Micrognathia, glossoptosis, and cleft palate comprise one of the most common malformation sequences, Robin sequence. It is a component of the TARP syndrome, talipes equinovarus, atrial septal defect, Robin sequence, and persistent left superior vena cava. This disorder is X-linked and severe, with apparently 100% pre- or postnatal lethality in affected males. Here we characterize a second family with TARP syndrome, confirm linkage to Xp11.23-q13.3, perform massively parallel sequencing of X chromosome exons, filter the results via a number of criteria including the linkage region, use a unique algorithm to characterize sequence changes, and show that TARP syndrome is caused by mutations in the RBM10 gene, which encodes RNA binding motif 10.

We further show that this previously uncharacterized gene is expressed in midgestation mouse embryos in the branchial arches and limbs, consistent with the human phenotype. We conclude that massively parallel sequencing is useful to characterize large candidate linkage intervals and that it can be used successfully to allow identification of disease-causing gene mutations.

Introduction Advances in genomic technologies can markedly speed the analysis of genetic contributions to disease and make once-intractable questions tractable. The technique of massively parallel sequencing with exon capture allows rapid assessment of mutations that cause human diseases. The syndrome we have chosen to study with this new technology is an X-linked pleiotropic developmental anomaly syndrome (MIM ) comprising micrognathia, glossoptosis, and cleft palate (currently described as Robin sequence), persistent left superior vena cava, atrial septal defect, and talipes equinovarus, which was originally called “Robin's syndrome” by Gorlin et al. Subsequently, this disorder was designated as TARP syndrome based on the acronym formed by talipes equinovarus, atrial septal defect, Robin sequence, and persistence of the left superior vena cava (to avoid confusion of Robin sequence and “Robin's syndrome”).

Conduire Un Vehicle Promenade Pdf Converter on this page. Linkage analysis of the family originally evaluated by Gorlin et al. Confirmed the X-linked inheritance by mapping the locus to Xp11.23-q13.3. Associated Tc4 Setup Sheet Template. Although this mapping confirmed the inheritance pattern and narrowed the candidate gene list, the region was nearly 28 Mb (from 46.42 Mb to 74.04 Mb; genome build 36) and contained more than 200 genes or transcripts, including several complex gene families of G antigen transcripts. Thus, the task of interrogating all of these genes for sequence variants and validating the variants was daunting. Bryan Adams Summer Of 69 Mp3 Download Skull. Here we report the identification of the second family manifesting this syndrome, describe the phenotype in three affected males, show that the second family has linkage that is consistent with that of the initial family, describe our use of chromosome X exon target capture and massively parallel (so-called “next-gen”) sequencing to identify RBM10 (MIM ) mutations in the two families, and show that the murine Rbm10 gene is expressed in midgestation embryos in a pattern consistent with the human phenotype. Target Selection and Sequencing DNA isolation, genotyping, and haplotype analysis were performed as previously described.