Coupon Accepted Successfully!


Single Gene Disorders with non Mendelian inheritance


Disorders of trinucleotide repeat mutations

  • Normally, a codon is triplet (trinucleotide).
  • In the normal people, the number of repeat of a particular triplet codon is small (e.g. for CGG it is 5-50 and CGG triplet codon can be repeated, at a stretch, 5-50 times).
  • In trinucleotide repeat mutations, this nucleotide sequence undergoes amplification (expansion of a stretch of nucleotide) and the same sequence is repeated many times in the genome.
  • Initially there is a small increase in trinucleotide copy number (e.g. 55-200 of CGG in fragile X syndrome) which is referred to as premutation. In premutation the disease is not manifested and the person acts as carrier.
  • If the expansion of repeats goes above a threshold level (e.g. > 200 of CGG repeat in fragile X-syndrome), gene function is impaired and the disease is manifested.
  • The repeat may be located in        
  1. Coding region → Huntington disease, Spinobulbar muscular atrophy.
  2. Non-coding region → Fragile-X syndrome, myotonic dystrophy)



  • Anticipation is a phenomenon where by the symptoms of genetic disorders become apparent at an earlier age as it is passed to next generation.
  • In triplet nucleotide repeat mutation, the DNA fragment is unstable and tends to expand further during cell division
  • So, in successive generations the expanded repeat increases and the manifestations of disease may worsen or to be observed at an earlier age; this phenomenon is referred to as anticipation.

Fragile - X syndrome    

  • Fragile - X syndrome is the prototype of diseases in which the mutation is characterized by a long repeating sequence of three nucleotides.
  • In fragile X syndrome, trinucleotide repeat mutation involves CGG on non coding region.
  • Clinical features of fragile - X syndrome
    • Mental retardation
    • Long face with large mandible  
    • Hyperextensible joint
    • Mitral valve prolapse
    • Large everted ears  
    • Large testis (macro-orchidism)
    • High arched palate
  • Fragile X syndrome is the second most common cause of mental retardation, after Down’s syndrome.

Genomic imprinting

  • Human inherits two copies of each gene, i.e. two alleles, from homologous maternal and paternal chromosomes.
  • There is no functional difference between the genes derived from mother or the father.
  • But, with respect to some genes, there are functional differences between the paternal gene and maternal gene.
  • These differences result from an epigenetic process, called genomic imprinting.
  • In most cases, genomic imprinting selectively inactivates either the maternal or paternal allele.
  1. Maternal genomic imprinting
    - Selective inactivation of maternal allele.
    - Example is Angelman syndrome.
  2. Paternal genomic imprinting
    - Selective inactivation of paternal allele.
    - Example is Prader - Willi syndrome.

Prader Willi Syndrome

Deletion occurs exclusively on paternal chromosome 15 (deletion of band q 12 in long arm of chromosome 15)


  • Diminished fetal activity
  • Hypotonia
  • Obesity
  • Mental retardation
  • Short stature
  • Hypogonadotropic hypogonadism

Angelman Syndrome

Deletion occurs exclusively on maternal chromosome 15


  • Hypotonia
  • Mental retardation
  • Seizures
  • Ataxia
  • Inappropriate laughter (Happy puppets)

Germline mosaicism

  • Germline mosaicism results from a mutation that occurs post zygotically during early embryonic development. In these a portion of the egg or sperm cells of a parent carries the mutation.
  • Because the mutation affects only cells destined to form the gonads the gametes carry the mutation but somatic cells of the individual are completely normal.
  • A phenotypically normal parent who has germ line mosaicism can transmit the disease causing mutation to the offspring through the mutant gamete.
  • Because the progenitor cells of the gamete carry the mutation there is a definite possibility that more than one child of such a parent would be affected.
  • Obviously, the likelihood of such an occurrence depends on the proportion of germ cells carrying the mutation.

Clinical Syndromes of Mitochondrial Disease


  1. Chronic progressive external ophthalmoplegia (CPEO)
  2. Kearns-Sayre -syndrome (KSS)
  3. Pearson syndrome
  4. Neurogenic weakness with ataxia and retinitis pigmentosa (NARP) 
  5. Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS)
  6. Myoclonic epilepsy with ragged-red fibers (MERRF)
  7. Leber hereditary optic neuropathy (LHON)


Test Your Skills Now!
Take a Quiz now
Reviewer Name