Discordant phenotype and sterol biochemistry in Smith-Lemli-Opitz syndrome.

American Journal of Medical Genetics. Part a
Grace KooForbes D Porter

Abstract

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.

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Citations

Jan 15, 2013·Current Opinion in Lipidology·Marisa W Medina, Ronald M Krauss
Aug 29, 2014·Case Reports in Pediatrics·Mehmet DemirdövenAlparslan Tonbul
Oct 13, 2012·American Journal of Medical Genetics. Part C, Seminars in Medical Genetics·Małgorzata J M Nowaczyk, Mira B Irons
Oct 9, 2012·American Journal of Medical Genetics. Part C, Seminars in Medical Genetics·Hans R Waterham, Raoul C M Hennekam
Jun 4, 2015·Journal of Pharmacy Practice·Nicole A SlaterArthur F Harralson
Jun 28, 2019·Systems Biology in Reproductive Medicine·Panagiotis NtostisDavid Miller
Apr 7, 2021·Molecular Psychiatry·Zeljka KoradeKároly Mirnics

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