title: Congenital generalized lipodystrophy: identification of novel variants and expansion of clinical spectrum.
abstract: Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder with two major subtypes. Variants in AGPAT2 result in CGL type 1 with milder manifestations, whereas BSCL2 variants cause CGL type 2 with more severe features. Muscle hypertrophy caused by lack of adipose tissue is present early in life in CGL patients. Our aim was to investigate 10 CGL patients from 7 different countries and report genotype-phenotype relationships. Genetic analysis identified disease-causing variants in AGPAT2 (five patients) and in BSCL2 (five patients), including three novel variants; c.134C>A (p.Ser45*), c.216C>G (p.Tyr72*) in AGPAT2 and c.458C>A (p.Ser153*) in BSCL2. We also report possible novel clinical features such as anemia, breast enlargement, steatorrhea, intraventricular hemorrhage and nephrolithiasis in CGL patients. Generalized lipodystrophy and muscular hypertrophy were the only features in all of our patients. Hepatomegaly was the second common feature. Some manifestations were exclusively noticed in our CGL2 patients; hypertrichosis, high-pitched voice and umbilical hernia. Bone cysts and history of seizures were noticed only in CGL1 patients. The findings of this study expand our knowledge of genotype-phenotype correlations in CGL patients. These results have important clinical applications in diagnosis and management of the CGL patients as well as in genetic counseling in families at-risk.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA, USA.|Department of Medicine and the Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, MA, USA.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: A
authors.initials: A
authors.lastname: Haghighi
authors.affiliation: Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran.
authors.forename: Z
authors.initials: Z
authors.lastname: Kavehmanesh
authors.affiliation: Toronto General Hospital, University of Toronto, Toronto, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Haghighi
authors.affiliation: Pediatric Department, Bouali Hospital, Ardabil University of Medical Sciences, Ardabil, Iran.
authors.forename: F
authors.initials: F
authors.lastname: Salehzadeh
authors.affiliation: CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.|Clinical Genetics Unit, INGEMM, IdiPAZ, Hospital Universitario La Paz, UAM, Madrid, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Santos-Simarro
authors.affiliation: Centre de génétique humaine, Université de FRanche-Comté, Besançon, France.
authors.forename: L
authors.initials: L
authors.lastname: Van Maldergem
authors.affiliation: Department of Human and Medical Genetics, Vilnius University, Vilnius, Lithuania.
authors.forename: L
authors.initials: L
authors.lastname: Cimbalistiene
authors.affiliation: Department of Clinical Genetics, Children's Hospital at Westmead, Sydney, Australia.
authors.forename: F
authors.initials: F
authors.lastname: Collins
authors.affiliation: Department of Medical Genomics, Royal Prince Alfred Hospital, Camperdown, Sydney, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Chopra
authors.affiliation: Gastroenterology Unit, Department of Child Health, Sultan Qaboos University Hospital, Muscat, Oman.
authors.forename: S
authors.initials: S
authors.lastname: Al-Sinani
authors.affiliation: Case Medical Center, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: S
authors.initials: S
authors.lastname: Dastmalchian
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka.
authors.forename: D C
authors.initials: DC
authors.lastname: de Silva
authors.affiliation: Pathology Department, Takht-e Jamshid Hospital, Karaj, Iran.
authors.forename: H
authors.initials: H
authors.lastname: Bakhti
authors.affiliation: Division of Nutrition and Metabolic Diseases, Department of Internal Medicine and the Center for Human Nutrition, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: A
authors.initials: A
authors.lastname: Garg
authors.affiliation: Institute of Pathology and Genetics, Gosselies, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Hilbert
keywords: AGPAT2; BSCL2; CGL1; CGL2; congenital generalized lipodystrophy; genotype-phenotype correlations; novel variants