This patient's clinical presentation is consistent with cystic fibrosis, which is usually caused by a three-nucleotide deletion. Deletion of three nucleotides is termed an "in-frame" mutation.
Several types of DNA mutations can yield changes in protein structure. In the case of cystic fibrosis, more than 65% of cases are caused by the "delta 508" mutation in the cystic fibrosis transmembrane regulator channel (CFTR). This channel allows cells in sweat glands to reabsorb chloride. The mutation leads to improper protein folding, which results in the classic, high-salt content in the sweat of patients with cystic fibrosis.
Solomon and Muenke discuss when to suspect that a patient may have a genetic disease. Signs that should warrant investigation of genetic diseases include dysmorphic features, multiple abnormalities in one patient, neurocognitive difficulties, and a family history of known genetic mutations.
Yang et al. discuss whole-exome sequencing as a method to identify genetic defects in patients thought to have a genetic disorder. The exome consists of all DNA sequences that are in the final, mature RNA, after transcription and processing. The authors find that whole-exome sequencing identified the underlying genetic abnormality in 25% of patients.
Illustration A shows the function of the CFTR channel. Illustration B shows the in-frame deletion that results in the delta 508 genotype. Illustration C illustrates examples of several different types of point mutations.
Answer 1: This results from an addition or deletion of 1 or 2 nucleotides, not 3 nucleotides.
Answer 3: This results in a stop codon, leading to early termination of the peptide during translation.
Answer 4: This results from DNA instability in diseases like Huntington's chorea.
Answer 5: This results in no change to the encoded protein.
Solomon BD, Muenke M. When to suspect a genetic syndrome. Am Fam Physician. 2012 Nov 1;86(9):826-33.
PMID:23113462 (Link to Abstract)
Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A, Ward PA, Braxton A, Beuten J, Xia F, Niu Z, Hardison M, Person R, Bekheirnia MR, Leduc MS, Kirby A, Pham P, Scull J, Wang M, Ding Y, Plon SE, Lupski JR, Beaudet AL, Gibbs RA, Eng CM. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med. 2013 Oct 17;369(16):1502-11.
PMID:24088041 (Link to Abstract)