• Human Molecular Genetics, 2e, Ch 2 (free Pubmed textbook, recommended genetics resource)
  • Nat Rev Genet. 2001 Apr;2(4):280-91.
  • William’s Obstetrics 23e, Ch 12
  • Nelson’s Textbook of Pediatrics, 18e
  • – short animations of mitosis, meiosis, and non-disjunction

Aneuploidy: gain or loss of a chromosome(s) such that the number of chromosomes is not a multiple of 23 (the human haploid number)

Can be due to two main mechanisms:

1)    Non-disjunction

  • Definition: failure of chromosomal separation in anaphase of either meiosis or mitosis
  • Results in a 1:1 ratio of daughter cells with an extra chromosome (2n+1) to those with a loss of a chromosome (2n-1)
  • If occurring during meiosis: is a germline mutation(in either a spermatocyte or oocyte) and thus transmissible to the next generation
    • In meiosis I: failure of homologous chromosome to separate
    • In meiosis II: failure of sister chromatids to separate
  • If non-disjunction occurs during mitosis, after ovum and sperm fuse (post-zygotic): individual will exhibit mosaicism, meaning only some of the cells with be aneuploid. The earlier the mutation occurs in embryogenesis, the greater the number of aneuploid fetal cells.
  • The mechanism of non-disjunction in mitosis is analogous to that in meiosis II; inability of sister chromatids to separate results in 1:1 ratio of (2n+1):(2n-1) in daughter cells.
  • Example: non-disjunction occurs in a cell in meiosis I to yield two daughter cells (2n+1) and (2n-1). These then divide in meiosis II to yield (n+1), and (n-1) daughter cells respectively.

2)    Anaphase Lag

  • Definition: delayed movement of a chromosome or chromatid during anaphase resulting in loss of the genetic material from inclusion into either daughter nucleus
  • Can occur during meiosis or mitosis
  • Normally, individuals are disomic for each gene (meaning the dosage of each gene is two)
  • Common aneuploid abnormalities are monosomy (loss of one chromosome) and trisomy (gain of an extra chromosome). Tetrasomy can also occur, but it is rare.
  • Autosomal constitutional monosomy is lethal in the womb and all living individuals with monosomic cells exhibit mosaicism. This is because all chromosomes have genes required for normal embryological development.

Euploidy = number of chromosomes is a multiple of 23; this definition includes normal human diploid cells and polyploidy

Polyploidy = number of chromosomes is a multiple of 23 and greater than 46; constitutional polyploidy is not compatible with human life (but is common amongst plants)

  • Polyploidy is normal in some human cell lines, e.g. osteoclasts, megakaryocytes.
  • Accounts for ~20% of abortions.
  • 2/3 of cases of triploidy (23 ´ 3 = 69 chromosomes) are caused by fertilization of one egg by two sperm. Other causes include fusion of a diploid ovum and a normal haploid sperm, or vice versa.

Risk factors: increased maternal age is not associated with polyploidy, but is associated with aneuploidy, and especially meiotic non-disjunction (risk increases with advancing maternal age starting at 35 years old).

  • In normal female embryos, developing oocytes are arrested in prophase I, with homologous chromosomes joined at chiasma (the points of crossover).
  • Meiosis I, and thus the first division, of each oocyte is only completed prior to its ovulation after the individual reaches puberty.
  • This period of latency between the initiation and completion of meiosis I can be decades long and is believed to account for the increasing risk of aneuploidy with increasing maternal age. The exact mechanism is unknown.
    • The leading hypothesis: based on recent studies in mice it has been shown that with increasing maternal age there is a decrease in the integrity of the proteins holding both homologous chromosomes and sister chromatids together (cohesins), which increases the chances of faulty segregation.
      Biol Reprod. 2012 Jan 10;86(1):1-7.
      Congenit Anom (Kyoto). 2012 Mar;52(1):8-15.

Sex chromosome aneuploidy: an abnormal number of either the X or Y chromosome exists resulting in neither the classical XY male nor XX female. Mechanisms are the same as those in autosomal aneuploidy. Example: 45,XO = Turner syndrome.

Diagnosis: cytogenetics

Screening: refer to prenatal screening for further details on obtaining fetal samples

Down syndrome (trisomy 21) in brief

Pediatrics. 2011 Aug;128(2):393-406. (current AAP guidelines on caring for children with Down syndrome)

Definition: most common genetic cause of intellectual disability, marked by classic facies and multi-organ involvement. Is caused by trisomy 21, which can be the result of non-disjunction (95%), chromosomal translocation (4%), or mosaicism (1%).

Clinical features

Life expectancy: 50-55 years of age

CNS: variable degree of intellectual disability, hypotonia

Craniofacial: flattened occiput, upslanting palpebral fissures, epicanthal folds, small nose, flat nasal bridge, flat face, small dysplastic pinnae, protruding tongue

Cardiac: congenital heart defects (AVSD, VSD, Tetralogy of Fallot, ASD, PDA)

MSK: hands (single transverse palmar crease, broad hands, fifth digit clinodactyly), joint hyperflexibility, redundant neck skin, pelvic dysplasia, wide gap between first and second toes (sandal gap), short stature

GI: duodenal and anorectal atresia, umbilical hernia

Ophthalmic: Brushfield spots

Males with Down syndrome are generally infertile. Females are typically capable of reproducing with a 50% chance of having a Down syndrome child.

Are at an increased risk for:

  • Hearing loss
  • Obstructive sleep apnea
  • Cataracts
  • Hypothyroidism
  • Hirschsprung Disease
  • Transient myeloproliferative disorder
  • Leukemia: ↑ acute myelogenous leukemia (AML) before age 4; ↑ acute lymphoblastic leukemia (ALL) after age 4
  • Alzheimer disease-like dementia: chromosome 21 has the gene for amyloid precursor protein (APP). Increased amyloid deposition in CNS tissues is associated with cognitive decline.


Prenatal or postnatal karyotype


  • First trimester: fetal nuchal translucency on ultrasound (increased), measurement of maternal free beta-human chorionic gonadotropin (increased in Down syndrome pregnancies), and pregnancy-associated plasma protein A (decreased)
  • Second trimester: quad screen with the following serum tests (relative expected level in Down syndrome pregnancies):
    • Beta-human chorionic gonadotropin (increased)
    • Unconjugated estriol (decreased)
    • Inhibin-A (increased)
    • Alpha-fetoprotein (decreased)

Refer to Prenatal screening for further details.