Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia

Kiran Musunuru; James P. Pirruccello; Ron Do; Gina M. Peloso; Candace Guiducci; Carrie Sougnez; Kiran V. Garimella; Sheila Fisher; Justin Abreu; Andrew J. Barry; Tim Fennell; Eric Banks; Lauren Ambrogio; Kristian Cibulskis; Andrew Kernytsky; Elena Gonzalez; Nicholas Rudzicz; James C. Engert; Mark A. DePristo; Mark J. Daly; Jonathan C. Cohen; Helen H. Hobbs; David Altshuler; Gustav Schonfeld; Stacey B. Gabriel; Pin Yue; Sekar Kathiresan

doi:10.1056/NEJMoa1002926

Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia

Kiran Musunuru, James P. Pirruccello, Ron Do, Gina M. Peloso, Candace Guiducci, Carrie Sougnez, Kiran V. Garimella, Sheila Fisher, Justin Abreu, Andrew J. Barry, Tim Fennell, Eric Banks, Lauren Ambrogio, Kristian Cibulskis, Andrew Kernytsky, Elena Gonzalez, Nicholas Rudzicz, James C. Engert, Mark A. DePristo, Mark J. DalyJonathan C. Cohen, Helen H. Hobbs, David Altshuler, Gustav Schonfeld, Stacey B. Gabriel, Pin Yue, Sekar Kathiresan

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Abstract

We sequenced all protein-coding regions of the genome (the "exome") in two family members with combined hypolipidemia, marked by extremely low plasma levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. These two participants were compound heterozygotes for two distinct nonsense mutations in ANGPTL3 (encoding the angiopoietin-like 3 protein). ANGPTL3 has been reported to inhibit lipoprotein lipase and endothelial lipase, thereby increasing plasma triglyceride and HDL cholesterol levels in rodents. Our finding of ANGPTL3 mutations highlights a role for the gene in LDL cholesterol metabolism in humans and shows the usefulness of exome sequencing for identification of novel genetic causes of inherited disorders. (Funded by the National Human Genome Research Institute and others.)

Original language	English (US)
Pages (from-to)	2220-2227
Number of pages	8
Journal	New England Journal of Medicine
Volume	363
Issue number	23
DOIs	https://doi.org/10.1056/NEJMoa1002926
State	Published - Dec 2 2010

ASJC Scopus subject areas

General Medicine

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Musunuru, K., Pirruccello, J. P., Do, R., Peloso, G. M., Guiducci, C., Sougnez, C., Garimella, K. V., Fisher, S., Abreu, J., Barry, A. J., Fennell, T., Banks, E., Ambrogio, L., Cibulskis, K., Kernytsky, A., Gonzalez, E., Rudzicz, N., Engert, J. C., DePristo, M. A., ... Kathiresan, S. (2010). Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. New England Journal of Medicine, 363(23), 2220-2227. https://doi.org/10.1056/NEJMoa1002926

Musunuru, K, Pirruccello, JP, Do, R, Peloso, GM, Guiducci, C, Sougnez, C, Garimella, KV, Fisher, S, Abreu, J, Barry, AJ, Fennell, T, Banks, E, Ambrogio, L, Cibulskis, K, Kernytsky, A, Gonzalez, E, Rudzicz, N, Engert, JC, DePristo, MA, Daly, MJ, Cohen, JC , Hobbs, HH, Altshuler, D, Schonfeld, G, Gabriel, SB, Yue, P & Kathiresan, S 2010, 'Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia', New England Journal of Medicine, vol. 363, no. 23, pp. 2220-2227. https://doi.org/10.1056/NEJMoa1002926

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AU - Pirruccello, James P.

AU - Do, Ron

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AU - Guiducci, Candace

AU - Sougnez, Carrie

AU - Garimella, Kiran V.

AU - Fisher, Sheila

AU - Abreu, Justin

AU - Barry, Andrew J.

AU - Fennell, Tim

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AU - Ambrogio, Lauren

AU - Cibulskis, Kristian

AU - Kernytsky, Andrew

AU - Gonzalez, Elena

AU - Rudzicz, Nicholas

AU - Engert, James C.

AU - DePristo, Mark A.

AU - Daly, Mark J.

AU - Cohen, Jonathan C.

AU - Hobbs, Helen H.

AU - Altshuler, David

AU - Schonfeld, Gustav

AU - Gabriel, Stacey B.

AU - Yue, Pin

AU - Kathiresan, Sekar

PY - 2010/12/2

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AB - We sequenced all protein-coding regions of the genome (the "exome") in two family members with combined hypolipidemia, marked by extremely low plasma levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. These two participants were compound heterozygotes for two distinct nonsense mutations in ANGPTL3 (encoding the angiopoietin-like 3 protein). ANGPTL3 has been reported to inhibit lipoprotein lipase and endothelial lipase, thereby increasing plasma triglyceride and HDL cholesterol levels in rodents. Our finding of ANGPTL3 mutations highlights a role for the gene in LDL cholesterol metabolism in humans and shows the usefulness of exome sequencing for identification of novel genetic causes of inherited disorders. (Funded by the National Human Genome Research Institute and others.)

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Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia

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