observed
  • Examples include baldness and hairy pinna (hairy ears)
• Mitochondrial Inheritance:

  • Mitochondrial genome is ~17kb
  • Maternally inherited only
  • Mutant alleles affect organs with high number of mitochondria
  • Examples include familial bilateral striatal necrosis, Kearns-Sayre syndrome, Leber’s hereditary optic neuropathy, and others
• Unorthodox Phenotypes in Mendelian Disorders:

  • Variations in dominant, recessive, and X-linked phenotypes
  • Includes penetrance and non-penetrance, variable expressivity, de novo mutations, mosaicism, genetic heterogeneity, phenocopy, parent-of-origin effect, and co-dominance
• Mendel’s Law of Segregation

  Alternative versions of genes are inherited from each parent, segregating during gamete production
• Single Gene Traits


  Involving only one gene
• Polygenic Traits

  Involving multiple genes
• Patterns of Inheritance

  1. Autosomal dominant

  2. Autosomal recessive

  3. X-linked recessive

  4. X-linked dominant

  5. Y-linked

  6. Mitochondrial
• Autosomal Dominant


  • Male = Female affected
  • Male = Female transmit the trait
  • Affected offspring has at least one affected parent
  • Gene product – non-enzymatic protein
  • Asymptomatic carriers
• Autosomal Recessive


  • Male = Female affected
  • Male = Female transmit the trait
  • Consanguineous partner increases risk sharing gene mutation
  • Unaffected parents have 25% risk to have affected child in subsequent pregnancy if they have one affected child
  • Unaffected child has 2/3 risk of being a carrier (if both parents unaffected)
  • Gene product – enzyme
• Diseases related to Autosomal Dominant

  • Huntington’s disease
  • Marfan syndrome
• Diseases related to Autosomal Recessive

  • Cystic fibrosis
  • Sickle-cell disease
• 1. linked Recessive


  • Male mostly affected
  • All daughters are carriers (if male affected)
  • No male-to-male transmission
  • Carrier female has a 50% risk of transmitting the trait to sons and daughters
  • Females affected if they have 'X' cytogenic abnormality or affected father and carrier mother
• 1. linked Dominant


  • Male and female affected
  • Female less severely affected due to mosaicism & random 'X' inactivation
  • Pedigree similar to autosomal dominant
  • No male-to-male transmission
• Diseases related to X-linked Recessive

  • Duchenne Muscular Dystrophy
  • Haemophilia A
• Diseases related to X-linked Dominant

  • Fragile X Syndrome
  • Incontinentia Pigmenti type 2
• 1. linked


  • Only male-to-male transmission is observed
• Mitochondrial


  • Maternally inherited
  • Affects organs with higher mitochondria (skeletal muscle & brain)
• Examples of Y-linked traits

  • Baldness
  • Hairy ears
• Examples of Mitochondrial diseases

  • Lactic acidosis and stroke-like episodes (MELAS) - mitochondrial disease primarily affecting the nervous system and muscles
• Details about Huntington’s Disease
• Details about Marfan Syndrome
• Patients inherited mutant allele by their mildly affected father
• Marfan Syndrome


  • Connective tissue disorder
  • Affects many structures - skeletons, lungs, eyes, heart & blood vessels
  • Unusually long limbs
  • Linked in mutation FBN1 gene that encodes glycoprotein (fibrillin-1) essential for proper formation of extracellular matrix including biogenesis & maintenance of elastic fibers
  • Mild to severe (variable expressivity)
• Cystic Fibrosis


  • Inherited disease of secretory glands
  • Caused by a defective CFTR (cystic fibrosis transmembrane conductance regulator) protein that acts as chloride channel
  • Produce abnormally thick & sticky fluid (in breathing passage of lungs & pancreas)