Evaluation of patients presenting with mosaicism, confined placental

mosaicism, or Robertsonian translocations, especially those involving

chromosome 6, 7, 14, or 15

 

Evaluation of patients presenting with features of disorders known to be

associated with UPD (eg, Russell-Silver syndrome)

 

Evaluation of disease mechanism in individuals with rare autosomal

recessive disease and only one carrier parent

 

UPD testing is available for all chromosomes; it may also be useful

 for evaluating abnormalities involving chromosomes other than

6, 7, 14, or 15

Molecular Genetics

Uniparental disomy (UPD) occurs when a child inherits 2 copies of

a chromosome from 1 parent and no copies of that chromosome

from the other parent. This error in division occurs during the formation

of egg or sperm cells (meiosis). When an error causing UPD occurs

during meiosis I both chromosome homologs from a single parent are

transmitted, and heterodisomy results. When the error causing UPD

occurs during meosis II or as a postzygotic event, and a single parental

homolog is transmitted to offspring in duplicate, isodisomy results.

Meiotic recombination events within the context of UPD often result in a

mixture of heterodisomy and isodisomy. UPD can involve an entire

chromosome or only a segment. Mosaicism for UPD also occurs, in

combination with either chromosomally normal or abnormal cell lines.  

 

UPD cannot be identified by gross cytogenetic analysis, and requires

DNA-based analysis using multiple polymorphic markers spanning the

chromosome of interest.  Specimens from both parents and the child/fetus

are required, such that markers from each individual can be compared

to determine the presence/absence of UPD. The American College of

Medical Genetics recommends that at least two fully informative loci are

required for result interpretation.

 

Clinical Effects of UPD

When UPD occurs, the imbalance of maternal versus paternal genetic

information for the involved chromosome can be associated with clinical

symptoms in the affected child. UPD does not always impart an

abnormal clinical phenotype however. In fact, while isodisomy can

result in disease due to a recessive allele at any location, heterodisomy

is not expected to result in an abnormal clinical phenotype unless the

involved chromosome or chromosomal segment includes imprinted

genes. Imprinted genes demonstrate differential expression depending

on parent of origin. Disorders that result from UPD of imprinted genes are

not due to a defect in the imprinting mechanism itself, but rather they are

due to an unbalanced parental contribution of normally imprinted alleles

that results in altered expression of imprinted genes.  For example, when

maternal UPD 15 (2 copies of the maternal chromosome 15 instead of

one maternal and one paternal copy of chromosome 15) occurs, it

causes Prader-Willi syndrome due to the lack of paternally expressed

genes at the imprinted site.  

 

UPD has been described for many but not all chromosomes and, as

mentioned previously, the presence of UPD does not always impart

clinical effect. In addition to the rare cases of autosomal recessive

disease that result from isodisomy, clinical syndromes associated with

UPD have been described for only a few chromosomes, including

Russell-Silver syndrome (UPD 7), Prader-Willi syndrome (UPD 15),

Angelman syndrome (UPD 15), and UPD of chromosomes 6 and 14.  

 

When to test for UPD

Determining the clinical relevance of UPD testing can sometimes be

challenging, especially in the prenatal setting. To guide clinical

decision making, the American College of Medical Genetics has

published practice guidelines for UPD diagnostic testing (Shaffer et al,

2001) which are as follows:

 

Testing for UPD in the prenatal setting should be considered when:

-Confined placental mosaicism (level II or III) occurs in CVS and involves

 chromosome 6, 7, 11, 14, or 15.

-Level II mosaicism for amniotic fluid occurs and involves chromosomes

 6, 7, 11, 14, or 15.

-Prenatal identification of a Robertsonian translocation or possible

 isochromosome involving chromosomes 14 or 15 regardless of whether

 the Robertsonian translocation is determined to be familial.

-Prenatal ultrasound detects anomalies associated with known UPD

 syndromes regardless of whether a structural chromosome abnormality

 affecting the suspected chromosome has been identified.

 

Testing for UPD in the pediatric setting should be considered when: 

-Infants or children show multiple congenital anomalies, developmental

 delay or mental retardation, and carry a Robertsonian translocation

 involving chromosomes 14 or 15.

-Newborns or infants have neonatal diabetes mellitus.

-Infants or children show clinical features consistent with Russell-Silver

 syndrome

-Infants or children show clinical features consistent with Beckwith-

 Wiedemann syndrome, have a normal karyotype, and show no

 duplication of 11p15.5 by FISH.

-Abnormal methylation pattern for chromosome 15 is observed in

 conjunction with features of Prader-Willi or Angelman syndrome.

An interpretive report will be provided which will include a risk

analysis (probability of being a carrier).

Per American College of Medical Genetics guidelines, at minimum two

informative markers are required for result interpretation.

 

Reports include interpretation of results and a pedigree illustrating

segregation of marker alleles for the specific chromosome

requested.

UPD may not be detected by our assay in cases where there is low

level mosaicism for a particular chromosome.

 

This test will detect non-paternity.

 

Although UPD testing is available for all chromosomes, prenatal

testing for UPD for chromosomes other than those associated with

known phenotypes should be done only after genetic counseling

involving adequate discussion of risks, benefits, and limitations of

testing. In the prenatal setting, positive UPD results for

chromosomes not associated with known clinical phenotypes may

actually cause more harm than impart benefit.

1.   Schaffer LG, Agan N, Goldberg JD, et  al:  American College

      of Medical Genetics Statement on Diagnostic Testing for

      Uniparental Disomy.  Genet Med 2001;3:206-211

 

2.   Kotzot D, Utermann G:  Uniparental Disomy (UPD) Other than 15:

      Phenotypes and Bibliography Updated. Am J Med Genet 2005;136A:

      287-305

 

3.   Ledbetter DH, Engel E:  Uniparental disomy in humans: development

      of an imprinting map and its implications for prenatal diagnosis. Hum

      Mol Genet 1995;4:1757-1764

 

4.   Berend SA, Horwitz J, McCaskill C, Shaffer LG:  Identification of

      uniparental disomy following prenatal detection of Robertsonian

      translocations and isochromosomes. Am J Hum Genet 2000;

      66:1787-1793

 

5.  D. Kotzot:  Prenatatl testing for uniparental disomy: indications and

      clinical relevance. Ultrasound Obstet Gynecol. 2008:31:100-105