chromosomal deletion

DEFINITION: Loss of part of a chromosome, resulting in hemizygosity (partial monosomy) for the missing genes. Deletions can be terminal (loss of a chromosome end) or interstitial (loss of an internal segment). Large deletions are often visible on karyotype. Microdeletions (<5 Mb) need FISH or chromosomal microarray (CMA).

MECHANISMS: Unequal crossover in meiosis (non-allelic homologous recombination) between repeat sequences, which also produces a reciprocal duplication. Chromosome breakage with failure of repair. Unbalanced segregation from a parental translocation or inversion (e.g., a parent with a balanced rearrangement). De novo errors are common.

PATHOPHYSIOLOGY: Haploinsufficiency, where one functional copy does not produce enough gene product. Deletions can also unmask a recessive mutation on the remaining allele. Deletions are generally more severe than duplications of equal size. Phenotype depends on which genes are lost and the deletion size.

HIGH-YIELD DELETION SYNDROMES: - Cri-du-chat (5p-): high-pitched cat-like cry, microcephaly, intellectual disability, VSD, epicanthal folds. - Williams syndrome (7q11.23, elastin gene): elfin facies, supravalvular aortic stenosis, hypercalcemia, outgoing "cocktail party" personality, intellectual disability. Detected by FISH. - 22q11.2 deletion (DiGeorge/velocardiofacial): CATCH-22 (Cardiac defects such as truncus arteriosus and tetralogy of Fallot, Abnormal facies, Thymic aplasia causing T-cell deficiency, Cleft palate, Hypocalcemia from parathyroid hypoplasia). Failure of 3rd/4th pharyngeal pouch development. Increased risk of schizophrenia. - Prader-Willi (paternal 15q11-q13 deletion): hypotonia, hyperphagia/obesity, hypogonadism, intellectual disability. Maternal genes are silenced by imprinting (SNRPN). - Angelman (maternal 15q11-q13 deletion, UBE3A): "happy puppet" with seizures, ataxia, inappropriate laughter, severe intellectual disability. - WAGR (11p13, WT1 and PAX6): Wilms tumor, Aniridia, Genitourinary anomalies, Retardation (intellectual disability). - Langer-Giedion (8q24). - Smith-Magenis (17p11.2). - 1p36 deletion. - Wolf-Hirschhorn (4p-). - Jacobsen (11q-). - Deletion of 5q is seen in myelodysplastic syndrome (5q- syndrome), with macrocytic anemia, normal or high platelets, and response to lenalidomide. - Tumor suppressors: RB1 (13q14) in retinoblastoma, and 17p (TP53) and 5q (APC) deletions in cancers. - Duchenne muscular dystrophy: often a large deletion in the dystrophin gene (Xp21), usually causing a frameshift. - Cystic fibrosis: ΔF508 is a 3-bp deletion, but this is a gene-level (not chromosomal) deletion.

IMPRINTING PEARL: Prader-Willi and Angelman are the same 15q11-q13 region. The parent of origin of the deleted allele determines the phenotype. Methylation studies detect both. A deletion causes about 70% of cases. Uniparental disomy causes most of the rest (maternal UPD in PWS, paternal UPD in Angelman).

DIAGNOSIS: Karyotype (G-banding) for large deletions. FISH for known microdeletions (e.g., 22q11, 7q11.23). Chromosomal microarray is first-tier for developmental delay, congenital anomalies, and autism. Methylation-specific testing for 15q11-q13.

CLINICAL APPROACH: Look for multiple congenital anomalies plus intellectual disability. Most deletions are de novo, with low recurrence risk. Recurrence risk rises if a parent carries a balanced translocation or inversion, so parental karyotype is indicated. Management is supportive and multidisciplinary, with surveillance for associated problems (cardiac, calcium, immune, renal).

CONTRAST WITH OTHER STRUCTURAL ABNORMALITIES: Duplication (extra segment), inversion (paracentric excludes the centromere, pericentric includes it), translocation (Robertsonian or reciprocal), isochromosome (e.g., i(Xq) in Turner syndrome), ring chromosome (deletion of both ends with fusion), and insertion.