Structural Variants and Segregation

Structural variants (SVs) are genomic alterations larger than ~50 bp, including copy-number variants, balanced and unbalanced rearrangements, and inversions. Their pathogenic mechanisms and reproductive consequences depend on whether genetic material is gained, lost, or simply repositioned, and on how the rearrangement segregates through meiosis.

Gains or losses of contiguous DNA segments.

• Deletions: heterozygous deletions cause disease via haploinsufficiency (whole-gene loss of dosage-sensitive genes) or gene disruption (intragenic deletion of one or more exons producing a null allele).
• Duplications: tandem or inserted duplications cause disease via triplosensitivity (extra dosage of a dosage-sensitive gene, e.g., MECP2 duplication, PMP22 duplication in CMT1A) or by disrupting a gene at the duplication breakpoint.
• Triplications: three copies of a region. Often more severe than duplications (e.g., SNCA triplication in autosomal dominant Parkinson disease).
• Gene fusion: when a CNV breakpoint joins parts of two genes in frame (most classic at translocation junctions), producing a chimeric protein. The mechanism dominates oncogenesis (BCR-ABL1, EWSR1-FLI1) but also occurs in germline disease.
• ClinGen dosage sensitivity: curated haploinsufficiency and triplosensitivity scores (0-3) inform CNV classification under the 2020 ACMG/ClinGen CNV guidelines (separate from the 2015 sequence variant guidelines).

Exchange of segments between non-homologous chromosomes.

• Reciprocal translocations: balanced exchanges. Carriers are usually phenotypically normal unless a breakpoint disrupts a gene or a position effect alters expression. At meiosis, a quadrivalent forms; segregation produces gametes that are alternate (balanced, viable: parental and balanced-translocation), adjacent-1 (homologous centromeres separate, unbalanced - partial trisomy and partial monosomy), adjacent-2 (homologous centromeres co-segregate, unbalanced and rare), or 3:1 (tertiary trisomy/monosomy). Net effect: recurrent miscarriage, infertility, and risk of liveborn unbalanced offspring.
• Robertsonian translocations: whole-arm fusion of two acrocentric chromosomes (13, 14, 15, 21, 22) at or near the centromere with loss of the satellited short arms. Total chromosome count drops to 45.
  • t(13;14) is the most common Robertsonian, ~1 in 1300 in the general population.
  • t(14;21) and t(21;21) carriers have markedly elevated risk of translocation Down syndrome offspring; t(21;21) carriers can produce only trisomy-21 or monosomy-21 conceptions, so the recurrence risk approaches 100% for any liveborn pregnancy.
  • General empiric recurrence risk for Down syndrome from a maternal Robertsonian carrier is ~10-15%, paternal ~1-2%.

A segment is excised and reinserted in reverse orientation on the same chromosome.

• Pericentric inversion: includes the centromere; can change arm ratio and is visible on karyotype.
• Paracentric inversion: confined to one arm; often cytogenetically cryptic.
• Reproductive risk: at meiosis the inverted region forms an inversion loop to allow homologous pairing. A single crossover within the loop produces recombinant gametes carrying duplications and deletions of the chromosomal segments distal to the inversion breakpoints. Pericentric inversion crossovers yield viable recombinant offspring more often than paracentric (paracentric crossovers usually produce acentric or dicentric fragments that are lethal, so paracentric carriers tend to have miscarriages rather than abnormal liveborns).

Rare three-strand exchange events in which a segment of one chromosome is inserted into a non-homologous chromosome. Carriers can produce gametes with duplication or deletion of the inserted segment depending on segregation, with up to 50% recurrence risk for unbalanced offspring in some configurations.