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Genotype-phenotype relationships in Berardinelli-Seip congenital lipodystrophy
  1. L Van Maldergem1,
  2. J Magré2,
  3. T E Khallouf3,
  4. T Gedde-Dahl, Jr4,
  5. M Delépine5,
  6. O Trygstad6,
  7. E Seemanova7,
  8. T Stephenson8,
  9. C S Albott1,
  10. F Bonnici9,
  11. V R Panz10,19,
  12. J-L Medina11,20,
  13. P Bogalho12,21,
  14. F Huet13,22,
  15. S Savasta14,23,
  16. A Verloes15,24,
  17. J-J Robert16,25,
  18. H Loret17,26,
  19. M de Kerdanet18,27,
  20. N Tubiana-Rufi,
  21. A Mégarbané,
  22. J Maassen,
  23. M Polak,
  24. D Lacombe,
  25. C R Kahn,
  26. E L Silveira,
  27. F H D’Abronzo,
  28. F Grigorescu,
  29. M Lathrop5,
  30. J Capeau2,
  31. S O’Rahilly
  1. 1Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Loverval, Belgium
  2. 2INSERM U 402, Faculté de Médecine Saint Antoine, Paris, France
  3. 3Service de Pédiatrie, Hotel-Dieu de France, Beirut, Lebanon
  4. 4Department of Dermatology and Institute of Forensic Medicine, Rikshospitalet, Oslo, Norway
  5. 5Centre National de Génotypage, Evry, France
  6. 6Department of Paediatrics, Rikshospitalet, Oslo, Norway
  7. 7Department of Clinical Genetics, Charles University, Prague, Czech Republic
  8. 8Department of Child Health, University Hospital, Nottingham, UK
  9. 9Paediatric Endocrine Services, University of Cape Town, Cape, South Africa
  10. 10Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa
  11. 11Department of Endocrinology, Hospital S Joäo, Porto, Portugal
  12. 12Unidade de Endocrinologia, Hospital Curry Cabral, Lisbon, Portugal
  13. 13Service de Pédiatrie, Hôpital d’Enfants du Bocage, Dijon, France
  14. 14Clinica Pediatrica, Policlinico S Matteo, Università di Pavia, Pavia, Italy
  15. 15Centre de Génétique Humaine, CHU Sart-Tilman, Liége, Belgium
  16. 16Service de Diabétologie Infantile, Hôpital Necker, Paris, France
  17. 17Service de Pédiatrie, CHU, Fort-de-France, Guadeloupe
  18. 18Unité d’Endocrinologie Pédiatrique, CHU Rennes, France
  19. 19Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa
  20. 20Department of Endocrinology, Hospital S Joäo, Porto, Portugal
  21. 21Unidade de Endocrinologia, Hospital Curry Cabral, Lisbon, Portugal
  22. 22Service de Pédiatrie, Hôpital d’Enfants du Bocage, Dijon, France
  23. 23Clinica Pediatrica, Policlinico S Matteo, Università di Pavia, Pavia, Italy
  24. 24Centre de Génétique Humaine, CHU Sart-Tilman, Liége, Belgium
  25. 25Service de Diabétologie Infantile, Hôpital Necker, Paris, France
  26. 26Service de Pédiatrie, CHU, Fort-de-France, Guadeloupe
  27. 27Unité d’Endocrinologie Pédiatrique, CHU Rennes, France
  1. 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

Abstract

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.

  • genotype-phenotype correlation
  • lipodystrophy
  • mental retardation
  • seipin
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