Comparison of complementary and genomic DNA sequencing for the detection of mutations in the HMBS gene in British patients with acute intermittent porphyria: identification of 25 novel mutations

Acute intermittent porphyria (AIP) is a low-penetrant autosomal dominant di sorder caused by mutations in the hydroxymethylbilane synthase (HMBS) gene. Direct detection of mutations is becoming the method of choice for the acc urate identification of asymptomatic affected individuals within AIP famili es so that they can be advised to avoid drugs and other compounds that prov oke the life-threatening acute neurovisceral crises that characterise the c ondition. We describe a prospective comparison of direct automated sequenci ng of cDNA (29 patients) or genomic DNA (28 patients) to identify HMBS muta tions in 57 patients referred consecutively for mutational analysis; 39 dif ferent mutations were identified in 54 patients. The sensitivity of the cDN A and genomic DMA methods was 69% and 95%, respectively, indicating that an alysis of genomic DNA provides a higher mutation detection rate. Thirty mut ations were restricted to a single family; only one (R173W) occurred in mor e than three families. Of the mutations (6 missense, 8 splice defects, 10 f rameshifts, 1 nonsense), 25 have not been reported previously. One novel mu tation (344+33G-->T) was located in a putative intron splice enhancer in in tron 7. Our results define the extent of allelic heterogeneity and the type s (41% missense; 59% truncating) and distribution (35% in exons 10, 12, 14) of HMBS mutations, for AIP in the United Kingdom.