@article{913ffc2c0d2a4af9a7bec1542e30197e,
title = "Squalene Synthase Deficiency: Clinical, Biochemical, and Molecular Characterization of a Defect in Cholesterol Biosynthesis",
abstract = "Mendelian disorders of cholesterol biosynthesis typically result in multi-system clinical phenotypes, underlining the importance of cholesterol in embryogenesis and development. FDFT1 encodes for an evolutionarily conserved enzyme, squalene synthase (SS, farnesyl-pyrophosphate farnesyl-transferase 1), which catalyzes the first committed step in cholesterol biosynthesis. We report three individuals with profound developmental delay, brain abnormalities, 2-3 syndactyly of the toes, and facial dysmorphisms, resembling Smith-Lemli-Opitz syndrome, the most common cholesterol biogenesis defect. The metabolite profile in plasma and urine suggested that their defect was at the level of squalene synthase. Whole-exome sequencing was used to identify recessive disease-causing variants in FDFT1. Functional characterization of one variant demonstrated a partial splicing defect and altered promoter and/or enhancer activity, reflecting essential mechanisms for regulating cholesterol biosynthesis/uptake in steady state.",
keywords = "FDFT1, cholesterol biosynthesis, dysmorphism, syndactyly",
author = "David Coman and Vissers, {Lisenka E.L.M.} and Riley, {Lisa G.} and Kwint, {Michael P.} and Roxanna Hauck and Janet Koster and Sinje Geuer and Sarah Hopkins and Barbra Hallinan and Larry Sweetman and Engelke, {Udo F.H.} and Burrow, {T. Andrew} and John Cardinal and James McGill and Anita Inwood and Christine Gurnsey and Waterham, {Hans R.} and John Christodoulou and Wevers, {Ron A.} and James Pitt",
note = "Funding Information: The authors would, first and foremost, like to thank the families, without whose participation this work would not have been possible. This work was supported by the Kevin Milo Trust and internal research funds at the Children's Hospital at Westmead. The authors would like to thank the Genome Aggregation Database (gnomAD) and the groups that provided exome and genome variant data to this resource. A full list of contributing groups can be found at http://gnomad.broadinstitute.org/about. The research conducted at the Murdoch Children's Research Institute was supported by the Victorian Government's Operational Infrastructure Support Program. Funding Information: The authors would, first and foremost, like to thank the families, without whose participation this work would not have been possible. This work was supported by the Kevin Milo Trust and internal research funds at the Children{\textquoteright}s Hospital at Westmead . The authors would like to thank the Genome Aggregation Database (gnomAD) and the groups that provided exome and genome variant data to this resource. A full list of contributing groups can be found at http://gnomad.broadinstitute.org/about . The research conducted at the Murdoch Children{\textquoteright}s Research Institute was supported by the Victorian Government{\textquoteright}s Operational Infrastructure Support Program . Publisher Copyright: {\textcopyright} 2018",
year = "2018",
month = jul,
day = "5",
doi = "10.1016/j.ajhg.2018.05.004",
language = "English (US)",
volume = "103",
pages = "125--130",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "1",
}