• The average practising orthopaedic surgeon requires a basic knowledge of disease inheritance and genetic disorders.
• For the exam it is important to be able to draw a family pedigree of single gene inheritance and to know the gene mutations of the more common orthopaedic conditions.

• Genetic abnormalities can be inherited or mutations.
• Forty-six chromosomes, 22 pairs of autosomes and two sex chromosomes; male XY, female XX.
• An allele is one of several possible alternative forms of a gene, only one of which may be present in any one chromosome.
• Two alleles of a particular gene occupy the same relative positions on a pair of homologous chromosomes.
• If both alleles are similarly involved, then there is a homozygous trait. If the alleles differ, then there is a heterozygous trait.
• Phenotype refers to the features (traits) exhibited because of genetic make-up.
• Genotype refers to the presence or absence of particular genes, not the traits expressed.
• Incomplete penetrance can cause skipped generations, genotype present but no expression.
• Variable expressivity: some disorders affect several systems to varying degrees in different individuals.

• Monosomy = loss of a chromosome = 45 chromosomes, e.g. XO Turner syndrome.
• Trisomy = 47 chromosomes – trisomy 13, trisomy 21, XXY Klinefelters.
• Translocation – scoliosis, genu-valgum, clubfoot, vertical talus, mental retardation.
• Mosaicism = two cell lines in one individual.
• Indications for chromosomal studies:

• Multiple orthopaedic abnormalities
• Two or more siblings with same condition
• Multiple miscarriages in mother
• Multiple organ system abnormalities
• Mental retardation

• Autosomal dominant (AD)
• Autosomal recessive (AR)
• Sex-linked dominant
• Sex-linked recessive
• Multiple inheritance patterns
• Additional inheritance effects:

• Imprinting
• Anticipation

Autosomal dominant (Figure 1)

• A mutation in one copy of an autosomal gene causes the disease.
• A person with such a disease has one mutated and one normal copy of the disease gene.
• Risk of 1 in 2 to pass on to offspring.
• Variable expressivity (severity of the disorder) and incomplete penetrance(probability of a person with a mutation manifesting signs of the disease) suppress or minimise the expression of dominant inheritance.
• Autosomal dominant conditions usually produce structural abnormalities.

Examples

• Syndactyly
• Polydactyly
• Marfan’s syndrome
• Cleidocranial dysostosis
• Hereditary multiple exostosis
• Achondroplasia
• Multiple epiphyseal dysplasia (MED)
• Metaphyseal chondrodysplasia (Schmid and Jansen types)
• Kniest dysplasia
• Malignant hyperthermia
• Ehlers–Danlos syndrome
• Osteogenesis imperfecta (types I and IV)
• Multiple hereditary exostosis
• Osteopetrosis (tarda, mild form)

Autosomal recessive (Figure 2)

• Two copies of an abnormal gene must be present in order for the disease or trait to develop. 
• A person with a recessive mutation in one copy and a normal second copy is a carrier or heterozygote. 
• Both parents of a patient with an autosomal recessive disease are always carriers. 
• Usually the parents do not know they are carriers until the birth of the first affected. 
• The risk on future children with the disease (recurrence risk) is 1 in 4 for each child. 
• Each child has a 25% chance of being affected, a 50% chance of being a carrier and a 25% chance of being normal.
• Autosomal recessive conditions are often metabolic or enzyme defects.

Examples

• Diastrophic dysplasia 
• Friedreich’s ataxia 
• Gaucher disease
• Spinal muscular atrophy 
• Sickle cell anaemia 
• Osteogenesis imperfecta (II and III) 
• Hypophosphatasia 
• Osteopetrosis (infantile, malignant form)

X-Linked recessive (Figure 3)

• Most of the X-linked recessive diseases are in men as they have only one X chromosome (XY).
• Women possessing one X-linked recessive mutation are considered carriers and will generally not manifest clinical symptoms of the disorder.
• All offspring of a carrier woman have a 50% chance of inheriting the mutation if the father does not carry the recessive allele.
• All female children of an affected father will be carriers (assuming the mother is not affected or a carrier), as daughters possess their father’s X chromosome. 
• No male children of an affected father will be affected, as sons only inherit their father’s Y chromosome.
• In recessive X-linked inheritance, the woman is affected only in the rare situation in which both genes of the genetic pair are abnormal.

