Genetics & Modes of Inheritance in Orthopaedics

These concepts drive counselling and recurrence-risk estimates. A patient with an apparently sporadic AD condition may have a de novo mutation (low sibling-recurrence risk but 50% for the patient's own offspring) or germline mosaicism in a parent (raising sibling-recurrence risk). Reduced penetrance and variable expressivity mean an "unaffected" relative may still carry the gene — important before reassuring a family.

A family asks whether a bone condition will be passed on, and for one group the answer is no even though the disease is unquestionably genetic. These are the conditions caused by a mutation arising after fertilisation, so it is confined to the cell lineages descended from that one cell and is absent from the germline:

• Fibrous dysplasia and McCune-Albright syndrome — activating GNAS mutation. The reason it can only ever be mosaic is worth knowing, because it is the mechanism that makes the fact stick: a constitutional (germline) activating GNAS mutation is not survivable, so every living patient necessarily acquired theirs post-zygotically. How early the mutation occurred determines the phenotype — very early gives widespread polyostotic disease with café-au-lait patches and endocrinopathy (McCune-Albright); later gives monostotic fibrous dysplasia. The café-au-lait borders are the clue to mosaicism itself, following developmental lines with the classically ragged "coast of Maine" edge, unlike the smooth "coast of California" borders in NF1.
• Ollier disease and Maffucci syndrome — mosaic IDH1 or IDH2 mutations. The characteristic unilateral or strikingly asymmetric distribution of enchondromas is the mosaicism made visible: only the affected cell lineage carries the mutation, so the disease respects no bilateral symmetry.

What to tell the family: the condition is genetic in origin but not heritable, and the recurrence risk for siblings and for the patient's own children is essentially that of the general population. This is the opposite counsel from germline mosaicism, and confusing the two is the error to avoid — one raises the risk you would otherwise quote, the other removes it.

What still needs surveillance is the tumour risk, not the family. Ollier and Maffucci carry a substantial lifetime risk of malignant transformation to chondrosarcoma, and Maffucci adds the spindle-cell haemangiomas and a broader visceral malignancy risk — so these patients need long-term follow-up for their own sake even though no one else in the family is at risk.

When asked to counsel a family, structure it: (1) confirm the pattern and recurrence risk (50% for an AD heterozygote's offspring; 25% for two AR carriers); (2) flag that a de novo case has low sibling risk but 50% for the patient's own children, while germline mosaicism in a phenotypically normal parent can still raise sibling risk; (3) acknowledge reduced penetrance/variable expressivity so an "unaffected" relative may still carry the gene; (4) refer to clinical genetics for formal counselling, confirmatory testing and discussion of prenatal or preimplantation options. Surgeons recognise the phenotype and coordinate — they do not give definitive genetic counselling alone.

"Refer for confirmatory testing" means choosing the right molecular test for the question:

• Karyotype - whole-chromosome analysis for aneuploidy and balanced translocations.
• FISH - targeted detection of a specific locus or microdeletion.
• Chromosomal microarray (array-CGH / SNP array) - genome-wide copy-number; the first-tier test for unexplained developmental delay / multiple congenital anomalies.
• Targeted (Sanger) single-gene testing - when one gene/variant is expected (the recurrent FGFR3 mutation in achondroplasia, or a known familial variant).
• Multigene NGS panels - for a phenotype with locus heterogeneity (a skeletal-dysplasia or OI panel).
• Whole-exome / whole-genome sequencing - for the undiagnosed or atypical case.

Pick by scenario: a known familial pathogenic variant → targeted testing of that variant; a clinically obvious single-gene condition → that gene; a heterogeneous/unclear phenotype → a panel or exome.

Once the causative variant is identified, families can be offered, through clinical genetics:

• Prenatal diagnosis - chorionic villus sampling (CVS, ~11-14 weeks, placental tissue) or amniocentesis (from ~15-16 weeks, amniocytes) - both definitive for the known variant but invasive with a small miscarriage risk.
• Preimplantation genetic testing for monogenic disease (PGT-M) - IVF with embryo biopsy to transfer only unaffected embryos; requires a known familial mutation and avoids a termination decision.
• Non-invasive prenatal testing (cell-free DNA) is largely a screen (mainly for aneuploidy) and does not replace definitive testing for most monogenic skeletal disorders.

The orthopaedic surgeon's role is to recognise the phenotype and refer; clinical genetics delivers these options and the formal counselling.

The OI inheritance and classification facts come from Marini et al. (Nat Rev Dis Primers 2017, DOI); the achondroplasia FGFR3 gain-of-function mechanism from Ornitz & Legeai-Mallet (Dev Dyn 2017, DOI); and the multiple-hereditary-exostoses EXT1/EXT2 genetics and chondrosarcoma risk from Bovée (Orphanet J Rare Dis 2008, DOI). All three are narrative reviews (Level V), appropriate for established genetic facts rather than comparative effectiveness. The remaining gene-condition pairings (Marfan-FBN1, NF1-neurofibromin, X-linked hypophosphataemic rickets-PHEX) are standard, well-established medical genetics.