A 65-year-old female patient, who has a 68-year-old sister operated because of a femoral neck fracture due to osteoporosis, approached the outpatient clinic for bone mass density tests and asking if she is genetically prone to fracture due to osteoporosis because of her sister.

What we have in our hands about the genetic basis of osteoporosis is very limited, involving many functional variants [20]. This is similar for other complex human diseases representing serious health problems like diabetes and obesity. Recent advances in next-generation sequencing technologies have greatly enhanced our ability to discover functional rare variants. But on the other hand; these technologies are very expensive to be applied for whole population [21].

It is estimated that osteoporosis affects more than 75 % of women 70 years of age. Fractures related to osteoporosis result in significant morbidity and increased mortality. It is generally classified as primary or secondary (due to endocrine dysfunction, medications, and inflammatory disorders).

According to bone mass density, genetic variations are estimated to be more than 70 % to cause such differences [22]. And according to the femoral neck geometry and bone turnover, these variations are between 50 and 80 % [23]. Besides, the heritability of fracture itself is relatively low, close to 25 % due to fall-related factors such as vision, balance, and strength [24].

Genetic disorders involving the skeletal system with their great variety in number occur due to any kind of mutation in skeletal development.

The recent years have witnessed major advances in our understanding of the genetic basis for many skeletal disorders. By means of technological improvement, the responsible gene for each disorder has been mapped, and the exact locus has been defined, the mutations clearly shown, and the functional significance of mutations determined; these are all important steps to clarify the molecular basis for pathogenesis.

In this chapter, we focus on our current understanding of the genetic basis and pathogenic mechanisms for disorders of bone homeostasis.

For researchers who are interested in genetics, Online Mendelian Inheritance in Man (http://​www.​ncbi.​nlm.​nih.​gov/​omim) and the human genome database are important and serve as a database.

From these databases, we have a long list of genes involved in skeletal disorders (Table 14.1).