Interpretation of Test Results

Novel missense mutations always present a diagnostic dilemma: Are they the cause of the disease or are they benign variants? The task is somewhat easier for the FGFR genes because the genes are relatively nonpolymorphic and most changes seem to be pathogenic. Many missense mutations that might seem potentially innocuous on theoretical grounds, because the amino acid changes are relatively conservative (e.g., S252L, I288S, and A314S in FGFR2), are actually pathogenic. Nevertheless, interpretation is facilitated if the newly detected mutation is a de novo mutation in an isolated case of the disease or changes an evolution-arily conserved amino acid to one that could not fulfill the same function. For example, a novel 3-base insertion that adds a glycine residue at codon 272 (G272GG) in exon 3a of FGFR2 was detected in a patient with Crouzon syndrome. The mutation could not be established as a de novo mutation because one parent was unavailable for testing.

However, there was precedent for this being a disease-causing mutation in that a very similar type of mutation (also the insertion of 3 bases encoding glycine) had previously been reported at a nearby location in the gene (T268TG). At the time, interpretation was more difficult because more limited experience with testing of the FGFR genes had not yet established that almost all changes are pathogenic. Up-to-date listings of known mutations in each FGFR gene are available through the Human Gene Mutation Database.4

Some disorders are so severe that, although the inheritance pattern theoretically would show dominant transmission, the mutations are not normally transmitted due to their lethality, and all affected individuals have a new mutation. Although the parent who transmitted the mutant allele does not have the syndrome, since they are alive, the possibility of germline mosaicism or more rarely somatic and germline mosaicism in that parent must never be overlooked by either the genetic counselor or the diagnostic laboratory. If a mutation was identified in the affected individual, offering prenatal diagnosis for all future pregnancies is advisable. All FGFR test results should be interpreted in the context of the family history by an individual with expertise in clinical molecular genetics.

Comprehensive reviews of the clinical features of each syndrome are available.6-8 In addition, many valuable online resources are available. Particularly useful resources are OMIM2 and GeneReviews.3 A fairly simple description of the various molecular mechanisms of dominance can be found in Strachan and Read,9 and much more detailed descriptions of the molecular mechanisms as they apply to the skeletal dysplasias can be found in Wilkie.1,10

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