Integrin Alpha 8 Recessive Mutations Are Responsible for Bilateral Renal Agenesis in Humans

Renal hypodysplasia (RHD) is a heterogeneous condition encompassing a spectrum of kidney development defects including renal agenesis, hypoplasia, and (cystic) dysplasia. Heterozygous mutations of several genes have been identified as genetic causes of RHD with various severity. However, these genes and mutations are not associated with bilateral renal agenesis, except for RET mutations, which could be involved in a few cases. The pathophysiological mechanisms leading to total absence of kidney development thus remain largely elusive. By using a whole-exome sequencing approach in families with several fetuses with bilateral renal agenesis, we identified recessive mutations in the integrin α8-encoding gene ITGA8 in two families. Itga8 homozygous knockout in mice is known to result in absence of kidney development. We provide evidence of a damaging effect of the human ITGA8 mutations. These results demonstrate that mutations of ITGA8 are a genetic cause of bilateral renal agenesis and that, at least in some cases, bilateral renal agenesis is an autosomal-recessive disease

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Anévrisme/dissection de l'aorte thoracique avec persistance du canal artériel (une nouvelle entité)

DIJON-BU Médecine Pharmacie (212312103) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Polycystic kidney disease associated with intracranial hypertension revealing a mutation of the OFD1 gene

International audienc

Automatic determination of aortic compliance with cine-magnetic resonance imaging - An application of fuzzy logic theory

International audienceAbstract: RATIONALE AND OBJECTIVES. Aortic compliance is defined as the relative change in aortic cross-sectional area divided by the change in arterial pressure. Magnetic resonance imaging (MRI) is a useful imaging modality for the noninvasive evaluation of aortic compliance. However, manual tracing of the aortic contour is subject to important interobserver variations. To estimate the aortic compliance from cine-MRI, a method based on fuzzy logic theory was elaborated. MATERIALS AND METHODS. Seven healthy volunteers and eight patients with Marfan syndrome were examined using an ECG gated cine-MRI sequence. The aorta was imaged in the transverse plane at the level of the pulmonary trunk. A method based on fuzzy logic was developed to automatically detect the aortic contour. RESULTS. Through our robust automatic contouring method, the calculation of aortic cross-sectional areas allows an estimation of the aortic compliance. CONCLUSION. The aortic compliance can be obtained from a fuzzy logic based automatic contouring method, thereby avoiding the important interobserver variation often associated with manual tracing

Compliance and Pulse Wave Velocity Assessed by MRI Detect Early Aortic Impairment in Young Patients With Mutation of the Smooth Muscle Myosin Heavy Chain

International audienc

Should aortic stiffness be evaluated in thoracic aortic aneurysm/dissection relatives to prevent risks?

International audienc

Genotype-phenotype analysis in 2,405 patients with a dystrophinopathy using the UMD-DMD database: a model of nationwide knowledgebase

International audienceUMD-DMD France is a knowledgebase developed through a multicenter academic effort to provide an up-to-date resource of curated information covering all identified mutations in patients with a dystrophinopathy. The current release includes 2,411 entries consisting in 2,084 independent mutational events identified in 2,046 male patients and 38 expressing females, which corresponds to an estimated number of 39 people per million with a genetic diagnosis of dystrophinopathy in France. Mutations consist in 1,404 large deletions, 215 large duplications, and 465 small rearrangements, of which 39.8% are nonsense mutations. The reading frame rule holds true for 96% of the DMD patients and 93% of the BMD patients. Quality control relies on the curation by four experts for the DMD gene and related diseases. Data on dystrophin and RNA analysis, phenotypic groups, and transmission are also available. About 24% of the mutations are de novo events. This national centralized resource will contribute to a greater understanding of prevalence of dystrophinopathies in France, and in particular, of the true frequency of BMD, which was found to be almost half (43%) that of DMD. UMD-DMD is a searchable anonymous database that includes numerous newly developed tools, which can benefit to all the scientific community interested in dystrophinopathies. Dedicated functions for genotype-based therapies allowed the prediction of a new multiexon skipping (del 45-53) potentially applicable to 53% of the deleted DMD patients. Finally, such a national database will prove to be useful to implement the international global DMD patients' registries under development