Testing the test

From a clinic note: "She was diagnosed with neurofibromatosis type 1. On review of chart, I was unable to find the genetic testing confirming this.  She does have several café au lait spots on her trunk and lower extremities. She does have half-siblings with neurofibromatosis type 1, and her father also has NF (neurofibromatosis) type 1."  It would seem that the purport of genetic testing in this instance would be to test the test, rather than to confirm the patient's diagnosis. The diagnosis seems quite secure; it is the test's sensitivity that is in question. I have another patient whose father clearly has NF1 and the patient has both cutaneous and cranial MRI stigmata of the disorder. When the patient had the most sensitive molecular genetic test then available, no abnormality was detected. As the test evolved in the same laboratory, the patient and his father were found to have pathogenic mutations in the neurofibromin gene.

Ultimately, the patient above did have genetic testing done, which showed a 3 bp deletion c.2970_2972delAAT(p.Met991del). This alteration was previously reported in 21 unrelated probands and families. This particular deletion is associated with a very mild phenotype in the majority of cases, with a paucity of cutaneous, subcutaneous and superficial plexiform neurofibromas.
 

In a similar vein, I had a patient with juvenile Huntington's disease. His mother had Huntington's disease, as did others in her lineage. When molecular genetic testing for Huntington's became available, his result was normal. In actuality, he had so many trinucleotide repeats on the affected gene that the test then available read only the number on the unaffected gene. The director of the laboratory initially testing rather superciliously told me to pursue another diagnosis. Alternative forms of testing subsequently established the the affected gene had a very high number of trinucleotide repeats, rendering it opaque to the original form of testing. See: Nance MA, Mathias-Hagen V, Breningstall G, Wick MJ, McGlennen RC. Analysis of a very large trinucleotide repeat in a patient with juvenile Huntington's disease. Neurology. 1999 Jan 15;52(2):392-4.  I sent a copy of the article to the laboratory director above.

 

See also:  Mao R, Aylsworth AS, Potter N, Wilson WG, Breningstall G, Wick MJ,
Babovic-Vuksanovic D, Nance M, Patterson MC, Gomez CM, Snow K. Childhood-onset
ataxia: testing for large CAG-repeats in SCA2 and SCA7. Am J Med Genet. 2002 Jul
15;110(4):338-45.