What are the implications and management strategies for an individual with an inversion of chromosome 16 in their Deoxyribonucleic acid (DNA)?

Constitutional Inversion of Chromosome 16 in General DNA

A constitutional (germline) pericentric inversion of chromosome 16, inv(16)(p13q22), found in an individual's general DNA is fundamentally different from the acquired somatic inv(16) seen in acute myeloid leukemia and carries reproductive risks rather than cancer risk for the carrier. 1

Critical Distinction: Constitutional vs. Somatic Inv(16)

You must distinguish between constitutional (present in all cells from birth) and acquired somatic inv(16) (present only in bone marrow/leukemia cells):

• Constitutional inv(16) is inherited or occurs de novo in germline cells and is present in every cell of the body, including blood, skin, and reproductive cells 1
• Somatic inv(16) associated with AML (specifically the favorable-risk inv(16)(p13.1q22) with CBFB-MYH11 fusion) occurs only in leukemic cells and is classified as a favorable prognostic marker in acute myelomonocytic leukemia with abnormal eosinophils 2

The key pitfall: Do not confuse a constitutional chromosomal variant with the leukemia-associated rearrangement—they have completely different clinical implications 3

Health Implications for Carriers

Individuals carrying constitutional inv(16)(p13q22) are generally in good health with normal life expectancy:

• Carriers typically have no increased personal cancer risk or hematologic abnormalities 1
• No specific medical surveillance is required for the carrier themselves beyond routine health maintenance 1
• The inversion itself does not cause disease in balanced form 1

Reproductive Risks and Genetic Counseling

The primary concern is reproductive risk due to unbalanced recombinant chromosomes in offspring:

• Carriers are prone to reproductive loss including miscarriages and stillbirths 1
• Recombinant offspring (those inheriting an unbalanced chromosome from crossover during meiosis) can have serious major congenital malformations 1
• Two different types of recombinant offspring were identified with duplication/deletion of chromosome 16 segments, both associated with severe abnormalities 1

Mandatory genetic counseling should address:

• 50% chance of passing the balanced inversion to offspring (who would be carriers like the parent) 1
• Risk of unbalanced recombinant offspring varies but can result in pregnancy loss or live births with multiple congenital anomalies 1
• Prenatal testing options including chorionic villus sampling or amniocentesis with karyotype analysis 1
• Preimplantation genetic testing (PGT-SR for structural rearrangements) if pursuing in vitro fertilization 2

Management Algorithm

For an individual with constitutional inv(16)(p13q22):

1. Confirm the inversion is constitutional by testing non-hematologic tissue (skin fibroblasts or buccal cells) to exclude somatic mosaicism 1

2. Refer to medical genetics/genetic counseling for comprehensive family planning discussion 2

3. Obtain detailed family history focusing on:

   • Recurrent pregnancy losses 1
   • Children with congenital anomalies 1
   • Other family members who may be carriers 1

4. Offer cascade testing to at-risk family members, particularly those of reproductive age 1

5. Reproductive options counseling should include:

   • Natural conception with prenatal diagnosis 1
   • PGT-SR with IVF to select embryos with balanced chromosomes 2
   • Use of donor gametes 2
   • Adoption 2

What NOT to Do

Critical errors to avoid:

• Do not initiate hematologic surveillance or AML screening—constitutional inv(16) does not increase leukemia risk 2, 1
• Do not confuse this with the favorable-risk AML subtype that has somatic inv(16)(p13.1q22) with CBFB-MYH11 fusion 2
• Do not perform bone marrow examination unless there are independent clinical indications (cytopenias, abnormal blood counts) 4
• Do not restrict the individual's activities or employment based on this finding 1

Documentation and Communication

Ensure proper documentation states:

• "Constitutional pericentric inversion of chromosome 16, inv(16)(p13q22)" to distinguish from leukemia-associated rearrangements 1
• Balanced carrier status with normal phenotype 1
• Reproductive implications clearly outlined 1

Communicate to the patient that:

• They are healthy and this does not affect their personal health or lifespan 1
• The concern is exclusively reproductive, affecting future pregnancies 1
• Genetic counseling before conception is strongly recommended 2, 1