Identification of 28 novel mutations in the Bardet-Biedl syndrome genes: the burden of private mutations in an extensively heterogeneous disease.

Jean Muller; Corinne Stoetzel; Marie-Claire Vincent; Carmen C Leitch; Virginie Laurier; Jean Marc Danse; S. Hellé; Vincent Marion; V. Bennouna-Greene; Serge Vicaire; André Mégarbané; Josseline Kaplan; Valérie Drouin-Garraud; M. Hamdani; Sabine Sigaudy; Christine Francannet; Joëlle Roume; P. Bitoun; Alice Goldenberg; Nicole Philip; Sylvie Odent; J. Green; M. Cossée; Erica E Davis; Nicholas Katsanis; Dominique Bonneau; Alain Verloes; Olivier Poch; Jean-Louis Mandel; Hélène Dollfus

doi:10.1007/s00439-010-0804-9

Journal articles

Identification of 28 novel mutations in the Bardet-Biedl syndrome genes: the burden of private mutations in an extensively heterogeneous disease.

Jean Muller ^{1, 2, *} Corinne Stoetzel ³ Marie-Claire Vincent ² Carmen C Leitch ⁴ Virginie Laurier ³ Jean Marc Danse ³ S. Hellé ³ Vincent Marion ³ V. Bennouna-Greene ³ Serge Vicaire ¹ André Mégarbané ⁵ Josseline Kaplan ⁶ Valérie Drouin-Garraud ⁷ M. Hamdani ⁸ Sabine Sigaudy ⁹ Christine Francannet ¹⁰ Joëlle Roume ¹¹ P. Bitoun ¹² Alice Goldenberg ⁷ Nicole Philip ¹³ Sylvie Odent ¹⁴ J. Green ¹⁵ M. Cossée ² Erica E Davis ^{4, 16} Nicholas Katsanis ^{4, 16} Dominique Bonneau ¹⁷ Alain Verloes ¹⁸ Olivier Poch ¹⁹ Jean-Louis Mandel ^{2, 19, 20} Hélène Dollfus ³

* Corresponding author

1 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire

2 Laboratoire de diagnostic génétique

3 LGM - Laboratoire de Génétique Médicale

4 McKusick-Nathans Institute of Genetic Medicine

5 Unité de Génétique Médicale

6 Inserm U781 - Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement

7 Service de génétique [Rouen]

8 Hôpital 20 Août 1953

9 Service de Génétique et de Diagnostic Prénatal

10 Unité de Génétique Médicale

11 Service de génétique médicale

12 Service de Pédiatrie [Jean Verdier]

13 Département de génétique médicale [Hôpital de la Timone - APHM]

14 Service de Génétique Clinique

15 Department of Genetics

16 Center for Human Disease Modeling

17 Service de génétique [Angers]

18 Unité fonctionnelle de génétique clinique

19 IGBMC - Institut de génétique et biologie moléculaire et cellulaire

20 Chaire de Génétique Humaine

Abstract : Bardet-Biedl syndrome (BBS), an emblematic disease in the rapidly evolving field of ciliopathies, is characterized by pleiotropic clinical features and extensive genetic heterogeneity. To date, 14 BBS genes have been identified, 3 of which have been found mutated only in a single BBS family each (BBS11/TRIM32, BBS13/MKS1 and BBS14/MKS4/NPHP6). Previous reports of systematic mutation detection in large cohorts of BBS families (n > 90) have dealt only with a single gene, or at most small subsets of the known BBS genes. Here we report extensive analysis of a cohort of 174 BBS families for 12/14 genes, leading to the identification of 28 novel mutations. Two pathogenic mutations in a single gene have been found in 117 families, and a single heterozygous mutation in 17 families (of which 8 involve the BBS1 recurrent mutation, M390R). We confirm that BBS1 and BBS10 are the most frequently mutated genes, followed by BBS12. No mutations have been found in BBS11/TRIM32, the identification of which as a BBS gene only relies on a single missense mutation in a single consanguineous family. While a third variant allele has been observed in a few families, they are in most cases missenses of uncertain pathogenicity, contrasting with the type of mutations observed as two alleles in a single gene. We discuss the various strategies for diagnostic mutation detection, including homozygosity mapping and targeted arrays for the detection of previously reported mutations.

Document type :

Journal articles

Domain :

Life Sciences [q-bio] / Genetics

Life Sciences [q-bio] / Development Biology

Complete list of metadatas

https://www.hal.inserm.fr/inserm-00462147
Contributor : Hervé de Villemeur <>
Submitted on : Monday, March 8, 2010 - 4:56:32 PM
Last modification on : Wednesday, September 23, 2020 - 4:35:01 AM

Identification of 28 novel mutations in the Bardet-Biedl syndrome genes: the burden of private mutations in an extensively heterogeneous disease.

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Identification of 28 novel mutations in the Bardet-Biedl syndrome genes: the burden of private mutations in an extensively heterogeneous disease.

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