Mosaicism

Position of mosaicism among inheritance types

Unlike classical Mendelian inheritance patterns, mosaicism belongs to rare genetic mechanisms. To understand the context:

• In autosomal dominant (AD) inheritance, the risk of transmitting the pathology to offspring is 50%. However, many cases (e.g., a mutation in the FGFR3 gene in achondroplasia) arise as spontaneous mutations in healthy parents.
• In autosomal recessive (AR) inheritance, both parents are asymptomatic carriers, and the risk of having an affected child is 25%.

Mosaicism, however, forms after fertilization. If a mutation occurs in somatic cells during embryonic development, somatic mosaicism arises. It is believed that for a number of severe autosomal dominant disorders, complete (non-mosaic) carriage of the mutation in all cells is incompatible with life. Patients with such genetic defects survive solely due to the fact that a portion of their cells remains healthy.

Clinical manifestations and syndromes

The presence of a mutant cell pool alongside healthy ones leads to uneven tissue development. Classical clinical signs of somatic mosaicism include:

• Pronounced asymmetry of the body or limbs.
• Local excessive growth (overgrowth).
• Focal skin pigmentation disorders.
• Vascular anomalies (hemangiomas).

These signs often form the basis of syndromes accompanied by asymmetric shortening or excessive growth (Overgrowth). Such pathologies include:

• Beckwith-Wiedemann syndrome (Beckwith-Wiedemann syndrome).
• Klippel-Trénaunay syndrome (Klippel-Trénaunay syndrome).
• McCune-Albright syndrome (McCune-Albright syndrome).
• Sturge-Weber syndrome (Sturge-Weber syndrome).
• Hypomelanosis of Ito (Hypomelanosis of Ito).
• Various dysplasias (e.g., hemimelic epiphyseal dysplasia or polyostotic fibrous dysplasia).

The diagnosis of such conditions requires the synthesis of a vast amount of clinical, biochemical, radiological, and genetic data, which sometimes takes years. Unlike dysostoses, which have a static phenotype, dysplasias in these syndromes feature a developing (evolving) phenotype. An accurate diagnosis is critical: it allows anticipating complications, prescribing specific treatment, and conducting competent genetic counseling.

Mosaicism and preimplantation genetic testing (PGT)

The problem of mosaicism is acute in reproductive medicine. Patients at high risk of transmitting hereditary pathology are indicated for PGT to prevent the birth of affected offspring.

Testing is prescribed to the following groups:

1. Carriers of gene mutations linked to the X/Y chromosomes.
2. Carriers of mutations causing monogenic diseases (PGT-M is performed).
3. Carriers of structural chromosomal abnormalities (PGT-SR is performed).

Important: This recommendation is always relevant, regardless of the couple's fertility status and obstetric history.

If embryos with signs of mosaicism are detected during testing, the situation requires an individualized approach. The presence of mosaicism does not mean automatic rejection of the embryo; however, a mandatory consultation with a clinical geneticist is necessary to decide on the possibility and safety of its transfer.

Class and exam questions

What else to study on this topic

• Preimplantation genetic testing (PGT-M and PGT-SR)
• Uniparental disomy and genomic imprinting (Angelman and Prader-Willi syndromes)
• Constitutional bone diseases: dysplasias, osteodystrophies, and dysostoses
• Overgrowth syndromes
• Radiological signs of genetic pathologies ("coat hanger" sign, bisphosphonate lines)

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.