Osteogenesis Imperfecta (OI), commonly known as brittle bone disorder, is characterized by bones that fracture easily, often from minor trauma. This fragility stems from a fundamental defect in the body’s connective tissue structure, not a lack of calcium. Because OI is rooted in a person’s genetic code, achieving an accurate diagnosis relies heavily on specialized genetic analysis. Understanding the specific genetic change is the most definitive way to confirm the condition and inform long-term medical care.
Understanding Osteogenesis Imperfecta Causes
The underlying cause of OI is a flaw in the production of type I collagen, the protein that provides the structural framework for bone, skin, tendons, and the white part of the eye. This structural protein is assembled from components encoded by specific genes. Over 80% of OI cases are linked to mutations in the COL1A1 or COL1A2 genes, which contain the instructions for making the two alpha-chains that form the type I collagen molecule.
Mutations in these primary collagen genes lead to two main problems: the cell produces an insufficient amount of normal type I collagen, or it produces a structurally compromised, malformed protein. The mildest form of OI is associated with a reduction in the total amount of collagen protein. More severe forms result from the production of an abnormal collagen molecule that disrupts the entire bone matrix structure.
Less common forms of the disorder are caused by mutations in other genes, such as SERPINF1, CRTAP, and LEPRE1. These genes do not code for collagen but for proteins that help process, modify, or fold the collagen molecule correctly. These non-collagen gene mutations often result in forms of OI inherited in a recessive pattern, meaning both parents must contribute a copy of the altered gene.
When and Why Genetic Testing is Necessary
Genetic testing for Osteogenesis Imperfecta moves beyond a clinical suspicion based on symptoms like frequent fractures or a bluish tint to the whites of the eyes. A specialized test provides definitive confirmation of the diagnosis by identifying the specific mutation in the patient’s DNA. This molecular evidence is important for distinguishing OI from other conditions that cause bone fragility, such as certain forms of child physical abuse or other skeletal dysplasias, a process known as differential diagnosis.
Identifying the exact gene mutation offers prognostic information, as the location and type of mutation correlates with the expected severity of the condition. This clarity allows clinicians to tailor a personalized management plan, which may include physical therapy or drug therapies like bisphosphonates. Genetic analysis is also important for family planning, providing couples with an accurate calculation of the recurrence risk for future children. Prenatal diagnosis can be offered in subsequent pregnancies when the causative mutation in the family is already known.
The Different Methods of Genetic Analysis
The primary approach to identifying the genetic change in OI involves extracting DNA, typically from a blood sample, and then analyzing the sequence of the relevant genes. Modern testing frequently utilizes a technology called Next-Generation Sequencing (NGS) to examine multiple genes simultaneously. This method sequences the COL1A1 and COL1A2 genes, along with a panel of other genes known to be associated with OI or similar bone fragility disorders.
Using a multi-gene panel is an efficient way to capture both the common collagen gene mutations and the rarer mutations in genes that affect collagen processing. This process involves reading the individual “letters” of the DNA code in the target genes to pinpoint a single-letter change or a small insertion or deletion. However, sequencing may miss larger structural changes in the DNA.
For this reason, genetic analysis includes a separate step called deletion/duplication analysis, which looks for large sections of a gene that may be missing or duplicated. These larger copy number variants (CNVs) are less frequent, accounting for around 1% or less of pathogenic findings in OI. The combined use of gene sequencing and deletion/duplication testing provides a comprehensive analysis for known OI-causing mutations.
Interpreting and Applying Test Results
Genetic test results generally fall into three categories, each carrying distinct implications for the patient and their family.
Pathogenic or Likely Pathogenic Result
A pathogenic or likely pathogenic result confirms the diagnosis by identifying a mutation known to cause OI. This result directly links the patient’s clinical symptoms to a molecular cause, which guides immediate medical management and provides a solid basis for genetic counseling regarding family recurrence risks.
Negative Result
A negative result means no known OI-causing mutation was found in the genes tested, but this does not entirely rule out the condition. Since not all OI genes are known, or the mutation may lie in a region the current technology cannot read, a strong clinical diagnosis of OI may still prompt a recommendation for further testing, such as whole exome sequencing.
Variant of Uncertain Significance (VUS)
The third category is a Variant of Uncertain Significance (VUS), which is a change in the DNA sequence whose effect on the protein is not yet definitively known. A VUS presents a challenge because it cannot confirm or deny a genetic diagnosis. In these cases, the geneticist may recommend functional studies or testing of parents and relatives to see if the variant segregates with the disorder. Genetic counseling is necessary, as the counselor helps translate the technical lab report into understandable information about the patient’s prognosis and future family planning options.