Congenital generalized lipodystrophy: identification of novel variants and expansion of clinical spectrum

A Haghighi; Z Kavehmanesh; A Haghighi; F Salehzadeh; F Santos-Simarro; L Van Maldergem; L Cimbalistiene; F Collins; M Chopra; S Al-Sinani; S Dastmalchian; D C de Silva; H Bakhti; A Garg; P Hilbert

doi:10.1111/cge.12623

Congenital generalized lipodystrophy: identification of novel variants and expansion of clinical spectrum

Clin Genet. 2016 Apr;89(4):434-441. doi: 10.1111/cge.12623. Epub 2015 Jul 20.

Authors

A Haghighi^{1

2

3}, Z Kavehmanesh⁴, A Haghighi⁵, F Salehzadeh⁶, F Santos-Simarro^{7

8}, L Van Maldergem⁹, L Cimbalistiene¹⁰, F Collins¹¹, M Chopra¹², S Al-Sinani¹³, S Dastmalchian¹⁴, D C de Silva¹⁵, H Bakhti¹⁶, A Garg¹⁷, P Hilbert¹⁸

Affiliations

¹ Department of Genetics, Harvard Medical School, Boston, MA, USA.
² Department of Medicine and the Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, MA, USA.
³ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
⁴ Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran.
⁵ Toronto General Hospital, University of Toronto, Toronto, Canada.
⁶ Pediatric Department, Bouali Hospital, Ardabil University of Medical Sciences, Ardabil, Iran.
⁷ CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.
⁸ Clinical Genetics Unit, INGEMM, IdiPAZ, Hospital Universitario La Paz, UAM, Madrid, Spain.
⁹ Centre de génétique humaine, Université de FRanche-Comté, Besançon, France.
¹⁰ Department of Human and Medical Genetics, Vilnius University, Vilnius, Lithuania.
¹¹ Department of Clinical Genetics, Children's Hospital at Westmead, Sydney, Australia.
¹² Department of Medical Genomics, Royal Prince Alfred Hospital, Camperdown, Sydney, Australia.
¹³ Gastroenterology Unit, Department of Child Health, Sultan Qaboos University Hospital, Muscat, Oman.
¹⁴ Case Medical Center, Case Western Reserve University, Cleveland, OH, USA.
¹⁵ Department of Physiology, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka.
¹⁶ Pathology Department, Takht-e Jamshid Hospital, Karaj, Iran.
¹⁷ Division of Nutrition and Metabolic Diseases, Department of Internal Medicine and the Center for Human Nutrition, UT Southwestern Medical Center, Dallas, TX, USA.
¹⁸ Institute of Pathology and Genetics, Gosselies, Belgium.

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.

Keywords: AGPAT2; BSCL2; CGL1; CGL2; congenital generalized lipodystrophy; genotype-phenotype correlations; novel variants.

Grants and funding

R01 DK105448/DK/NIDDK NIH HHS/United States