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Author: Laurie Ann Demmer, M.D.
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Clinical Cytogenetics (Part II)


Jorde, Carey, Bamshad & White: Medical Genetics, 3rd edition, C.V. Mosby Publishing, 2005.

  • Chapter 6, 111-132

Chromosome Abnormalities

Chromosome Abnormalities can be divided into 2 types: numerical and structural.

In general a balanced karyotype (no missing or extra pieces of chromosomes) is necessary in order to produce a ‘normal’ individual. Unbalanced karyotypes involving autosomes almost always result in pregnancy loss, or live born with congenital abnormalities and mental retardation. Sex chromosome aberrations, however, result in much less severe distortion of phenotype. In fact, most females with XXX and males with XYY remain undiagnosed.

Numerical Abnormalities

  1. Aneuploidy
    1. -monosomy (45,X : Turner Syndrome)
    2. -trisomy (47,XY,+21 : Down Syndrome)
    3. -tetrasomy (48,XXXX)
  2. Polyploidy
    1. -triploidy (69,XXY)
    2. -tetraploidy (92,XXYY)

Structural Abnormalities

  1. Translocation – balanced vs. unbalanced
    1. Reciprocal (46,XY, t(2,4)(p23;q25))
    2. Robertsonian (45,XX, der(13;14)(q10;10))
  2. Deletions (46,XX, del(1)(q21))
  3. Inversions
    1. Paracentric (46,XX,inv(X)(p12p21))
    2. Pericentric (46,XX,inv(9)(p12q12))
  4. Ring Chromosome (46,XX,r22) 5. Isochromosome (46,X, i(Xq); Turner Variant)

Incidence of Chromosome Abnormalities

15-20% of all recognized pregnancies end in spontaneous abortion. 50% of all first trimester abortions have a chromosome abnormality. It is likely that the incidence of chromosome abnormalities at the time of conception is significantly higher than 15-20%, with most resulting zygotes/embryos being so abnormal that survival beyond the first few days/weeks of pregnancy is not possible.

Chromosome Abnormalities

Down Syndrome (Trisomy 21)


1:700. Strong association between the incidence of Down Syndrome and advancing maternal age.

Clinical Features

The most common features in the newborn period are flat facial profile, upward slanting palpebral fissures with epicanthal folds, small ears, nose and mouth, with protruding tongue, congenital heart disease, and hypotonia. 50% of babies with Down syndrome will have a single palmar crease and at least 50% will have clinodactyly.

Natural History

Range of IQ is broad but generally falls in the 25-75 region, with moderate mental retardation. Social skills are relatively advanced, and children with Down syndrome tend to be happy and affectionate. Short stature (adult height of about 150 cm) and microcephaly are common. Life expectancy is around 50 years with early Alzheimers disease very common. The presence of a severe cardiac anomaly, or leukemia, can result in early childhood death.

Chromosome Findings

95% of Down syndrome is due to Trisomy 21. Chromosome analysis should always be obtained when Down syndrome is suspected to distinguish between Trisomy 21, mosaicism (which can be less severe), and translocation (which can be secondary to a familial translocation in 1/3 of cases).

Recurrence Risk

For straightforward Trisomy 21 the recurrence risk is generally 1% or less, but can be higher with advanced maternal age. In translocation cases that are not familial, the recurrence risk is less than 1%. However if the translocation is inherited from the mother, the recurrence risk is 10-15%. If the translocation is inherited from the father, the recurrence risk is 1-3%. If the translocation is an inherited 21q21q, then the recurrence risk is 100%, as all gametes of the carrier parent will be abnormal. Prenatal diagnosis by either chorionic villous sampling or amniocentesis is routinely offered to all couples who have previously given birth to a baby with Down Syndrome.

Recurrence Risk

Trisomy 18 (Edwards Syndrome)


1-2:6000 liveborns

Clinical Findings

Prenatal growth deficiency, microcephaly, micrognathia, small mouth, congenital contractures, low-set ears, prominent occiput, overlapping fingers, congenital heart disease, rocker bottom feet.

Natural History

Many Trisomy 18 infants are stillborn or die shortly after birth. Infants are quite feeble and have a significantly limited capacity for survival. 50% of infants die within the first week and 95% die by the end of the first year. Development is severely delayed in long-term survivors.


More than 95% are complete Trisomy 18. Mosaicism is also possible, but rare. As in all trisomies, there is a strong maternal age effect.

Trisomy 13 (Patau Syndrome)


1-2:10,000 liveborns

Clinical Findings:

  • Oral-facial clefts
  • Microphthalmia
  • Microcephaly
  • Cardiac anomalies
  • Polydactyly of hands and/or feet
  • CNS malformations and a scalp defect (cutis aplasia) are also common.

