Uniparental Disomy: Causes and Effects

Uniparental disomy (UPD) is a genetic anomaly that, while rare, presents significant implications for human health. This condition arises when an individual inherits two copies of a chromosome, or a segment of a chromosome, from one parent and none from the other. This deviation from normal biparental inheritance can lead to a myriad of clinical manifestations, ranging from benign to severe.

What Is Uniparental Disomy?

Uniparental disomy occurs when both copies of a chromosome come from a single parent. This can happen due to errors in meiosis or mitosis, the cellular processes responsible for distributing chromosomes during reproduction and cell division, respectively. UPD is classified into two types:

Heterodisomy: This occurs when a child inherits two different chromosomes from one parent due to a nondisjunction event in meiosis I.
Isodisomy: This occurs when a child inherits two identical chromosomes from one parent, usually due to an error in meiosis II or postzygotic duplication.

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Causes of Uniparental Disomy

UPD is often a result of a phenomenon known as trisomy rescue. Initially, three copies of a chromosome are present (trisomy), but one is lost to return the cell to a normal diploid state. If the two remaining chromosomes are from the same parent, UPD results. Additionally, UPD can occur through monosomy rescue or compensatory UPD, where a missing chromosome from one parent is compensated by duplicating the chromosome from the other parent.

Symptoms of Uniparental Disomy

The clinical manifestations of UPD depend largely on the specific chromosomes involved and whether those chromosomes carry imprinted genes. Imprinted genes are expressed in a parent-of-origin-specific manner, meaning the gene from one parent is "silenced" while the other is active. Disruption of normal imprinting can lead to various syndromes and diseases.

Commonly Affected Chromosomes

Chromosome 15: UPD of chromosome 15 is associated with Prader-Willi syndrome and Angelman syndrome. In Prader-Willi syndrome, the paternal chromosome is missing, while in Angelman syndrome, the maternal chromosome is absent.
Chromosome 11: This can lead to Beckwith-Wiedemann syndrome, characterized by overgrowth and an increased risk of childhood tumors.
Chromosome 7: Maternal UPD of chromosome 7 is linked to Russell-Silver syndrome, which results in growth retardation and asymmetry.

General Symptoms

Developmental delays
Intellectual disabilities
Physical growth abnormalities
Behavioral issues

The severity and presence of symptoms can vary widely, even among individuals with the same type of UPD.

Diagnosis of Uniparental Disomy

Diagnosing UPD requires a combination of genetic testing and clinical evaluation. Some of the primary methods include:

Karyotyping: This involves examining the size, shape, and number of chromosomes in a sample of body cells to identify any abnormalities.
Methylation Analysis: This test assesses the imprinting status of genes on the chromosome suspected of UPD. It can confirm conditions like Prader-Willi and Angelman syndromes by detecting abnormal methylation patterns.
Microsatellite Analysis: By comparing the DNA sequences of the child with those of the parents, this analysis can determine the parental origin of chromosomes.
Chromosomal Microarray Analysis: This is a high-resolution method that can detect small deletions or duplications that might indicate UPD.

Early diagnosis is crucial for managing symptoms and improving the quality of life for affected individuals.

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Treatment for Uniparental Disomy

Currently, there is no cure for UPD. Treatment focuses on managing symptoms and supporting the individual’s developmental and medical needs.

Symptomatic Management

Developmental Therapies: Interventions such as physical, occupational, and speech therapy can help mitigate developmental delays and improve quality of life.

Medical Management: Regular monitoring for associated health issues, such as obesity in Prader-Willi syndrome or tumor surveillance in Beckwith-Wiedemann syndrome, is essential.

Behavioral Interventions: Addressing behavioral issues with appropriate therapeutic strategies can be beneficial.

Genetic Counseling

Genetic counseling is recommended for affected families to understand the inheritance pattern, recurrence risks, and implications for future pregnancies.

Management of Uniparental Disomy

Managing UPD involves a multidisciplinary approach, with input from geneticists, pediatricians, endocrinologists, and other specialists as needed. Regular follow-ups and individualized care plans are essential to address the unique needs of each patient.

Long-term Care Considerations

Regular Health Assessments: Continuous monitoring of growth, development, and potential complications is critical.
Family Support and Education: Providing resources and support to families can help them navigate the challenges associated with UPD.