chromosomal duplication

DEFINITION: A structural chromosomal aberration in which a segment of DNA is repeated, so the genome has >2 copies of that region (partial trisomy). Duplications can be tandem (adjacent), reverse/inverted, or displaced (elsewhere on the same or another chromosome). Net gain of genetic material is the key point, unlike balanced rearrangements (inversions, reciprocal translocations).

MECHANISMS: - Unequal crossing over in meiosis (misaligned homologous chromosomes or sister chromatids) yields one gamete with a duplication and one with a reciprocal deletion. - Non-allelic homologous recombination (NAHR) between low-copy repeats (segmental duplications) causes recurrent microduplications/microdeletions. - Unbalanced segregation from a parental balanced translocation or inversion carrier (e.g., adjacent-1 segregation or recombination within an inversion loop) produces duplication plus deletion in offspring. - Retrotransposition and replication errors (e.g., fork stalling and template switching) are other causes.

PATHOPHYSIOLOGY: Gene dosage effect. Extra copies of dosage-sensitive genes lead to overexpression. Duplications are generally less severe than deletions of the same region, but large duplications cause developmental delay, intellectual disability, and congenital anomalies. Duplications are also an evolutionary source of new genes (gene families, e.g., globin genes).

HIGH-YIELD EXAMPLES: - Charcot-Marie-Tooth disease type 1A: duplication of PMP22 on 17p12 (HNPP is the reciprocal deletion, from NAHR). Presents as a demyelinating peripheral neuropathy with pes cavus, hammer toes, distal weakness and atrophy ("inverted champagne bottle" legs), and slowed nerve conduction velocity. - MECP2 duplication syndrome (Xq28): males with severe intellectual disability, hypotonia, recurrent infections, and seizures. Loss of MECP2 causes Rett syndrome, so dosage in either direction is harmful. - 22q11.2 duplication: a milder and more variable phenotype than DiGeorge/22q11.2 deletion. - 15q11-q13 duplication (maternal origin): autism spectrum disorder, seizures, and developmental delay. The deletion causes Prader-Willi (paternal) or Angelman (maternal). - 7q11.23 duplication: speech delay and anxiety. The deletion causes Williams syndrome. - 16p11.2 duplication/deletion: autism, schizophrenia, and BMI changes. - Duchenne muscular dystrophy: about 5-10% of cases are due to exon duplications, with the rest mostly deletions. Out-of-frame mutations cause Duchenne and in-frame mutations cause Becker. - Duplication of the whole gene or oncogene (gene amplification) in cancer: HER2/neu in breast cancer, N-myc in neuroblastoma. - Other: Trisomy 21 by Robertsonian translocation shows how extra chromosomal material can arise through translocation. Partial trisomies result from unbalanced translocations.

DIAGNOSIS: Karyotype detects only large duplications (>5-10 Mb). FISH detects targeted regions. Chromosomal microarray (array CGH/SNP array) is the first-tier test for developmental delay, intellectual disability, autism, and multiple congenital anomalies, because it detects copy number variants (CNVs) (gains and losses). MLPA or qPCR can confirm exon-level duplications. Balanced rearrangements are not detected by microarray.

CLINICAL PEARLS: - Parental testing is important to determine whether the duplication is de novo or inherited. Incomplete penetrance and variable expressivity are common for recurrent CNVs. - Recurrent reciprocal deletion/duplication pairs arise by NAHR, and the deletion is often more severe. - Management is supportive and genetic counseling is provided, with recurrence risk higher if a parent carries a balanced rearrangement.

BOARD TRAPS: Duplication is a structural abnormality causing gain of material (not aneuploidy of the whole chromosome). Distinguish from insertion, translocation, inversion (balanced, usually no phenotype for the carrier), and trinucleotide repeat expansion (a different mechanism, e.g., Fragile X, Huntington).