Ciliary disorder of the skeleton Huber, Celine; Cormier-Daire, Valerie
American journal of medical genetics. Part C, Seminars in medical genetics,
15 August 2012, Volume:
160C, Issue:
3
Journal Article
The application of massively parallel sequencing technology to the field of skeletal disorders has boosted the discovery of the underlying genetic defect for many of these diseases. It has also ...resulted in the delineation of new clinical entities and the identification of genes and pathways that had not previously been associated with skeletal disorders. These rapid advances have prompted the Nosology Committee of the International Skeletal Dysplasia Society to revise and update the last (2015) version of the Nosology and Classification of Genetic Skeletal Disorders. This newest and tenth version of the Nosology comprises 461 different diseases that are classified into 42 groups based on their clinical, radiographic, and/or molecular phenotypes. Remarkably, pathogenic variants affecting 437 different genes have been found in 425/461 (92%) of these disorders. By providing a reference list of recognized entities and their causal genes, the Nosology should help clinicians achieve accurate diagnoses for their patients and help scientists advance research in skeletal biology.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The “Nosology of genetic skeletal disorders” has undergone its 11th revision and now contains 771 entries associated with 552 genes reflecting advances in molecular delineation of new disorders ...thanks to advances in DNA sequencing technology. The most significant change as compared to previous versions is the adoption of the dyadic naming system, systematically associating a phenotypic entity with the gene it arises from. We consider this a significant step forward as dyadic naming is more informative and less prone to errors than the traditional use of list numberings and eponyms. Despite the adoption of dyadic naming, efforts have been made to maintain strong ties to the MIM catalog and its historical data. As with the previous versions, the list of disorders and genes in the Nosology may be useful in considering the differential diagnosis in the clinic, directing bioinformatic analysis of next‐generation sequencing results, and providing a basis for novel advances in biology and medicine.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract This article presents two fetal cases of gnathodiaphyseal dysplasia (GDD), a rare autosomal dominant disorder, and reviews the relevant literature. The cases involved two fetuses exhibiting ...bone bowing, which led to the diagnosis of GDD. Genetic testing revealed two de novo variants of the ANO5 gene, confirming the diagnosis. A literature review was conducted to explore GDD's clinical and paraclinical presentation, diagnosis, and management. GDD is a rare but frequently inherited cause of bone fragility and jaw lesions characterized by a gain‐of‐function variant within the ANO5 gene. Clinical manifestations range from recurrent dental infections with mild jaw lesions to severe bone fragility with several fractures associated with large jaw lesions requiring disfiguring surgeries. Diagnostic techniques depend on the context and include targeted genetic testing of ANO5 , untargeted molecular analysis with whole‐exome sequencing, or whole‐genome sequencing. This case report highlights the importance of recognizing GDD as a novel cause of bone bowing and fractures during pregnancy. By summarizing the literature, this article contributes to healthcare professionals' knowledge and improves the recognition, diagnosis, and care of patients with GDD.
Key points What is already known about this topic Rare Skeletal Disorder: Gnathodiaphyseal dysplasia is a rare genetic condition linked to mutations in the ANO5 gene characterized by bone fragility and jaw lesions. What does this study add Fetal Case Discovery: This review highlights the pioneering diagnosis of the first two fetal cases, expanding the phenotypic spectrum. Literature Overview: Providing a literature review, this report synthesizes current knowledge, aiding healthcare professionals in accurate diagnosis and management strategies.
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Low‐density lipoprotein receptor‐related protein 6 (LRP6) is a co‐receptor of the Wnt signaling pathway, which plays an essential role in various biological activities during embryonic and postnatal ...development. LRP6 is exceptionally associated with rare diseases and always with autosomal dominant inheritance. Here we report a familial phenotype of high bone mass associated with skeletal anomalies and oligodontia but also persistent left superior vena cava, inguinal hernia, hepatic cysts, abnormal posterior fossa and genital malformations. Molecular analysis revealed a novel heterozygous variant, NM_002336.2: c.724T>C, p.(Trp242Arg), in affected individuals. This variant is located in the first β‐propellant motif of LRP6, to which sclerostin (SOST) and dickkopf1 (DKK1), two LRP6 co‐receptor inhibitors and various Wnt ligands bind. According to the literature and integrating data from structural analysis, this variant distorts the binding of SOST and DKK1, thus leading to overactivation of Wnt signaling pathways involved in osteoblast differentiation. This novel heterozygous variant in LRP6 underlies the role of LRP6 in skeletal and dental disorders as well as, probably, cardiac, cerebral and genital developments.
This study identified, by quartet genome sequencing, a heterozygous variant of LRP6 (NM_002336.2: c.724T>C, p.(Trp242Arg)) in a family with a severe and atypical phenotype. This LRP6 variation at residue 242 affects the binding capacity of DKK1 (yellow) and SOST.
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Two to three thousand syndromes modify facial features: their screening requires the eye of an expert in dysmorphology. A widely used tool in shape characterization is geometric morphometrics based ...on landmarks, which are precise and reproducible anatomical points. Landmark positioning is user dependent and time consuming. Many automatic landmarking tools are currently available but do not work for children, because they have mainly been trained using photographic databases of healthy adults. Here, we developed a method for building an automatic landmarking pipeline for frontal and lateral facial photographs as well as photographs of external ears. We evaluated the algorithm on patients diagnosed with Treacher Collins (TC) syndrome as it is the most frequent mandibulofacial dysostosis in humans and is clinically recognizable although highly variable in severity. We extracted photographs from the photographic database of the maxillofacial surgery and plastic surgery department of Hôpital Necker–Enfants Malades in Paris, France with the diagnosis of TC syndrome. The control group was built from children admitted for craniofacial trauma or skin lesions. After testing two methods of object detection by bounding boxes, a Haar Cascade‐based tool and a Faster Region‐based Convolutional Neural Network (Faster R‐CNN)‐based tool, we evaluated three different automatic annotation algorithms: the patch‐based active appearance model (AAM), the holistic AAM, and the constrained local model (CLM). The final error corresponding to the distance between the points placed by automatic annotation and those placed by manual annotation was reported. We included, respectively, 1664, 2044, and 1375 manually annotated frontal, profile, and ear photographs. Object recognition was optimized with the Faster R‐CNN‐based detector. The best annotation model was the patch‐based AAM (p < 0.001 for frontal faces, p = 0.082 for profile faces and p < 0.001 for ears). This automatic annotation model resulted in the same classification performance as manually annotated data. Pretraining on public photographs did not improve the performance of the model. We defined a pipeline to create automatic annotation models adapted to faces with congenital anomalies, an essential prerequisite for research in dysmorphology.
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