Indications for Testing
Molecular testing for skeletal dysplasias is useful to
- Confirm a clinical diagnosis based on prenatal or postpartum findings suggestive of a skeletal dysplasia
- Help exclude a skeletal dysplasia when there is suspicion of nonaccidental injury
- Determine specific causative variant(s) in affected adults planning a pregnancy
- Provide accurate genetic counseling, recurrence risk, and prenatal testing options
Molecular analysis, in addition to clinical assessment and radiography, is recommended for definitive diagnosis of a skeletal dysplasia in affected individuals and can be performed prenatally or postnatally. Such testing can also determine the mode of inheritance and risk of recurrence in future pregnancies. Targeted testing of variants identified in an affected child may be recommended in unaffected parents to confirm whether the identified variants are on opposite chromosomes. The genetic cause has been determined for more than 350 of the over 450 known skeletal dysplasias. A list of tested genes and their corresponding disorder(s) can be found in the Skeletal Dysplasia Panel Test Fact Sheet.
Because some skeletal disorders are due to variants in more than one gene and because one clinical feature may not be specific to a certain skeletal dysplasia, a multigene panel is often recommended to identify the pathogenic variant(s). Panels are especially useful when a differential diagnosis includes more than one type of skeletal dysplasia. Panel testing can also reduce the time to diagnosis and, therefore, can be more cost- and time-efficient than testing individual genes.
Testing for a single condition may be appropriate when there is high clinical suspicion for a particular skeletal dysplasia. Otherwise, panel testing is preferred, as testing for a specific disorder targets only the particular variants known to cause the condition. For example, disorder-specific testing is offered for the following three common skeletal dysplasias caused by FGFR3 gene variants.
Achondroplasia is the most common nonlethal skeletal dysplasia in humans and is characterized by short stature with disproportionately short arms and legs, a large head, and normal intelligence. Although individuals with achondroplasia have increased risk for death in infancy from compression of the spinal cord and/or upper airway obstruction, most have a normal lifespan. Two FGFR3 gene variants, c.1138G>A and c.1138G>C, are causative for >99% of cases. Achondroplasia is autosomal dominant, and 80% of cases are due to de novo variants.
Hypochondroplasia is characterized by short stature, stocky build, a large head, shortening of the proximal or middle segments of the extremities, short, broad hands and feet, limitation of elbow extension, and mild joint laxity. It is an autosomal dominant condition, usually arising from a de novo mutation, with 70% of cases resulting from an adenine or guanine substitution for cytosine at nucleotide 1620 in the FGFR3 gene. Clinical features are not evident in infancy but become apparent in childhood.
Thanatophoric dysplasia (TD) is characterized by micromelia, macrocephaly, short ribs, and a narrow thorax. It is divided into TD type 1 (bowed femurs) and TD type 2 (straight femurs and a cloverleaf skull). Death usually occurs from respiratory insufficiency or brain stem compression within hours or days of birth. There are 13 pathogenic variants in the FGFR3 gene known to be causative for TD.