Confirmation of TFAP2A gene involvement in branchio-oculo-facial syndrome (BOFS) and report of temporal bone anomalies.

International audienceBranchio-oculo-facial syndrome (BOFS) is an autosomal-dominant condition characterized by three main features, respectively: branchial defects, ocular anomalies, and craniofacial defects including cleft lip and/or palate (CL/P). We report on one family with three affected, and two sporadic cases that have been found to carry missense mutations in the newly reported BOFS gene: TFAP2A. This report confirms the involvement of this transcription factor in this developmental syndrome with clinical variability. Moreover, we present CT scan temporal bone anomalies in the familial cases, related to branchial arch defects, highlighting the importance of radiological investigations for differential diagnosis

The Renpenning syndrome spectrum: new clinical insights supported by 13 new PQBP1-mutated males.

International audienceSince the first reports of polyglutamine-binding protein 1 (PQBP1) mutations in Renpenning syndrome and related disorders, the spectrum of PQBP1-linked clinical manifestations has been outlined from rare published case reports. The phenotypic description is often obtained from medical archives, and therefore, heterogeneous. Moreover, some aspects such as brain imaging or cognitive and behavioral functioning are rarely described. In this study, 13 PQBP1-mutated French patients were subjected to a standardized clinical, cognitive and behavioral assessment. Physical measurements of their relatives were also collected. We report on a recognizable clinical and radiological phenotype. All patients presented with microcephaly, leanness and mild short stature, relative to familial measurements. Three new clinical features are described: upper back progressive muscular atrophy, metacarpophalangeal ankylosis of the thumb and velar dysfunction. The specific facial dysmorphic features included at least four of the following signs: long triangular face, large ridged nose, half-depilated eyebrows, dysplastic or protruding ears and rough slightly sparse hair. An over-aged appearance was noticed in elderly patients. Cortical gyrification was normal based on available magnetic brain imaging of six patients. PQBP1-linked microcephaly (or Renpenning syndrome) is an X-linked mental retardation syndrome, which has clinically recognizable features

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

International audienceBardet-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