title: Whole exome sequencing of extreme morbid obesity patients: translational implications for obesity and related disorders.
abstract: Whole-exome sequencing (WES) is a new tool that allows the rapid, inexpensive and accurate exploration of Mendelian and complex diseases, such as obesity. To identify sequence variants associated with obesity, we performed WES of family trios of one male teenager and one female child with severe early-onset obesity. Additionally, the teenager patient had hypopituitarism and hyperprolactinaemia. A comprehensive bioinformatics analysis found de novo and compound heterozygote sequence variants with a damaging effect on genes previously associated with obesity in mice (LRP2) and humans (UCP2), among other intriguing mutations affecting ciliary function (DNAAF1). A gene ontology and pathway analysis of genes harbouring mutations resulted in the significant identification of overrepresented pathways related to ATP/ITP (adenosine/inosine triphosphate) metabolism and, in general, to the regulation of lipid metabolism. We discuss the clinical and physiological consequences of these mutations and the importance of these findings for either the clinical assessment or eventual treatment of morbid obesity.
authors.affiliation: Genome Biology Department, The John Curtin School of Medical Research, The Australian National University, Garran Rd, building 131, Acton, Canberra, ACT 0200, Australia. gilberto.pazfilho@anu.edu.au.
authors.forename: Gilberto
authors.initials: G
authors.lastname: Paz-Filho
authors.affiliation: Endocrine Division (SEMPR), Department of Internal Medicine, Federal University of Parana, Avenida Agostinho Leão Junior, 285-Alto da Glória. CEP 80030-110, Curitiba-PR, Brazil. margabogus@uol.com.br.
authors.forename: Margaret C S
authors.initials: MC
authors.lastname: Boguszewski
authors.affiliation: Genome Biology Department, The John Curtin School of Medical Research, The Australian National University, Garran Rd, building 131, Acton, Canberra, ACT 0200, Australia. Claudio.mastronardi@anu.edu.au.
authors.forename: Claudio A
authors.initials: CA
authors.lastname: Mastronardi
authors.affiliation: Genome Biology Department, The John Curtin School of Medical Research, The Australian National University, Garran Rd, building 131, Acton, Canberra, ACT 0200, Australia. Hardip.Patel@anu.edu.au.
authors.forename: Hardip R
authors.initials: HR
authors.lastname: Patel
authors.affiliation: Genome Biology Department, The John Curtin School of Medical Research, The Australian National University, Garran Rd, building 131, Acton, Canberra, ACT 0200, Australia. u4842377@anu.edu.au.
authors.forename: Angad S
authors.initials: AS
authors.lastname: Johar
authors.affiliation: Genome Biology Department, The John Curtin School of Medical Research, The Australian National University, Garran Rd, building 131, Acton, Canberra, ACT 0200, Australia. Aaron.Chuah@anu.edu.au.
authors.forename: Aaron
authors.initials: A
authors.lastname: Chuah
authors.affiliation: Genome Biology Department, The John Curtin School of Medical Research, The Australian National University, Garran Rd, building 131, Acton, Canberra, ACT 0200, Australia. gavin.huttley@anu.edu.au.
authors.forename: Gavin A
authors.initials: GA
authors.lastname: Huttley
authors.affiliation: Endocrine Division (SEMPR), Department of Internal Medicine, Federal University of Parana, Avenida Agostinho Leão Junior, 285-Alto da Glória. CEP 80030-110, Curitiba-PR, Brazil. clbogus@uol.com.br.
authors.forename: Cesar L
authors.initials: CL
authors.lastname: Boguszewski
authors.affiliation: Mind and Brain Theme, South Australian Health and Medical Research Institute, and Department of Psychiatry, School of Medicine, Flinders University, PO Box 11060 Adelaide SA 5001, Adelaide, Australia. maliwong7@gmail.com.
authors.forename: Ma-Li
authors.initials: ML
authors.lastname: Wong
authors.affiliation: Genome Biology Department, The John Curtin School of Medical Research, The Australian National University, Garran Rd, building 131, Acton, Canberra, ACT 0200, Australia. Mauricio.Arcos-Burgos@anu.edu.au.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Arcos-Burgos
authors.affiliation: Mind and Brain Theme, South Australian Health and Medical Research Institute, and Department of Psychiatry, School of Medicine, Flinders University, PO Box 11060 Adelaide SA 5001, Adelaide, Australia. julio.licinio@sahmri.com.
authors.forename: Julio
authors.initials: J
authors.lastname: Licinio