Chromosome Alterations

Nondisjunction in Meiosis

Failure of homologous chromosomes or sister chromatids to separate properly during cell division, resulting in gametes with abnormal chromosome number (aneuploidy)

Causes of Nondisjunction

Errors in spindle fiber attachment; Cohesin protein defects; Advanced maternal age; Abnormal recombination; Environmental factors (toxins, radiation)

Nondisjunction in Meiosis I

Occurs in Anaphase I when homologous chromosomes fail to separate, producing two gametes with (n+1) and two with (n−1)

Nondisjunction in Meiosis II

Occurs in Anaphase II when sister chromatids fail to separate, producing two normal gametes, one (n+1), and one (n−1)

Fertilization after Nondisjunction

Produces abnormal zygotes: Trisomy (2n+1) or Monosomy (2n−1); Examples: Trisomy 21 → Down syndrome, Monosomy X → Turner syndrome, Trisomy 18 → Edwards syndrome, Trisomy 13 → Patau syndrome

Syndrome

A set of signs and symptoms that occur together and characterize a condition (e.g., Turner Syndrome)

Disorder

A disruption of normal physical or mental functions, may or may not have a known cause (e.g., anxiety disorder)

Disease

A pathological condition with a known cause, progression, and symptoms, often caused by infection, genetics, or environment (e.g., tuberculosis)

Klinefelter Syndrome

Male with XXY; small testes, infertility, lower IQ, tall stature, poor muscle tone, reduced secondary sexual traits, gynecomastia; May have variants XXXXXY or XXYY; Risk of osteoporosis, breast cancer; Normal lifespan with treatment

Supremacy Y Syndrome (XYY)

Male with extra Y chromosome; Taller than average, normal male appearance, impulsivity, average intelligence; May have learning and speech delays; Normal lifespan and fertility

Triple X Syndrome (Metafemale)

Female with XXX; Normal appearance, limited fertility, sometimes taller stature or learning disabilities; Normal lifespan

Turner Syndrome

Female with XO; Short stature, webbed neck, sterile, poor breast development, normal intelligence; May have heart/kidney problems; Treated with growth hormone and estrogen

Deletion

Loss of a chromosome fragment; Severe if large; Example: Cri du Chat (5p deletion)

Types of Deletion

Terminal deletion (end of chromosome); Interstitial deletion (within chromosome); Microdeletion (small, detected with molecular methods, e.g., Williams, DiGeorge)

Cri du Chat Syndrome

Deletion of 5p; Cat-like cry, microcephaly, intellectual disability, low birth weight, hypotonia, distinct facial features; High infant mortality; Treated with therapy

Wolf-Hirschhorn Syndrome

Deletion of 4p; Distinct facial features, broad nasal bridge, high forehead, seizures, developmental delay, “greek warrior helmet”

Jacobsen Syndrome

Terminal deletion of 11q; Features include widely set eyes, droopy eyelids, macrocephaly, thin lips, low ears; Developmental delays, platelet deficiency

Duplication

Chromosome fragment joins homologous chromosome

Types of Duplication

Interchromosomal (to different chromosome); Intrachromosomal (within same chromosome); Direct tandem (same orientation, adjacent); Reverse tandem (opposite orientation, adjacent); Displaced tandem (elsewhere on chromosome); Terminal tandem (at end of chromosome)

Cat-eye Syndrome

Inverted duplication of chromosome 22; Anal, heart, kidney, genital, skeletal, and abdominal defects; Cleft palate; Short stature; Abnormal facial features

Edward’s Syndrome (Trisomy 18)

Severe disability, small head/jaw, low birth weight, clenched fists, heart defects; Most die in infancy; Rare survival beyond childhood

Patau Syndrome (Trisomy 13)

Three copies of chromosome 13; Severe growth defects, heart problems, spinal issues, profound intellectual disability; Most infants die within first year

Inversion

Fragment reattaches in reverse orientation; All genes present but order altered, causing abnormal recombination

Types of Inversion

Paracentric (excludes centromere, both breaks in one arm); Pericentric (includes centromere, breaks in both arms)

Hemophilia A

Sex-linked disorder often involving X-chromosome inversion disrupting Factor VIII; Prolonged bleeding; Severity depends on Factor VIII levels; Treated with factor replacement

Translocation

Chromosome fragment attaches to a non-homologous chromosome

Types of Translocation

Reciprocal (exchange between two chromosomes, may be balanced or unbalanced); Robertsonian (fusion of two acrocentric long arms, short arms lost; chromosomes 13,14,15,21,22); Unbalanced (extra or missing genetic material in offspring)

Clinical Effects of Translocation

Some Down syndrome cases caused by Robertsonian translocation of chromosome 21; Associated with cancers and congenital disorders

Chronic Myelogenous Leukemia (CML)

Reciprocal translocation between 9 and 22 (Philadelphia chromosome); Activates oncogene causing leukemia

Robertsonian Translocation

Balanced carriers normal, can pass for generations; Unbalanced forms lead to disorders or miscarriage; Often chromosomes 13,14,15,21,22; Fusion at centromere with loss of short arms