Examples

• Duchenne muscular dystrophy 
• Becker’s muscular dystrophy 
• Mucopolysaccaridoses type II (Hunter's syndrome)
• Haemophilia A. Genetic defect in factor VII
• Spondylo-epiphyseal dysplasia (SED) tarda

Example of X-linked recessive condition

Duchenne muscular dystrophy

• Incidence approximately one in 4000 boys.
• This is one of the dystrophinopathies caused by a mutation in the dystrophin gene (Xp21). 
• The dystrophin protein provides structural stability to the dystroglycan complex of the muscle cell membrane, which is lost as a result of the mutation. Women rarely show musculoskeletal signs of the disease, although there is an increased risk of dilated cardiomyopathy in female carriers.
• There is a high spontaneous new mutation rate.

Clinical features

• Age of onset is usually before 6 years. Progressive proximal myopathy of the lower limbs with noticeable calf pseudohypertrophy.
• Compensatory toe walking is an adaptation to knee extensor weakness.
• Frequent falls/fatigue.
• Speech delay and difficulty with motor skills with learning difficulties in approximately a third of affected boys.
• Lumbar lordosis/scoliosis.
• Usually wheelchair bound by 12 years and life expectancy is around 25 years.
• Gower’s sign positive: the child is unable to jump up quickly from a crossed leg position without bracing their arms against their legs to support the proximally weak muscles.

X-Linked dominant

• Rare.
• Each child of a mother affected with an X-linked dominant trait has a 50% chance of inheriting the mutation and thus being affected with the disorder.
• If only the father is affected, 100% of the daughters will be affected, because they inherit their father's X chromosome, and 0% of the sons will be affected, because they inherit their father's Y chromosome. This distinguishes its inheritance from autosomal dominant.
• Men are usuallymore severely affected than women because in each affected woman there is one normal allele producing a normal gene product and one mutant allele producing the non-functioning product, while in each affected man there is only the mutant allele with its non-functioning product and the Y chromosome, no normal gene product at all.
• Some X-linked dominant alleles are lethal in men because their sole X chromosome is the disease-carrying chromosome. In the next generation, sons of an affected father are unaffected because their X chromosome is from their mother. Daughters of an affected father are always affected as one of their chromosomes is inherited from their father.

Examples

• Hypophosphatemic rickets
• Leri–Weill dyschondrosteosis (bilateral Madelung's deformity)

Multiple inheritance patterns

Examples

• Charcot-Marie-Tooth (AD, AR, Xlink) 
• Osteopetrosis (AD, AR) 
• Osteogenesis imperfecta (AR, AD) 
• Neurofibromatosis (AD, AR)
• SED (AD, Xlink)

Imprinting

• Patients inherit two copies of their genes -one from their mother and one from their father. Usually both copies of each gene are active, or “turned on” in cells. In some cases, however, only one of the two copies is normally turned on. Which copy is active depends on the parent of origin.
• This phenomenon of monoallelic, parent-of-origin expression of genes is termed genomic imprinting. Imprinted genes are normally involved in embryonic growth and behavioural development, but occasionally they also function inappropriately as oncogenes and tumour suppressor genes.
• Examples:

1. Angelman syndrome
2. Prader–Willi syndrome 

Anticipation

• Anticipation typically occurs with disorders that are caused by an unusual type of mutation called a trinucleotide repeat expansion. A trinucleotide repeat is a sequence of three DNA building blocks (nucleotides) that is repeated a number of times in a row.
• DNA segments with an abnormal number of these repeats are unstable and prone to errors during cell division. The number of repeats can change as the gene is passed from parent to child.
• If the number of repeats increases, it is known as a trinucleotide repeat expansion. In some cases, the trinucleotide repeat may expand until the gene stops functioning normally. This expansion causes the features of some disorders to become more severe with each successive generation.