Search for the best indicators for the presence of a VPS13B gene mutation and confirmation of diagnostic criteria in a series of 34 patients genotyped for suspected Cohen syndrome

Salima El Chehadeh (1) , Bernard Aral (1) , Nadège Gigot (1) , Christel Thauvin-Robinet (1) , Anne Donzel (1) , Marie-Ange Delrue (2) , Didier Lacombe (2) , Albert David (3) , Lydie Burglen (4) , Nicole Philip (5) , Anne Moncla (6) , Valérie Cormier-Daire (7) , Marlène Rio (7) , Patrick Edery (8) , Alain Verloes (9) , Dominique Bonneau (10) , Alexandra Affenjar (11) , Aurélia Jacquette (11) , Delphine Heron (11) , Pierre Sarda (12) , Lucille Pinson (12) , Bérénice Doray (13) , Jacqueline Vigneron (14) , Bruno Leheup (14) , Anne-Marie Frances-Guidet (15) , Gwenaelle Dienne (16) , Muiel Holder (17) , Alice Masurel-Paulet (1) , Frédéric Huet (1) , Jean-Raymond Teyssier (1) , Laurence Faivre (1)

1 Service de Cardiologie (hôpital général, CHU Dijon)
2 CHU Bordeaux
3 CHU Nantes - Centre Hospitalier Universitaire de Nantes
4 CHU Trousseau [APHP]
5 CHU de Marseille
6 CHU Marseille
7 Hôpital Necker - Enfants Malades [AP-HP]
8 CHU de Lyon
9 Hôpital Robert Debré
10 CHU Angers - Centre Hospitalier Universitaire d'Angers
11 CHU Pitié-Salpêtrière [AP-HP]
12 CHU de Montpellier
13 CHU Strasbourg - Centre Hospitalier Universitaire [Strasbourg]
14 Service de Médecine Nucléaire [CHRU Nancy]
15 CH Toulon
16 Service Anatomie et cytologie pathologiques [CHU Toulouse]
17 Service d'explorations fonctionnelles respiratoires [Lille]

Background: Cohen syndrome is a rare autosomal recessive inherited disorder that results from mutations of the VPS13B gene. Clinical features consist of a combination of mental retardation, facial dysmorphism, post-natal microcephaly, truncal obesity, slender extremities, joint hyperextensibility, myopia, progressive chorioretinal dystrophy and intermittent neutropenia. Patients and Methods: The aim of our study was to determine which of the above clinical features were the best indicators for the presence of VPS13B gene mutations in a series of 34 patients with suspected Cohen syndrome referred for molecular analysis of VPS13B. Results: Fourteen VPS13B gene mutations were identified in 12 patients, and no mutation was found in 22 patients. The presence of chorioretinal dystrophy (92% versus 32%, p=0.0023), intermittent neutropenia (92% versus 5%, p<0.001) and postnatal microcephaly (100% versus 48%, p=0.0045) was significantly higher in the group of patients with a VPS13B gene mutation compared to the group of patients without a mutation. All patients with VPS13B mutations had chorioretinal dystrophy and/or intermittent neutropenia. The Kolehmainen diagnostic criteria provided 100% sensibility and 77% specificity when applied to this series. Conclusion: From this study and a review of more than 160 genotyped cases from the literature, we conclude that, given the large size of the gene, VPS13B screening is not indicated in the absence of chorioretinal dystrophy or neutropenia in patients aged over 5 years. The follow-up of young patients could be a satisfactory alternative unless there are some reproductive issues.

Mots clés: Diagnostics tests; Clinical genetics

Salima El Chehadeh, Bernard Aral, Nadège Gigot, Christel Thauvin-Robinet, Anne Donzel, et al.. Search for the best indicators for the presence of a VPS13B gene mutation and confirmation of diagnostic criteria in a series of 34 patients genotyped for suspected Cohen syndrome. Journal of Medical Genetics, 2010, 47 (8), pp.549. ⟨10.1136/jmg.2009.075028⟩. ⟨hal-00557384⟩