OI and Genetic Bone Disorders Panel

Posted on by Dru Leistritz

The Collagen Diagnostic Laboratory offers a comprehensive Osteogenesis Imperfecta (OI) and Genetic Bone Disorder panel of 42 genes.  The OI and Genetic Bone Disorders panel includes 4 genes associated with autosomal dominant forms of OI, COL1A1, COL1A2, IFITM5 and PLS3, and 13 genes associated with autosomal recessive forms of OI and hypophosphatasia, FKBP10, CRTAP, P3H1/LEPRE1, PPIB, SERPINH1, SP7/OSX, SERPINF1, PLOD2, ALPL, BMP1, TMEM38B, WNT1 and CREB3L1.  It also includes testing for hypophosphatasia, x-linked osteoporosis, bone mineralization disorders, and other skeletal dysplasias (see complete list on test requisition form).

This panel may be done in a tiered manner, with the dominant genes tested first and the remaining genes only tested if the dominant genes were normal (please indicate this on the test requisition form).  Over 95% of OI phenotypes result from a single dominant mutation in either COL1A1 or COL1A2, the two genes that encode the chains of type I procollagen, so this test is always recommended as a first step in testing individuals with a clinical diagnosis of OI.

When considering recessive forms of OI or other bone disorders, consultation with the laboratory genetic counselors or laboratory director is recommended as clinical and family history and x-ray review may be needed.  Occasionally new candidate genes for recessive form of OI will be included as part of the panel; there is no additional charge for testing of these genes.

For guidelines on the correct test to order and for pertinent references, consult the Osteogenesis Imperfecta Test Guide.

Comprehensive Dominant OI Panel

Posted on by Melanie Pepin

PLEASE NOTE:  As of August 1, 2017 this panel has been replaced by the OI and Genetic Bone Disorders Panel.  Please contact the laboratory (206-543-5464) to special order.

The Comprehensive Dominant OI Panel offers sequencing for non-recessive forms of OI. Causative mutations have been identified in several genes associated with autosomal dominant forms of Osteogenesis Imperfecta (OI):  most commonly in COL1A1, COL1A2 and IFITM5 but also in P4HB, LRP5, ALPL and WNT1.  Recently, mutations in a single gene associated with X-linked OI, PLS3, have been identified.

Over 95% of OI phenotypes result from a single dominant mutation in either COL1A1 or COL1A2, the two genes that encode the chains of type I procollagen.  The phenotype that results from the disease-causing variant is a consequence of the underlying mutation type and location in the a1 or a2 chain of type I procollagen.  Null mutations of COL1A1 result in OI type I and missense mutations in either COL1A1 or COL1A2 result in variable phenotypes within a spectrum of age of onset, fracture frequency, stature and deformity.

OI type V is also a dominant form of OI resulting from a mutation in IFITM5, the gene that encodes interferon induced transmembrane protein 5.  Type V has a wide range of presentation but with distinguishing clinical and radiological features that can include a propensity to hyperplastic callus formation, calcification of the forearm interosseous membrane, radiodense metaphyseal bands, and radial head dislocation.

Hemizygous mutations in PLS3 are associated with osteoporosis and bone fragility in childhood.

For guidelines on the correct test to order and for pertinent references, consult the Osteogenesis Imperfecta Test Guide.

Osteopetrosis Panel

Posted on by Stephen Schildbach

The CDL offers a 14 gene panel examining genes associated with autosomal dominant and recessive forms of osteopetrosis (AMER1, CA2, CLCN7, CTSK, FAM20C, FERMT3, LEMD3, LRP5, OSTM1, PLEKHM1, SNX10, TCIRG1, TNFRSF11A, and TNFSF11).  Osteopetrosis is a bone disease that results in unusually dense bones that are prone to fracture. Autosomal dominant osteopetrosis is the most common form, affecting approximately 1 in 20,000 individuals, and is also the milder form. The major features in these individuals include multiple fractures, scoliosis, arthritis, and osteomyelitis and typically begin to manifest in late childhood or adolescence.

Autosomal recessive osteopetrosis is a more severe form of the disorder with a frequency of approximately 1 in 250,000 individuals. Affected individuals have a high risk of fracture, even from minor bumps and falls and may have short stature, dental abnormalities, and hepatosplenomegaly. The abnormally dense skull bones can pinch cranial nerves resulting in vision and hearing loss. These individuals may also experience problems with abnormal bleeding and recurrent infections due to impaired bone marrow function.

This panel is recommended for individuals with possible autosomal dominant or recessive osteopetrosis.