Editor—Smith-Lemli-Opitz (SLO) syndrome (MIM 270400) is an autosomal recessive disorder characterised by a wide spectrum of developmental abnormalities including craniofacial malformations, growth and mental retardation, and multiple congenital anomalies.1-3 The disorder is caused by deficient activity of 7-dehydrocholesterol reductase (7-DHCR), the enzyme that catalyses the reduction of the C₇-C₈ (Δ7) double bond of 7-dehydrocholesterol to produce cholesterol.4 5 As a consequence, patients with SLO syndrome have low plasma cholesterol and raised plasma 7-dehydrocholesterol concentrations, thus constituting the biochemical hallmark used to confirm the clinical diagnosis of the syndrome.

Recently, we and others have identified the cDNA coding for human 7-DHCR and confirmed that SLO syndrome is caused by mutations in the corresponding 7-DHCR gene.6-8 So far, 19 different disease causing mutations have been reported, which were identified after analysis of only 33 patient alleles. In our previous report, we described an aberrantly spliced mutant 7-DHCR cDNA with an insertion of 134 bp which we identified in two of three Dutch patients analysed with SLO syndrome, one of whom was a homozygote and the other a compound heterozygote.6 Upon translation, this insertion not only introduces additional amino acids but also causes a frameshift, which leads to an inactive, truncated protein with a changed C-terminus.6 Since the same insertion was also reported by two other groups,7 8 and since the affected patients were not related to one another, this finding suggested that the insertion is the result of a frequently occurring mutation. To evaluate this, we analysed 17 additional patients with SLO syndrome for the occurrence of the 134 bp insertion using allele specific RT-PCR. Furthermore, we studied the underlying mechanism that gives rise to the aberrant splicing, which results in the 134 bp insertion at the cDNA level.

First strand …