What genetic tests are available for osteoporosis, particularly for patients with a family history of the condition?

Genetic Testing Available for Osteoporosis

For patients with suspected genetic osteoporosis, particularly those with family history, early-onset disease, or multiple fractures, the primary genetic tests available are COL1A1/COL1A2 mutation analysis (DNA-based testing) and biochemical collagen screening from cultured fibroblasts, with additional gene-specific testing available for rarer monogenic bone disorders. 1, 2

Primary Genetic Testing Options

COL1A1/COL1A2 Mutation Analysis (DNA-Based Testing)

• This is the first-line genetic test for suspected osteogenesis imperfecta (OI), the most common monogenic cause of osteoporosis and bone fragility. 1, 2
• DNA-based testing identifies mutations in the two genes encoding type I collagen chains, which cause most cases of OI types I, II, III, and IV. 1
• Testing can be performed on blood samples, cultured fibroblasts, chorionic villus samples (CVS), or amniocytes. 1
• Turnaround time is approximately 7-14 days from tissue sampling to results. 1
• Available through specialized laboratories including University of Washington and Tulane University Matrix DNA Diagnostic Lab. 1

Biochemical Collagen Screening

• Biochemical analysis evaluates type I procollagen synthesized by cultured skin fibroblasts to detect either reduced collagen production or structurally abnormal collagen molecules. 1
• This test has high sensitivity for detecting OI types I-IV but requires skin biopsy and cell culture. 1
• Turnaround time is approximately 3-4 weeks from biopsy to final diagnosis. 1
• Consider biochemical testing when DNA testing is inconclusive but clinical suspicion remains high. 3
• Available at University of Washington pathology laboratory. 1

Gene-Specific Testing for Other Monogenic Bone Disorders

When Clinical Features Suggest Alternative Diagnoses

• TNSALP gene testing for hypophosphatasia when patients present with severe undermineralization, bone deformity, fractures, elevated urinary phosphoethanolamine, and low serum alkaline phosphatase. 1, 2, 3
• PLOD2 gene testing for Bruck syndrome when osteoporosis occurs with joint contractures, fractures, and short stature. 1, 2
• TNFRSF11B gene testing for juvenile Paget's disease when patients show rapidly remodeling bone, osteopenia, fractures, and progressive skeletal deformity. 1, 2
• CAII gene testing for osteopetrosis with renal tubular acidosis when fractures occur before age 2 with short stature, delayed development, cerebral calcifications, and mental retardation. 1, 2
• FGF23 and HYP gene testing for hypophosphatemic osteomalacia when patients present with low serum phosphorus, elevated alkaline phosphatase, and low urine calcium. 1

Clinical Indications for Genetic Testing

Strong Indications Requiring Testing

• Multiple or recurrent fractures with minimal trauma, especially in children or young adults. 2, 4
• Blue sclerae (particularly beyond infancy), dentinogenesis imperfecta, early hearing loss, or short stature. 2, 3
• Family history of multiple fractures, early-onset osteoporosis, or known OI. 1, 2
• Severe or early-onset osteoporosis (premenopausal women, men under 50) without secondary causes. 4, 5
• Unexplained fractures in infants where distinguishing genetic causes from non-accidental injury is critical. 1, 3

Supporting Laboratory Evaluation Before Genetic Testing

• Obtain serum calcium, phosphorus, alkaline phosphatase, and urinary calcium excretion to help direct gene-specific testing. 2, 3
• Radiographic studies to evaluate bone mineralization, fracture patterns, and characteristic skeletal abnormalities. 2, 3
• Bone biopsy with histomorphometry may reveal low bone formation rates suggesting osteoblast dysfunction, which can guide genetic testing decisions. 5

Limitations and Diagnostic Yield

Test Sensitivity Considerations

• COL1A1/COL1A2 testing does not detect OI types V, VI, or VII, which account for approximately 8% of all OI cases. 1
• The combined sensitivity of biochemical and DNA-based testing is high but not 100%, and it remains unclear if sensitivity is additive. 1
• Whole exome sequencing (WES) identified likely pathogenic variants or relevant variants of uncertain significance in only 11% of premenopausal women with idiopathic osteoporosis. 5
• Most patients with early-onset osteoporosis have no identifiable monogenic cause, suggesting heterogeneous pathogenesis including polygenic and environmental factors. 5

Important Clinical Pitfalls

• Blue sclerae occur normally in infants before 12 months of age and should not trigger genetic testing in isolation. 1, 3
• OI types I, IV, V, and VI may present with normal sclerae and only fractures, making clinical diagnosis difficult without laboratory confirmation. 1, 3
• Many OI cases represent de novo mutations without family history, so absence of family history does not exclude genetic osteoporosis. 2
• When evaluating unexplained fractures in infants, biochemical or DNA testing may be the best safeguard against missing OI and incorrectly attributing fractures to non-accidental injury. 1

Prenatal and Preconception Testing

For Families with Known OI

• Targeted ultrasound should be offered at 13-14 weeks gestation for pregnancies at risk for OI type II (lethal form) and 16-20 weeks for OI type III. 1
• Biochemical collagen analysis on cultured chorionic villus cells can be performed if the affected parent or previous infant had documented abnormal collagen screening. 1
• Mutation analysis using DNA from CVS or amniocytes is available when the familial mutation is known, with 7-14 day turnaround. 1
• Risk to fetus is 50% when a parent has OI, but varies from 0-50% when only a sibling is affected due to possible parental mosaicism. 1

Emerging Genetic Testing Approaches

Broader Genomic Analysis

• Over 50 monogenic disorders presenting primarily with low bone mass and increased fracture risk have been described, expanding beyond traditional OI. 4
• Whole exome sequencing may identify rare variants in genes like LRP5, PLS3, FKBP10, SLC34A3, and HGD in select patients. 5
• Genome-wide association studies have identified over 80 genetic variants implicated in osteoporosis risk, though these explain only a small portion of BMD variation. 6
• Current clinical utility of polygenic risk scores remains limited for routine practice. 7, 6, 8