Natural History:

Over 80% die within the first month, and 95% die within 6 months. Like Trisomy 18 infants, long-term survivors have severe developmental delay.


Only 80% of Trisomy 13 cases have straight Trisomy 13. Translocations involving the long arm of chromosome 13 are common, and, can be familial in origin. If a translocation is detected in the infant, the parents should be checked to see if one of them is a carrier of a balanced (Robertsonian) translocation.

Chromosome Deletion Syndromes

Example: 5p- Syndrome

Cri-du-chat syndrome (Cat cry): Infants are often diagnosed by characteristic cat-like cry heard in newborn period, which is thought to be related to abnormal laryngeal development. Dysmorphic features and failure to thrive are typically seen in the newborn period, and severe mental retardation is typical in older children and adults. This is caused by a deletion of the terminal part of chromosome 5 and can be detected either by conventional cytogenetics or FISH. Eighty-five percent of cases result from a sporadic, de novo deletion, however sometimes the syndrome derives from a parental translocation involving 5p.

Sex Chromosome Abnormalities

Turner Syndrome

45,X or variant


1-2/10,000 live born females

Clinical Features:

Prenatal:Common cause of early miscarriage. Some patients are detected by finding increased fluid, swelling, cystic hygroma about the neck, or hydrops (generalized increased fluid or edema).

Birth: 1/3 of babies detected at birth because of residual signs of the prenatal lymph blockage including webbed neck, puffy hands and feet, low-set, rotated ears. Other findings include (usually left-sided) congenital heart disease, low posterior hairline, increased carrying angles at the elbows, short fourth metacarpals, widely spaced nipples.

Childhood: 1/3 of Turner patients are detected during childhood, usually due to short stature.


  • 1/3 of patients are diagnosed when they present with delayed puberty.
  • Intelligence is usually normal.
  • Short stature is treated with growth hormone.
  • Delayed puberty is treated with estrogen replacement therapy.
  • Patients with complete Turner syndrome generally have streak (essentially absent) ovaries.
  • Pregnancy has been achieved via in vitro fertilization and egg donation.

Chromosome Findings

Chromosome Findings

Only about ½ of Turner patients are complete 45,X. Mosaicism and X chromosome variants are also common. The phenotype in mosaicism and variants can vary significantly between normal and complete Turner syndrome.

Klinefelter Syndrome (47, XXY)


1:1000 male liveborns

Clinical Features

Affected children often have learning disabilities and social immaturity. IQ is usually in normal range, but often 10-15 points below that of siblings. On average, males with Klinefelter are relatively tall with long legs. About 50% have gynecomastia and 100% have testes that remain small, even after puberty. Testosterone replacement is essential for the development of secondary sexual characteristics and to decrease the risk of osteoporosis. Adults are generally infertile due to low sperm counts, however, pregnancy has been achieved by obtaining sperm via testicular biopsy.

Chromosome Findings

47,XXY is the usual karyotype. Rarely, males with more than two X chromosomes are encountered as well (48,XXXY or 49,XXXXY), although these males are generally mentally retarded.

XYY Males


1:1000 live born males

Clinical Features

Physical appearance is usually normal, stature is often above average. Intelligence is usually normal, although IQ scores are often 10-15 points below that of siblings. Emotional immaturity and impulsive behavior are common.

Chromosome Findings

This is usually as a result of non-disjunction in paternal meiosis II, or as a postzygotic mitotic non-disjunction.

XXX Females


1:1000 live born females

Clinical Features

Physical appearance is usually normal. IQ is generally 10-15 points below that of siblings. Verbal language is often delayed. Women with 47,XXX karyotypes usually have normal fertility but there is an increased incidence of fertility problems compared to the normal population. Their children usually have normal chromosomes, but there is a (theoretical) risk of having XXX or XXY offspring.

Chromosome Findings

  • 47,XXX
  • The extra X chromosome is usually maternal in origin and often associated with advanced maternal age.
  • Women with more than three X chromosomes have a high incidence of mental retardation.

Sub-microscopic Deletions: Contiguous Gene Syndromes

A deletion too small to be seen by conventional cytogenetics, can sometimes be detected by FISH techniques. Several contiguous genes are deleted, resulting in a clinically recognizable syndrome. This is most often a sporadic deletion, but can be inherited from one of the parents in a dominant fashion.

Examples of Common Contiguous Gene Syndromes

Prader Willi chromosome 15
Angelman chromosome 15
Velo-Cardio-Facial/DiGeorge chromosome 22
Williams chromosome 7

Miller-Dieker (lissencephaly)

chromosome 17