Trisomy 21 mosaicism in two subjects from two generations

Area of Science:

• Human Genetics
• Cytogenetics
• Cancer Predisposition Syndromes

Background:

• Xeroderma pigmentosum is a cancer-prone hereditary disorder associated with DNA repair defects.
• Chromosome fragility studies are crucial for understanding genetic instability in hereditary diseases.
• Down syndrome (Trisomy 21) is typically characterized by the presence of an extra copy of chromosome 21.

Observation:

• A low proportion of cells with trisomy 21 karyotype (47,XY,+21) was unexpectedly observed in lymphocyte cultures of a xeroderma pigmentosum patient without Down syndrome symptoms.
• This trisomy 21 mosaicism was also detected in the peripheral blood of the patient's healthy father, confirmed by chromosome painting.
• Fibroblast cultures from both individuals did not show the trisomic cell line.

Findings:

• Analysis of chromosome 21 heteromorphism suggested the mosaicism could arise from either a diploid or aneuploid zygote in both father and son.
• The extra chromosome 21 appeared identical in the trisomic cell lines of both individuals, postulating a familial predisposition to mitotic errors like non-disjunction or anaphase lagging.
• Investigations into the centromere separation index and DNA restriction patterns specific to chromosome 21 centromere did not reveal any peculiar features explaining the observed proneness to mitotic errors.

Implications:

• The study highlights the potential for mosaicism in individuals with genetic disorders, even in the absence of typical clinical manifestations.
• It suggests a possible inherited susceptibility to specific chromosomal mis-segregation events, particularly involving chromosome 21.
• Further research is needed to elucidate the underlying genetic mechanisms responsible for this familial predisposition to mitotic errors and its potential long-term health consequences.