Structural Rearrangements & NAHR

Structural chromosome rearrangements (translocations, deletions, duplications, inversions) fall into two big mechanistic camps. Recurrent rearrangements (the same breakpoints in unrelated families) almost always arise from non-allelic homologous recombination (NAHR) between flanking low-copy repeats (LCRs / segmental duplications). Non-recurrent rearrangements arise from non-homologous end joining (NHEJ) or replication-based mechanisms (FoSTeS / MMBIR) and have unique breakpoints in each patient. Recognizing which family a rearrangement belongs to predicts whether it's a known syndrome with a stereotyped phenotype, whether the carrier parent's other children share recurrence risk, and what test will detect it.

This leaf covers four mechanism families and three classes of balanced rearrangement (Robertsonian, reciprocal, inversion) with the segregation math you need to counsel a carrier couple.

LCRs (also called segmental duplications) are blocks of near-identical sequence (~10 kb to >500 kb) scattered across the genome, often in pericentromeric or subtelomeric regions. They make up ~5% of the human genome. When two LCRs sit on the same chromosome arm in the same orientation, an "out-of-register" pairing during meiosis (homologous chromosomes mismatching their LCRs) followed by a single crossover deletes everything between the LCRs on one chromosome and duplicates it on the other. This is the mechanism classically taught as unequal crossing over (or unequal recombination); NAHR is the modern name for the same event, and the reciprocal deletion-plus-duplication product is its signature.

Rules of thumb:

• Same-orientation LCRs (direct repeats) → reciprocal deletion + duplication. Both products are usually viable but pathogenic with characteristic syndromic phenotypes.
• Inverted-orientation LCRs → inversion. Often clinically silent in the carrier but can cause recurrence problems in offspring (see Inversions below).
• The deletion vs. duplication phenotype is rarely the same. 17p11.2 deletion = Smith-Magenis (sleep, behavior, distinctive facies); 17p11.2 duplication = Potocki-Lupski (autism spectrum, hypotonia, failure to thrive). Different syndromes from the same LCR pair.

Clinically Important Recurrent Microdeletion / Microduplication Syndromes

Detection: chromosomal microarray is the test of choice for these. They are too small for routine karyotype to detect.

When breakpoints are unique to each patient (no flanking LCRs), the rearrangement is sporadic and the size + location varies family-by-family. Microarray will detect them; karyotype will detect larger ones. Recurrence risk for parents is generally low (de novo), but parental mosaicism can drive cryptic recurrence; formal "0% recurrence" counseling isn't safe.

A Robertsonian translocation is a fusion at or near the centromere of two acrocentric chromosomes (13, 14, 15, 21, 22), creating a single derivative chromosome that contains both long arms; the short-arm material (NORs / rDNA repeats) is lost but is functionally redundant, so the balanced carrier is phenotypically normal with 45 chromosomes.

• Most common in the general population: rob(13;14) (~1/1,300).
• Most clinically relevant: rob(14;21) and rob(21;22), the parental carrier states underlying inherited Down syndrome.
• Acrocentrics only: 13, 14, 15, 21, 22 (the D group (13, 14, 15) and G group (21, 22) chromosomes).

Why Robertsonian translocations matter for Down syndrome counseling

A balanced carrier of rob(14;21) has 45 chromosomes (one rob, plus normal 14, normal 21, single 21). At meiosis the rob, the normal 14, and the normal 21 form a trivalent that segregates in six possible ways: only one is balanced normal, one is balanced carrier, and four are unbalanced (translocation Down syndrome, monosomy 21, monosomy 14, trisomy 14):

Empirically, the recurrence risk for a female carrier of rob(14;21) is ~10–15% per pregnancy (live-born trisomy 21), and for a male carrier ~1–2% (selection against unbalanced sperm). For rob(21;21), the rare homologous Robertsonian, 100% of viable offspring have Down syndrome since every gamete carries either the rob(21;21) or no 21.

These are the Robertsonian recurrence figures most often cited in counseling.

A reciprocal translocation is an exchange of segments between two non-homologous chromosomes. Carriers are usually phenotypically normal (balanced) but produce a disproportionate number of unbalanced gametes, leading to recurrent miscarriage, infertility, or affected offspring.

Quadrivalent Segregation

At meiosis, the two derivative chromosomes pair with the two normal chromosomes forming a quadrivalent (cross-shaped tetrad). Four segregation patterns:

The fraction of liveborn unbalanced offspring depends on:

• The specific chromosomes involved: translocations involving very small segments or chromosomes with high tolerance may give viable unbalanced offspring; larger imbalances are usually lethal early.
• The direction of selection: many unbalanced products miscarry early, so carrier couples often present with recurrent pregnancy loss rather than live-born affected children.

Counseling pearl: empiric live-born affected risk for most reciprocal translocation carriers is ~5–15%, but miscarriage risk is much higher, and PGT-A/PGT-SR is increasingly offered.

Cancer-associated reciprocal translocations

Somatic reciprocal translocations create oncogenic fusion genes. These are acquired, not inherited:

• t(9;22)(q34;q11): BCR-ABL1, chronic myeloid leukemia (Philadelphia chromosome)
• t(15;17)(q22;q21): PML-RARA, acute promyelocytic leukemia
• t(8;14)(q24;q32): MYC-IGH, Burkitt lymphoma
• t(11;14)(q13;q32): CCND1-IGH, mantle cell lymphoma
• t(14;18)(q32;q21): IGH-BCL2, follicular lymphoma

These belong in the conditions / cancer literature but are worth knowing as a contrast: somatic reciprocal translocations are the mechanism of many hematologic malignancies.

An inversion is a 180° rotation of a chromosome segment after a two-break event with reunion. Carriers are usually phenotypically normal (balanced).

• Pericentric (centromere within the inverted segment): pairing in meiosis forms an inversion loop; recombination within the loop produces gametes with duplications and deletions of the segments distal to the inversion breakpoints.
• Paracentric (centromere outside the inverted segment): recombination within the loop produces dicentric and acentric gametes that are usually inviable. Risk to live-born offspring is therefore much lower than for pericentric.
• Common normal-variant inversion: inv(9)(p11q13): clinically silent, found in ~1% of the population. Don't over-counsel.
• Pathogenic recurrent inversion: F8 intron 22 inversion: the most common cause of severe hemophilia A (~40% of severe cases). Detection requires inverse PCR or long-range PCR; standard sequencing misses it.

Counseling math for pericentric inversion carriers: live-born affected risk depends on the inverted segment size; only small distal duplications/deletions are viable. Risk roughly: small inversion (<30% of chromosome) → low risk; large inversion (>50%) → higher risk of viable unbalanced offspring. PGT-SR is offered for couples with prior unbalanced offspring or recurrent loss.

A balanced carrier with recurrent pregnancy loss needs a karyotype, not microarray (microarray will miss balanced rearrangements). For a child with multiple congenital anomalies and ID, microarray is first-line (catches NAHR-driven microdeletions that karyotype misses).

• Identify by parental karyotype when an affected child has an unbalanced rearrangement, or when a couple has recurrent pregnancy loss / infertility.
• Discuss: live-born affected risk, miscarriage risk, options (PGT-SR, prenatal diagnosis, donor gametes, accept-the-risk).
• Recurrence math is rearrangement-specific; empiric data tables exist for the common ones; for unique rearrangements, work from first principles + consult cytogenetics.
• Cascade testing of relatives is essential; many balanced carriers are clinically silent until a child is affected.