Genetics & Modes of Inheritance in Orthopaedics

Medical genetics recurs in the basic-science viva because so much of orthopaedic practice rests on a handful of single-gene (Mendelian) disorders with predictable inheritance: the skeletal dysplasias, the connective-tissue diseases, haemophilic arthropathy and the hereditary tumour syndromes. The examiner is rarely testing molecular detail. They want to see that you can read a pedigree, name the pattern, attach the gene and counsel recurrence risk in a few clean sentences.

How the page is built. The four classic patterns come first (autosomal dominant, autosomal recessive, X-linked recessive and dominant, mitochondrial), then the concepts that make real pedigrees messy (penetrance, expressivity, anticipation, mosaicism, de novo mutation), then what the pattern changes in clinic. The anchor conditions run through all of it so the genetics is never abstract: FGFR3 and achondroplasia, COL1A1/COL1A2 and osteogenesis imperfecta, FBN1 and Marfan syndrome, EXT1/EXT2 and multiple hereditary exostoses, NF1, and PHEX and X-linked hypophosphataemic rickets.

The four-question pedigree drill. For any pedigree, ask in order:

1. Is the trait in every generation (suggests dominant) or does it skip (suggests recessive)?
2. Are both sexes affected roughly equally (autosomal) or is there a strong male predominance (consider X-linked recessive)?
3. Is there male-to-male transmission? That proves autosomal inheritance and excludes X-linkage.
4. Is transmission exclusively maternal, to all children (mitochondrial)?

Four questions resolve almost every exam pedigree.

One allele is enough. In autosomal dominant (AD) inheritance a single mutant allele produces the phenotype, so the affected person is a heterozygote and each of their children has a 50% chance of inheriting the allele. The pedigree shows the trait in every generation (vertical transmission), in both sexes, and with male-to-male transmission, which rules out X-linkage because a father gives his sons a Y, not his X. Calling an obvious male-to-male pedigree "X-linked" is the classic trip-up; it is the single most decisive clue and points to autosomal dominant inheritance.

Why the family history can be blank. Many AD conditions arise from new (de novo) mutations: about 80% of achondroplasia, and a large share of NF1 and OI. A negative family history therefore does not exclude an AD disorder, and a family should never be reassured that a sporadic case "isn't genetic".

How one allele does the damage. AD conditions often result from a gain-of-function mutation, a dominant-negative effect (a faulty subunit poisoning a multimer, as in OI), or haploinsufficiency.

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The conditions. The high-yield AD pairings, with the mechanism the examiner may ask for:

What the phenotypes look like. The films behind the pairings.

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Two hits needed. In autosomal recessive (AR) inheritance both alleles must be mutated. The affected child usually has unaffected carrier parents, the trait commonly skips generations, both sexes are affected equally, and the risk rises with consanguinity. Two carrier parents have a 25% chance of an affected child, 50% carriers, 25% unaffected.

The orthopaedic examples. Many inborn errors of metabolism and storage disorders with skeletal manifestations (the mucopolysaccharidoses, for example), some severe or lethal forms of OI, and conditions such as diastrophic dysplasia follow AR inheritance.

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X-linked recessive. Males are hemizygous, with a single X, so one mutant X-allele causes disease; the conditions therefore predominantly affect males and are transmitted through carrier females. A carrier mother passes the condition, on average, to half her sons and carrier status to half her daughters. An affected father makes all his daughters carriers and none of his sons affected, because a son receives his Y, and that absence of male-to-male transmission is the key negative clue. The orthopaedic examples are Duchenne/Becker muscular dystrophy (dystrophin) and haemophilia A/B (factor VIII/IX), which the surgeon meets as haemophilic arthropathy.

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X-linked dominant. A single mutant X-allele causes disease in both sexes. An affected father transmits to all daughters and no sons; an affected mother to 50% of each. The classic orthopaedic example is X-linked hypophosphataemic rickets (PHEX): rickets or osteomalacia resistant to plain vitamin D, treated with phosphate and active vitamin D.

Mitochondrial. Mitochondria and their DNA are inherited only from the egg, so an affected mother passes the disorder to all her children and an affected father to none. Both sexes are affected. Heteroplasmy, a mix of normal and mutant mitochondria, explains the variable severity. Relevant to some mitochondrial myopathies. This is also the discriminator from X-linked recessive inheritance: both seem to spare father-to-son transmission, but only mitochondrial inheritance is strictly maternal to all children.

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Haemophilic arthropathy: the X-linked pedigree written on a joint. Factor VIII/IX deficiency writes itself on the joint, and the surgeon inherits the arthropathy: repeated haemarthroses, with the elbow and the ankle as the high-yield targets. Once the joint is gone, factor replacement does not restore cartilage; arthroplasty does. Counsel the inheritance first, then operate with factor cover and haematology in the room.

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Real pedigrees are messier than the four patterns. The concepts below explain why, and they drive counselling and recurrence-risk estimates.

Penetrance and expressivity in the clinic. Reduced penetrance and variable expressivity can make an AD trait appear to skip a generation or look mild in a known carrier. An "unaffected" relative may still carry the gene, so never declare an at-risk relative "unaffected, therefore non-carrier" without testing.

The mosaic bone diseases: genetic, but not inherited. 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, confined to the cell lineages descended from that one cell and absent from the germline.

Fibrous dysplasia and McCune-Albright syndrome. An activating GNAS mutation. It can only ever be mosaic, and the reason 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 the 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 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 spindle-cell haemangiomas and a broader visceral malignancy risk. These patients need long-term follow-up for their own sake even though no one else in the family is at risk.

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Knowing the inheritance pattern is not academic. It changes what you screen for, who you refer and what you tell the family, and the orthopaedic surgeon is often the first to recognise a heritable skeletal phenotype, so a structured response carries marks and changes care.

The counselling answer the examiner wants. 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 a 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 and variable expressivity before reassuring any relative.
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.

How the diagnosis is confirmed. "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 or multiple congenital anomalies.
• Targeted (Sanger) single-gene testing: when one gene or 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 calls for targeted testing of that variant; a clinically obvious single-gene condition for that gene; a heterogeneous or unclear phenotype for a panel or exome.

Reproductive options when the mutation is known. Once the causative variant is identified, clinical genetics can offer the family:

• Prenatal diagnosis: chorionic villus sampling (CVS, ~11-14 weeks, placental tissue) or amniocentesis (from ~15-16 weeks, amniocytes). Both are 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; it 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.