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Discordant phenotype and sterol biochemistry in Smith–Lemli–Opitz syndrome
Author(s) -
Koo Grace,
Conley Sandra K.,
Wassif Christopher A.,
Porter Forbes D.
Publication year - 2010
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.33540
Subject(s) - smith–lemli–opitz syndrome , sterol , biology , phenotype , cholesterol , 7 dehydrocholesterol reductase , mutant , medicine , endocrinology , reductase , compound heterozygosity , genetics , gene , biochemistry , enzyme
Smith–Lemli–Opitz syndrome (SLOS) is a malformation syndrome resulting from mutations of the 7‐dehydrocholesterol reductase ( DHCR7 ) gene. During cholesterol biosynthesis, DHCR7 catalyzes the conversion of 7‐dehydrocholesterol (7DHC) to cholesterol. A clinical diagnosis of SLOS is confirmed biochemically by the presence of elevated levels of 7DHC. Phenotypic severity of SLOS has previously been shown to correlate with the 7DHC/cholesterol ratio. We describe a patient with a severe SLOS phenotype, but a very low serum 7DHC/cholesterol ratio. We show that this discordance is due to alternative splicing of a previously unreported IVS5+3 A>T mutation. This mutation results in the transcription of both normal and mutant mRNA transcripts. We postulate that alternative splicing of the IVS5+3 A>T results in insufficient DHCR7 activity during embryogenesis, but sufficient DHCR7 activity once cholesterol synthetic rates decrease postnatally. This unique case underscores the adjunctive use of fibroblast and molecular testing in ambiguous cases of SLOS and may provide insight into the potential efficacy of therapeutic interventions altering postnatal cholesterol biosynthesis. Published 2010 Wiley‐Liss, Inc.