Chromosomal disorders

Chromosomal disorders involve changes visible at the level of whole chromosomes or large chromosome segments. They fall into two broad groups. Numerical abnormalities mean the wrong number of chromosomes — most often a trisomy (three copies) or a monosomy (one copy), which usually arises from nondisjunction, a failure of chromosomes to separate properly during meiosis. Structural abnormalities keep the count normal but rearrange the material through deletions, duplications, inversions, or translocations.

The best known autosomal trisomies are Down syndrome (trisomy 21), Edwards syndrome (trisomy 18), and Patau syndrome (trisomy 13). Incidence of nondisjunction rises with advancing maternal age, and trisomy 18 and 13 carry very high early mortality. Sex chromosome disorders include Turner syndrome (45,X), with short stature, webbed neck, and ovarian dysgenesis, and Klinefelter syndrome (47,XXY), with tall stature, testicular atrophy, and gynecomastia.

Structural changes produce their own recognizable syndromes. Microdeletions cause conditions such as DiGeorge syndrome (22q11.2 deletion) and cri-du-chat syndrome (deletion on the short arm of chromosome 5). A robertsonian translocation can give a phenotypically normal carrier a high risk of producing a trisomic child, and a reciprocal translocation between chromosomes 9 and 22 creates the Philadelphia chromosome of chronic myeloid leukemia. Diagnosis relies on karyotype, fluorescence in situ hybridization, and chromosomal microarray, with cell-free DNA screening and amniocentesis or chorionic villus sampling used prenatally.

USMLE Step 1 genetics questions expect you to match a karyotype or a clinical vignette to the specific disorder and to explain the underlying mechanism, especially nondisjunction versus translocation. CCMA candidates encounter chromosomal disorders more briefly, as one category of disease etiology alongside infectious, nutritional, and degenerative causes.