## Chromosomal Basis of Down Syndrome **Key Point:** Trisomy 21 resulting from nondisjunction during meiosis accounts for ~95% of all Down syndrome cases. ### Classification of Down Syndrome | Type | Frequency | Mechanism | Karyotype | Recurrence Risk | | --- | --- | --- | --- | --- | | **Nondisjunction trisomy 21** | ~95% | Failure of chromosome 21 separation during meiosis I or II | 47,XX,+21 or 47,XY,+21 | ~1% (maternal age-dependent) | | **Robertsonian translocation** | ~3–4% | Fusion of chromosome 21 with another acrocentric chromosome (usually 14) | 46,XX,der(14;21) or 46,XY,der(14;21) | ~10–15% if mother is carrier | | **Mosaic Down syndrome** | ~1–2% | Nondisjunction after fertilization; some cells trisomic, others diploid | 46,XX,21/47,XX,+21 | <1% | | **Isochromosome 21q** | <1% | Rare; duplication of 21q arm | 47,XX,+21,i(21q) | Variable | **High-Yield:** Nondisjunction is the most common cause and is strongly associated with **advanced maternal age** (risk increases exponentially after age 35). **Clinical Pearl:** Robertsonian translocation is the only form with significantly elevated recurrence risk in future pregnancies if a parent is a balanced carrier — this is why karyotyping of parents is essential in all Down syndrome cases. ### Why Nondisjunction Predominates Nondisjunction occurs due to failure of proper chromosome segregation during meiosis, particularly in oocytes that have been arrested in prophase I for years or decades. The longer the oocyte arrest, the greater the risk of cohesion failure between sister chromatids, leading to nondisjunction. This explains the strong maternal age effect. 
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