Uniparental Disomy

upd(6)pat

Russell-Silver syndrome – upd(7)mat

Beckwith-Wiedemann syndrome (BWS) – upd(11)pat

upd(14)mat

upd(14)pat

Prader-Willi syndrome – upd(15)mat

Angelman syndrome – upd(15)pat

Epidemiology and Etiology:

• A set of homologous chromosomes are both inherited from one parent
• Nondisjunction is most common mechanism
• Resulting conceptus has 3 copies or 1 copy of the chromosome
• “rescue event” (postfertilization)
• Trisomy rescue:
• loss of one of the extra chromosomes
• monosomy rescue (rare):
• duplication of the single chromosome
• more commonly as an isochromosome rather than a second “free” chromosome
• The diploid cell has a survival advantage compared to the trisomic or monosomic cells
• Note that most nondisjunction occurs in maternal meiosis I
• Therefore maternal UPD is more likely
• And in the rare case of monosomy rescue, paternal UPD is more likely
• Heterodisomy is most common (2 homologous chromosomes from the same parent)
• Regions of isodisomy may result from meiotic recombination
• Isodisomy is the result with monosomy rescue
• Other mechanisms
• Postfertilization error
• Mitotic nondisjunction and loss of the monosomic chromosome or vice versa
• Double recombination in the presence of heterodisomy
• resulting in isodisomy of a small segment of a chromosome
• (somatic recombination or gene conversion) (not involving the whole chromosome)
• Gametic complementation
• Fertilization of a disomic gamete by a nullisomic gamete
• Somatic replacement of a derivative chromosome
• risk factors:
• mosaicism (ex. A mixture of trisomic and diploid cells)
• or trisomic CVS and diploid amnio
• risk in mosaic trisomy 15 found in CVS is 11-25%
• structurally abnormal chromosome
• Robertsonian translocation
• risk is 0.6%
• Isochromsome of acrocentric chromosome
• high risk (66%)
• others?
• recessive genetic disease
• known UPD syndrome

Common sites:

Gross features:

Histologic features:

Immunophenotype:

Marker:

Sensitivity:

Specificity:

Molecular features:

• Testing:
• Short tandem repeat markers by multiplex PCR
• Parental bloods are tested along with the fetal / child’s sample
• At least 2 fully informative loci required to confirm or rule out UPD
• At least one other chromosome should be tested to demonstrate biparental inheritance
• Note that this testing can potentially uncover nonpaternity
• UPD testing guidelines

Other features:

• Prenatal testing for future pregnancies after a child with UPD is not indicated (unless another indication is present)
• No case of UPD recurrence has been reported to date
• Nomenclature:
• Ex. Upd(14)mat
• Presence of genomic imprinting in UPD chromosomes results in phenotypic effects
• ~100 genes estimated to be imprinted in the human genome
• Clustered in a small number of regions:
• 6q23
• 7p15
• 7q22
• 7q32
• 11p13
• 11p15
• 14q32
• 15q12
• Definite phenotypic effect for UPD has been demonstrated for:
• Maternal: 7,14,15
• Paternal: 6,11,14,15
• Unclear phenotypic effect for UPD:
• Maternal: 2,16,20
• Paternal: 20
• isodisomy may bring out a recessive disease if a mutant allele is present

History:

• UPD introduced by Engel in 1980.

References:

• Kotzot D. Prenatal testing for uniparental disomy: indications and clinical relevance. Ultrasound Obstet Gynecol. 2008;31(1):100-5.
• Shaffer LG, Agan N, Goldberg JD, et al. American College of Medical Genetics statement of diagnostic testing for uniparental disomy. Genet. Med. 2001;3(3):206-211.
• Shaffer LG. Risk estimates for uniparental disomy following prenatal detection of a nonhomologous Robertsonian translocation. Prenat. Diagn. 2006;26(4):303-307.

o CCMG Guidelines: Prenatal and Postnatal Diagnostic Testing for Uniparental Disomy (UPD). Clinical Genetics (in press, 2010).