Chromosomal Aberrations

• Chromosomal aberrations include: Deletion/Deficiency, Duplication/Repeat, Inversion, Translocation
• Cytogenetic notation:

  • ISCN stands for International System for Human Cytogenetic Nomenclature
  • Each area of a chromosome is given a number
  • The lowest number is closest (proximal) to the centromere, while the highest number is at the tips (distal) to the centromere
  • P represents the short arm, and Q represents the long arm of a chromosome
• Abbreviations:

  • Del stands for Deletion
  • i stands for Isochromosome
  • Inv stands for Inversion
  • r stands for Ring chromosome
  • t stands for Translocation
  • + represents Gain
  • - represents Loss
• Structural abnormalities result from the breakage of a chromosome region with loss or subsequent rejoining in an abnormal combination

  • Two general types are Balanced rearrangements and Imbalanced rearrangements
• Balanced rearrangements

  Change the chromosomal gene order but do not remove or duplicate any DNA of the chromosome
• Imbalanced rearrangements

  Change the gene dosage of a part of the affected chromosomes
• Teratogens are substances that cause congenital disorders
• Inversions

  • A segment of a chromosome is reversed end to end
  • Types include Pericentric inversions and Paracentric inversions
• Deletions

  A part of a chromosome is missing or deleted
• Ring chromosomes:

  • Result from double-strand breaks with loss of chromosomal material outside the break points
  • Example: Ring chromosome 14 syndrome (r(14)) characterized by seizures and intellectual disability
• Duplications:

  • Partial trisomy for part of a chromosome
  • Can result from unbalanced insertion or unequal crossing over in meiosis or mitosis
• Isochromosomes:

  • Arise from abnormal division of the centromeres
  • Each resulting daughter cell has a chromosome with the short arm or the long arm duplicated
• Insertions

  Involve movement of a chromosome segment from one location to another on the same chromosome or to another chromosome
• Translocations

  • Breakage in two chromosomes with each broken piece reuniting with another chromosome
  • Balanced translocation results in no loss or gain of chromatin, while unbalanced translocation leads to partial monosomy or trisomy
  • Example: Down syndrome where most of chromosome 21 is attached to chromosome 14
• Robertsonian translocation

  Involves centric fusion where the centromeres of two acrocentric chromosomes fuse to generate one large chromosome
• How a reciprocal translocation arises:

  1. Insertion - genetic material is added from another chromosome

  2. Translocation - material is swapped with another chromosome
• Robertsonian translocation arises from centric fusion where the centromeres of two acrocentric chromosomes fuse to generate one large chromosome
• CRI – DU – CHAT SYNDROME

  Cat – cry syndrome, 5P minus syndrome and Lejeune’s syndrome ● First described by Jerome Lejeune in 1963

  ● Deletion of certain genes on chromosome 5

  ● Deleted genes:

  o HTERT gene → DNA functioning

  o CTNND2 gene → Cell adhesion, Cell movement, Active in NS
• WOLF – HIRSCHHORN SYNDROME

  ● First described by Hirschhorn and Cooper in 1961

  ● Deletion of the distal short arm of chromosome 4

  ● Deleted genes

  o NSD2 → distinctive facial appearance and developmental delay

  o LETM1 → seizures or other abnormal electrical activity in the brain

  o MSX1 → dental abnormalities and cleft lip and/or palate
• GENOMIC IMPRINTING

  ● Normal form of gene regulation that causes a subset of genes to be expressed from one of the two parental chromosomes

  ● Most genes → Inherit working copies

  o One from mother, other from father

  ● Imprinting → Inherit one working copy

  o Either from paternal or maternal

  o Epigenetically silenced

  o Silencing occurring through addition of methyl groups during egg/sperm formation → DNA Methylation
• ANGELMAN SYNDROME

  ● Mutation in UBE3A gene in maternal chromosome 15 (q12)

  o Ubiquitin protein ligase

  ● Absence of chromosome region 15 (15q11–q13)

  ● Named after Harry Angelman who first described the syndrome in 1965
• PRADER – WILLI SYNDROME

  ● First described in 1956 by Swiss doctors Prof. A Prader, Dr. A Labhart and Dr. H Willi

  ● Occurs as the result of absence of expression of paternal genes from chromosome 15q11–q13
• FEATURES: PRADER – WILLI SYNDROME

  ● Hypotonia → decreased muscle tone (muscle dystrophy or cerebral palsy)

  ● Hypogonadism → occurs when the body’s sex glands produce little to no hormones
• Balanced translocation → if chromatin is neither lost nor gained the exchange

  ● Unbalanced translocation → loss or gain of chromatin material results in partial monosomy or trisomy for a segment of the chromosome