SNP Shot: Genomic Insights

Osteogenesis imperfecta (OI) encompasses a group of genetic conditions that primarily affect bone health. The name itself, "osteogenesis imperfecta," signifies imperfect bone formation. Individuals with OI are prone to bone fractures, often occurring with minimal trauma or even spontaneously. Frequent fractures are a hallmark of the condition, and in severe cases, these can begin before birth. In milder forms, a person may experience only a limited number of fractures throughout their life.

At least 19 distinct types of osteogenesis imperfecta have been identified, categorized as type I through type XIX. While signs and symptoms can vary among these types, there is also considerable overlap. Increasingly, genetic factors are used to define the rarer forms of OI. Type I, also known as classic non-deforming OI with blue sclerae (the whites of the eyes), represents the mildest form. Conversely, type II, or perinatally lethal OI, is the most severe. Types III (progressively deforming OI) and IV (common variable OI with normal sclerae) exhibit symptoms and severity levels that fall between these two extremes.

Milder forms of OI, such as type I, are characterized by bone fractures during childhood and adolescence, often resulting from minor injuries like falls while learning to walk. The frequency of fractures typically decreases in adulthood. Individuals with mild OI often have a blue or grey tint to their sclerae, and approximately half develop hearing loss as they age. Unlike individuals with more severe forms, those with type I usually reach a normal or near-normal height.

More severe types of osteogenesis imperfecta are associated with frequent bone fractures that may be present at birth and occur with minimal or no trauma. Other characteristics can include blue sclerae, short stature, spinal curvature (scoliosis), joint deformities (contractures), hearing loss, respiratory difficulties, and dentinogenesis imperfecta, a disorder affecting tooth development. Mobility can be limited, and some individuals may require assistive devices like walkers or wheelchairs. The most severe forms of OI, especially type II, can involve an abnormally small and fragile rib cage and underdeveloped lungs. Infants with these complications may experience life-threatening breathing problems and may die shortly after birth.

Inheritance:

OI caused by mutations in the COL1A1 or COL1A2 genes typically follows an autosomal dominant inheritance pattern. This means that inheriting just one copy of the mutated gene is enough to cause the condition. Many people with type I or type IV OI inherit the mutation from an affected parent. However, most infants with more severe forms of OI, such as type II and type III, have no family history of the condition. In these cases, the condition arises from a new (sporadic) mutation in the COL1A1 or COL1A2 gene. Type V OI also follows an autosomal dominant inheritance pattern.

Less commonly, OI can be inherited in an autosomal recessive pattern. This requires inheriting two copies of the mutated gene, one from each parent. The parents of a child with an autosomal recessive condition are usually unaffected carriers, each possessing one copy of the altered gene. Types VI through XVIII are inherited in this manner.

Osteogenesis imperfecta type XIX is inherited in an X-linked recessive pattern. An X-linked condition arises when the mutated gene responsible for the disorder is located on the X chromosome, one of the two sex chromosomes. In males, who have only one X chromosome, a mutation in that single copy is sufficient to cause the condition. Females, with two X chromosomes, would need mutations in both copies for the condition to manifest. Consequently, males are affected by X-linked recessive disorders far more often than females. A key characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.