Vol. 009
Uniparental Disomy

Uniparental Disomy【Abstract】
Uniparental disomy (UPD) is a unique phenomenon when an individual receives both copies
of a homologous chromosome pair from one parent only and no copies from the other parent.
Typically, a person should receive one copy from each parent. UPD is usually a sporadic event as aresult of errors in sperm/egg formation or in early embryonic/fetal development.
UPD is not associated with gains or losses of chromosomal segments or genes. However, UPD
occurring at chromosomes carrying imprinting genes can lead to clinically pathogenic syndromes
as imprinting genes rely on bi-parental inheritance to ensure proper expression and function.
A case example of UPD disorder is presented—a 3-year-old female with motor and speechdelays, social pervasive developmental delay and abnormal eye movement, who has complete
UPD of chromosome #15 [UPD(15)] detected by using a microarray platform with single nucleotide
polymorphism (SNP) probes. UPD(15) can be associated with Angelman syndrome, which wasconsistent with the clinical phenotype observed in this female child. Counseling points related tothis case are discussed. The concept of UPD and known UPD disorders, as well as a shortoverview of Angelman syndrome are also included.

【Case Example】
Tiffany is three years old. She is delayed in her motor and speech skills. She also has
behavioral issues of pervasive development delay. Her eye movement is also concerning. Tiffany’s
parents are concerned and brought her to get evaluated by a pediatric neurologist. Besides
wanting to understand how to best care for their daughter, Tiffany’s parents are also curious as towhy Tiffany has such challenges.
Based on Tiffany’s clinical findings, the neurologist suspected Tiffany may have an underlying
congenital genetic abnormality. After discussion with the family, a microarray array with SNPprobes (SNP array) was elected and performed. Identification of the underlying cause for Tiffany’s
health issues not only provides Tiffany’s family with an answer, but can also help the medical teamunderstand her disease prognosis, treatment options, and potential other complications.
Furthermore, whether Tiffany’s issues are hereditary can be clarified once a disease-causing
reason is found. Recurrence risk as well as reproductive testing options can be provided to Tiffany’s

GGA Corp. Genetic Counseling Newsletter – Vol. 009
Uniparental Disomy

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relatives to prevent birth of another child having to experience the same difficulties as Tiffany.
Tiffany’s SNP array showed interesting results. There were no gains or losses of chromosomalsegments; however, a loss of heterozygosity (LOH) of the entire chromosome #15 was present. Thisis consistent with uniparental disomy (UPD) of chromosome #15.
If both chromosome #15 are inherited from the mother only, it is called maternal UPD(15).
Maternal UPD(15) is associated with Prader-Willi syndrome. On the other hand, paternal UPD(15),when both chromosome #15 are inherited from the father, can lead to Angelman syndrome (AS).
Based on Tiffany’s SNP array result of LOH alone, it is not possible to distinguish between
maternal and paternal UPD(15). Further testing is needed, such as comparing Tiffany’s SNP array
result with both of her parents’ SNP array results, or using a different testing platform to assessparent-specific methylation patterns.
The clinical presentation of Prader-Willi syndrome and AS is quite different. Based on clinicalevaluation, Tiffany’s symptoms are consistent with that of AS. Finding out the underlying cause of
Tiffany’s clinical issues allows her medical team as well as her family to provide her with the bestcare she deserves.

Copy Number

3
Copy number variant (CNV):
CNV probes showed the same pattern for
chromosomes #14, #15 and #16.
There are two copies of eachchromosome, as normally expected.

21

Chromosome analysis(Karyotype)
Chromosomes #15 are numericallyand structurally normal

SNP Genotype Calls

Chr. 14

Chr. 15

Chr. 16
SNP allele difference:
The pattern for SNP genotype calls ofchromosome #15 is clearly different thanthose of chromosomes #14 and #16.

AAAB

A normal SNP genotype call pattern shouldhave three types--AA, AB, and BB.
Appearance of only two types--AA and BB
only--is called LOH. LOH can beassociated with UPD.

BB

SNP array result of case presented
Chromosomes #14, #15 and #16

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GGA Corp. Genetic Counseling Newsletter – Vol. 009
Uniparental Disomy

3【Counseling Discussion】
1.

Often times, a cure may still not be available for a child with congenital anomalies and/ordevelopmental delays even after an underlying cause of the abnormalities is identified.
However, understanding the underlying cause is still important not only to provide ananswer, but also to better understand the child’s prognosis, treatment options and prevent
other complications. Identifying a cause also clarifies the recurrence risk and theappropriate reproductive testing options for at-risk family members.

2.

The presenting clinical features of many genetic disorders are often similar and overlap
with one another. Sometimes, it is quite challenging to pinpoint one specific genetic
disorder as the working diagnosis. Selecting a genetic test that only screens for one genetic
condition may not be an easy, effective and/or cost-saving option.

3.

Practice guideline released by the American College of Medical Genetics in 2010 had
recommended microarray to be the first-line test in the initial postnatal evaluation ofindividuals with 1) multiple anomalies not specific to a well-delineated genetic syndrome, 2)apparently non-syndromic developmental delay/intellectual disability and 3) autism
spectrum disorders.

