The Invitae Osteogenesis Imperfecta Panel analyzes four genes that are associated with osteogenesis imperfecta (OI). Genetic testing can provide an accurate diagnosis, which may help guide medical management and surveillance decisions, predict disease progression and outcome, and determine the recurrence risk.
COL1A1 COL1A2 CRTAP P3H1
COL1A1 COL1A2 CRTAP P3H1
Osteogenesis imperfecta (OI) is associated with bone fragility that results in fractures despite minimal trauma. Additional features may include skeletal deformities and short stature, tooth erosion referred to as dentinogenesis imperfecta, hearing loss, and blue or gray sclera. The severity of OI can range from significant skeletal changes and multiple fractures in infancy to an extremely mild presentation with infrequent bone fracture.
COL1A1- and COL1A2-related OI is divided into four subtypes (I-IV) based on the number, type, and severity of clinical features. There is considerable overlap across these clinical subtypes.
CRTAP-related OI is characterized by frequent bone fractures and skeletal changes that can present in utero or be apparent at birth. It has been suggested that normocephaly, a round face with shallow orbits, normal or gray sclera, and rhizomelic shortening of the arms and legs may be distinctive features of CRTAP-related OI; however, due to the small number of individuals reported, the specificity of these clinical features is uncertain.
P3H1-related OI shares significant phenotypic overlap with CRTAP-related OI and can be lethal. Surviving children with P3H1-related OI have severe growth deficiency and bulbous metaphyses. A founder mutation, c.1080+1G>T, has been identified in approximately 1.5% of the West African population.
Of note, a single variant, c.3040C>T (p.Arg1014Cys; also known as p.Arg836Cys), in COL1A1 is associated with autosomal-dominant Caffey disease and would be identified by the Invitae Osteogenesis Imperfecta Panel. Caffey disease is characterized by fever, joint swelling, pain, and distinctive bone lesions that are identifiable by X-ray. Onset is in infancy; it typically resolves itself by the age of 2 years.
Pathogenic variants in COL1A1 and COL1A2 are identified in approximately 90% of individuals with OI. The clinical sensitivity for the CRTAP and P3H1 genes is not well established.
COL1A1- and COL1A2-related OI is autosomal dominant. The percentage of COL1A1 and COL1A2 de novo variants varies from 60%–100% depending on the OI subtype. CRTAP- and P3H1-related OI is autosomal recessive.
COL1A1- and COL1A2-related OI exhibits complete penetrance with variable expressivity. CRTAP-related OI exhibits reduced penetrance with approximately 90% of patients meeting diagnostic criteria for OI. Penetrance for P3H1-related OI is unknown.
The incidence of OI has been reported as approximately 6–7 in 100,000 live births. The incidence in Finland is higher, estimated at approximately 1 in 15,000 live births.
This panel may be appropriate for confirmation of a clinical diagnosis or establishment of a diagnosis in an individual with suspected OI.
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|