Karmous-Benailly Houda, Martinovic Jelena, Gubler Marie-Claire, Sirot Yoann, Clech Laure, Ozilou Catherine, Auge Joëlle, Brahimi Nora, Etchevers Heather, Detrait Eric, Esculpavit Chantal, Audollent Sophie, Goudefroye Géraldine, Gonzales Marie, Tantau Julia, Loget Philippe, Joubert Madeleine, Gaillard Dominique, Jeanne-Pasquier Corinne, Delezoide Anne-Lise, Peter Marie-Odile, Plessis Ghislaine, Simon-Bouy Brigitte, Dollfus Hélène, Le Merrer Martine, Munnich Arnold, Encha-Razavi Férechté, Vekemans Michel, Attié-Bitach Tania
Département de Génétique et Unité INSERM U-393, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
Am J Hum Genet. 2005 Mar;76(3):493-504. doi: 10.1086/428679. Epub 2005 Jan 21.
Bardet-Biedl syndrome (BBS) is a multisystemic disorder characterized by postaxial polydactyly, progressive retinal dystrophy, obesity, hypogonadism, renal dysfunction, and learning difficulty. Other manifestations include diabetes mellitus, heart disease, hepatic fibrosis, and neurological features. The condition is genetically heterogeneous, and eight genes (BBS1-BBS8) have been identified to date. A mutation of the BBS1 gene on chromosome 11q13 is observed in 30%-40% of BBS cases. In addition, a complex triallelic inheritance has been established in this disorder--that is, in some families, three mutations at two BBS loci are necessary for the disease to be expressed. The clinical features of BBS that can be observed at birth are polydactyly, kidney anomaly, hepatic fibrosis, and genital and heart malformations. Interestingly, polydactyly, cystic kidneys, and liver anomalies (hepatic fibrosis with bile-duct proliferation) are also observed in Meckel syndrome, along with occipital encephalocele. Therefore, we decided to sequence the eight BBS genes in a series of 13 antenatal cases presenting with cystic kidneys and polydactyly and/or hepatic fibrosis but no encephalocele. These fetuses were mostly diagnosed as having Meckel or "Meckel-like" syndrome. In six cases, we identified a recessive mutation in a BBS gene (three in BBS2, two in BBS4, and one in BBS6). We found a heterozygous BBS6 mutation in three additional cases. No BBS1, BBS3, BBS5, BBS7, or BBS8 mutations were identified in our series. These results suggest that the antenatal presentation of BBS may mimic Meckel syndrome.
巴德-比埃尔综合征(BBS)是一种多系统疾病,其特征为轴后多指(趾)畸形、进行性视网膜营养不良、肥胖、性腺功能减退、肾功能障碍和学习困难。其他表现包括糖尿病、心脏病、肝纤维化和神经学特征。该疾病在遗传上具有异质性,迄今为止已鉴定出八个基因(BBS1 - BBS8)。在30% - 40%的BBS病例中观察到11号染色体q13上BBS1基因的突变。此外,该疾病已确定存在复杂的三等位基因遗传——也就是说,在一些家族中,两个BBS基因座上的三个突变是疾病表达所必需的。BBS在出生时可观察到的临床特征有多指(趾)畸形、肾脏异常(肾囊肿)、肝纤维化以及生殖器和心脏畸形。有趣的是,在梅克尔综合征中也观察到多指(趾)畸形、多囊肾和肝脏异常(伴有胆管增生的肝纤维化),以及枕部脑膨出。因此,我们决定对一系列13例产前病例的八个BBS基因进行测序,这些病例表现为多囊肾和多指(趾)畸形和/或肝纤维化,但无脑膨出。这些胎儿大多被诊断为患有梅克尔或“梅克尔样”综合征。在6例病例中,我们在一个BBS基因中鉴定出隐性突变(BBS2中有3例,BBS4中有2例,BBS6中有1例)。我们在另外3例病例中发现了杂合的BBS6突变。在我们的系列病例中未鉴定出BBS1、BBS3、BBS5、BBS7或BBS8突变。这些结果表明,BBS的产前表现可能类似梅克尔综合征。