4.

Compared to G-banding chromosome analysis, microarray test allows simultaneous
evaluation of gains and losses of not only large chromosomal segments but also small
chromosomal pieces beyond those detectable by G-banding, i.e. microdeletions andmicroduplications. Microarray platforms that include SNP probes can additionally screen
for UPD disorders.

5.

Genotype calls can be inferred using data readings provided by the SNP probes. Thisevaluates the presence of LOH status, which can be associated with UPD disorders.
With SNP probes, it is possible to infer whether the genotype at a chromosome positionis AA, AB or BB.

If a large chromosomal region shows only homozygous “AA” or “BB” genotypes without
mixed of heterozygous “AB” genotype, then it is called a region of “loss of heterozygosity”(LOH).

LOH is neither associated with changes in the number or the structure of thechromosomes, nor directly pathogenic and disease-causing.

Reasons for LOH:
1) Biparental inheritance: The chromosome pair was inherited as expected—onechromosome from the father and one from the mother, and the fetus/childThis newsletter is produced and owned by GGA Corp.
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GGA Corp. Genetic Counseling Newsletter – Vol. 009
Uniparental Disomy

4coincidentally received identical genotypes from both parents. This generally does notdirectly lead to clinically abnormal disorders, though the risk for recessive disorders may
be increased.
2) Uniparental inheritance: Both chromosomes of a homologous pair were inheritedfrom a single parent only (meaning the two chromosomes of the same number camefrom only one parent). Clinically, this may lead to UPD disorders and abnormalsymptoms.
6.

UPD of specific chromosomes is associated with clinical abnormality.
UPD occurring at chromosomes carrying imprinting genes will lead to abnormal growth anddevelopment due to disruption of normal gene expression and function.

7.

UPD disorders are mostly sporadic. The recurrence risk for sibling of an affected individualis low.

8.

Having an abnormal microarray results does not always mean the chromosome analysis
result will be abnormal as well.
Different genetic testing methodology evaluates different types of genetic changes.
Every testing methodology and platform has its own advantages and disadvantages aswell as applicable situation.

Because UPD will not cause numerical or structural changes in chromosomal segments
and genes, testing platforms that only evaluate such variations, such as G-banding
chromosome analysis or microarray without SNP probes, would not be able to detect
UPD disorders.

Uniparental Disomy
Typically, a pair of homologous chromosomes should be inherited from both parents, i.e. one
chromosome from the father and one from the mother. When a person receives both copies of ahomologous chromosome pair from one parent only and no copies from the other parent, thenit is called “UPD”. UPD can involve an entire chromosome or just part of a chromosome. Paternal
UPD implies both copies of chromosomes are from the father only, i.e. no copy from the mother;whereas maternal UPD refers to when both copies are from the mother, i.e. no copy from thefather.

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GGA Corp. Genetic Counseling Newsletter – Vol. 009
Uniparental Disomy

5UPD can be further categorized into uniparental isodisomy or uniparental heterodisomy (seediagram below). Both subtypes can cause clinical pathogenicity.

ParentOffspring

Possible mechanisms leading to UPD:
1. Trisomy rescue: An embryo containing three copies of a chromosome (trisomy) andsubsequently loses one of the three chromosomes through self-rescue
2. Monosomy rescue: An embryo containing only one copy of a chromosome (monosomy) andsubsequent duplication of this chromosome occurs through self-rescue
3. Gamete complementation: Fertilization between a gamete with two copies of the same
chromosome and a gamete with no copies of that particular chromosome
4. Postzygotic/Post-fertilization error: Meiotic errors of an embryo originally with disomy
chromosomes
Molecular methodologies to detect UPD:

Polymorphic microsatellite markers
Methylation-specific PCR
Methylation-specific MLPA

Microarray with SNP probes

UPD-related disorders:
Most of the human genes are not dependent on which parent we inherited them from;therefore, as long as the copy number and the function of the genes are correct, they will
generally perform properly as expected. However, there are some genes in which their functions

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GGA Corp. Genetic Counseling Newsletter – Vol. 009
Uniparental Disomy

6and expressions vary depending on the parental origin. They are called the “imprinting genes”.
For these imprinting genes, biparental inheritance—inheriting one copy from the mother andone from the father—is very crucial to ensure proper growth and development of the person.
Only a few chromosomes are currently known to contain imprinting genes. UPD of thesechromosomes results in the lack of bi-parental inheritance of imprinting genes and will lead toabnormal physical and/or mental development.
The table below shows known UPD chromosomes associated with imprinting disorder.

