ORIGINAL ARTICLE

Genotype-phenotype relationships in Berardinelli-Seip congenital lipodystrophy

L Van Maldergem¹, J Magré², T E Khallouf³, T Gedde-Dahl, Jr⁴, M Delépine⁵, O Trygstad⁶, E Seemanova⁷, T Stephenson⁸, C S Albott¹, F Bonnici⁹, V R Panz^10,19, J-L Medina^11,20, P Bogalho^12,21, F Huet^13,22, S Savasta^14,23, A Verloes^15,24, J-J Robert^16,25, H Loret^17,26, M de Kerdanet^18,27, N Tubiana-Rufi, A Mégarbané, J Maassen, M Polak, D Lacombe, C R Kahn, E L Silveira, F H D’Abronzo, F Grigorescu, M Lathrop⁵, J Capeau², S O’Rahilly

¹ Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Loverval, Belgium
² INSERM U 402, Faculté de Médecine Saint Antoine, Paris, France
³ Service de Pédiatrie, Hotel-Dieu de France, Beirut, Lebanon
⁴ Department of Dermatology and Institute of Forensic Medicine, Rikshospitalet, Oslo, Norway
⁵ Centre National de Génotypage, Evry, France
⁶ Department of Paediatrics, Rikshospitalet, Oslo, Norway
⁷ Department of Clinical Genetics, Charles University, Prague, Czech Republic
⁸ Department of Child Health, University Hospital, Nottingham, UK
⁹ Paediatric Endocrine Services, University of Cape Town, Cape, South Africa
¹⁰ Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa
¹¹ Department of Endocrinology, Hospital S Joäo, Porto, Portugal
¹² Unidade de Endocrinologia, Hospital Curry Cabral, Lisbon, Portugal
¹³ Service de Pédiatrie, Hôpital d’Enfants du Bocage, Dijon, France
¹⁴ Clinica Pediatrica, Policlinico S Matteo, Università di Pavia, Pavia, Italy
¹⁵ Centre de Génétique Humaine, CHU Sart-Tilman, Liége, Belgium
¹⁶ Service de Diabétologie Infantile, Hôpital Necker, Paris, France
¹⁷ Service de Pédiatrie, CHU, Fort-de-France, Guadeloupe
¹⁸ Unité d’Endocrinologie Pédiatrique, CHU Rennes, France
¹⁹ Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa
²⁰ Department of Endocrinology, Hospital S Joäo, Porto, Portugal
²¹ Unidade de Endocrinologia, Hospital Curry Cabral, Lisbon, Portugal
²² Service de Pédiatrie, Hôpital d’Enfants du Bocage, Dijon, France
²³ Clinica Pediatrica, Policlinico S Matteo, Università di Pavia, Pavia, Italy
²⁴ Centre de Génétique Humaine, CHU Sart-Tilman, Liége, Belgium
²⁵ Service de Diabétologie Infantile, Hôpital Necker, Paris, France
²⁶ Service de Pédiatrie, CHU, Fort-de-France, Guadeloupe
²⁷ Unité d’Endocrinologie Pédiatrique, CHU Rennes, France

Correspondence to:
Correspondence to:
Dr L Van Maldergem, Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Allée des Templiers 41, B-6280 Loverval, Belgium;
vmald{at}skypro.be

Generalised lipodystrophy of the Berardinelli-Seip type (BSCL) is a rare autosomal recessive human disorder with severe adverse metabolic consequences. A gene on chromosome 9 (BSCL1) has recently been identified, predominantly in African-American families. More recently, mutations in a previously undescribed gene of unknown function (BSCL2) on chromosome 11, termed seipin, have been found to be responsible for this disorder in a number of European and Middle Eastern families. We have studied the genotype/phenotype relationships in 70 affected subjects from 44 apparently unrelated pedigrees of diverse ethnic origin. In all subjects, hepatic dysfunction, hyperlipidaemia, diabetes mellitus, and hypertrophic cardiomyopathy were significant contributors to morbidity with no clear differences in their prevalence between subjects with BSCL1 or BSCL2 and those with evidence against cosegregation with either chromosome 9 or 11 (designated BSCLX). BSCL2 appears to be a more severe disorder than BSCL1 with a higher incidence of premature death and a lower prevalence of partial and/or delayed onset of lipodystrophy. Notably, subjects with BSCL2 had a significantly higher prevalence of intellectual impairment than those with BSCL1 or BSCLX (p<0.0001, OR 17.0, CI 3.6 to 79.0). The higher prevalence of intellectual impairment and the increased risk of premature death in BSCL2 compared to BSCL1 emphasise the importance of molecular diagnosis of this syndrome and have clear implications for genetic counselling.

Keywords: genotype-phenotype correlation; lipodystrophy; mental retardation; seipin

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