Reference: Kearney (2011)【Reference】


Kearney HM, Kearney JB, Conlin LK. Diagnostic implications of excessive homozygosity detected by SNP-based
microarrays: consanguinity, uniparental disomy, and recessive single-gene mutations. Clin Lab Med. 2011
Dec;31(4):595-613.
Liehr, T. What is uniparental disomy (UPD)? [online] Oxford Gene Technology 2013. [cited 2017 Aug 30].
Available from: http://www.ogt.co.uk/cytosure_whatisUPD.html.
Manning M, Hudgins L; Professional Practice and Guidelines Committee. Array-based technology andrecommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. GenetMed. 2010 Nov;12(11):742-5.
Yamazawa K, Ogata T, Ferguson-Smith AC. Uniparental disomy and human disease: an overview. Am J Med
Genet C Semin Med Genet. 2010 Aug 15;154C(3):329-34.

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GGA Corp. Genetic Counseling Newsletter – Vol. 009
Uniparental Disomy

7【Angelman Syndrome】【Clinical Features】
Most affected patients do not show obvious abnormalities during newborn periods. Birth weightand head circumference are within normal range. Some patients may have feeding or sucking
difficulties and/or hypotonia. Developmental delays are usually first noted at around six monthsof age; however, the unique clinical features of AS typically many not manifest until after one yearof age. For some, it can take several years before the correct clinical diagnosis is made. Life spandata is limited, though it appears to be nearly normal.
Common clinical features:Severe developmental delay or intellectual
disability

Severe speech disability and limited verbal
language skills



Gait ataxia and/or tremulousness of thelimbs, the average child with AS walks
between 2.5-6 years of age

Inappropriate happy demeanor: frequent
laughing , smiling, and excitability

Microcephaly

Seizures, typically occurring between ages one and three years

Reference: GeneReviews【Management】
Symptom-oriented management

Physical therapy, occupational therapy, and speech therapy with emphasis on nonverbal
communication methodsAnti-epileptic medication, such as vigabatrin, tigabine and carbamazepine, should beavoided as they may exacerbate seizures【Prevalence】
1/12,000 - 1/24,000

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GGA Corp. Genetic Counseling Newsletter – Vol. 009
Uniparental Disomy

8【Angelman Syndrome】【Disease-causing Genetic Mechanism】
Abnormality at the q11.2q13 region of chromosome #15Mechanism% of Affected Patients

15q11.2q13 5Mb – 7Mb deletion

65-75%UBE3A gene mutation

11%

Paternal UPD

3-7%

Imprinting defect in the imprinting center

3%

Chromosomal translocation-related changes< 1%Others – unknown mechanism

10-15%【Inheritance Pattern】
Dependent on the underlying disease-causing mechanism of the affected family member;
Recurrence risk can range from <1% to nearly 100%

【Genetic Testing】
Different genetics mechanism requires different molecular methodology to detect, such as
methylation testing, UPD testing, microarray, FISH, gene sequencing and etc.

【Genetic Counseling】
Prenatal
1.

Most affected fetuses do not have ultrasound anomalies.

2.

Routine chromosomal analysis (karyotype) is difficult in detecting AS.

3.

Some of the new non-invasive prenatal tests (using cell-free DNA derived from placenta foranalysis) can detect deletion-type AS. Those with SNP-based analytical platform can also
detect UPD-type AS. These cell-free DNA tests are screening test only. Women whose
pregnancies are found to be at increased risks for AS through these tests should be offeredfollow-up diagnostic tests to clarify true fetal genetic status.

4.

Microarray can detect deletion-type AS. Array platforms that include SNP probes canadditionally screen for some UPD-type AS.

5.

Because of the various genetic mechanism leading to AS and because not all disease-causing
mechanism are yet known, routine prenatal testing cannot rule out all cases of AS toguarantee an unaffected child.

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GGA Corp. Genetic Counseling Newsletter – Vol. 009
Uniparental Disomy【Angelman Syndrome】

Pediatrics
1.

Most affected patients do not show obvious abnormalities during newborn periods. Birthweights and head circumferences are usually within normal range. Some patients may havefeeding or sucking difficulties and/or hypotonia.

2.

Developmental delays may be first noted at around six months of age; however, the uniqueclinical features of AS typically become apparent after one year of age. For some patients, it
can take several years before the correct clinical diagnosis is made. Data on life span islimited, though it appears to be nearly normal.

3.

If clinical features are highly suspicious of AS, targeted AS testing can be considered to ruleout this disorder. However, because not all disease-causing mechanism are fully known,
about 10% of patients with a clinical diagnosis of AS will not have an identifiable genetic
change.

4.

If the clinical features do not obviously suggest AS and/or possibly overlap with many otherconditions, microarray test can be considered to comprehensively assess numericalabnormalities of all the chromosomes while rule out most cases of AS at the same time.

5.

If AS is confirmed, care and management from multi-disciplinary specialties can assist thepatient in achieving his/her greatest potential. Anti-epileptic medication, such as vigabatrin,
tigabine and carbamazepine, should be avoided as they may exacerbate seizures.

【Extended Reading and Reference】
 GeneReviews – Angelman Syndrome [Cited 2017 Aug 30]

https://www.ncbi.nlm.nih.gov/books/NBK1144/
Genetics Home Reference – Angelman Syndrome

https://ghr.nlm.nih.gov/condition/angelman-syndrome

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