Congenital hydrocephalus : new Mendelian mutations and evidence for oligogenic inheritance

Peer reviewe

Spondyloenchondrodysplasia Due to Mutations in ACP5: A Comprehensive Survey

Purpose: Spondyloenchondrodysplasia is a rare immuno-osseous dysplasia caused by biallelic mutations in ACP5. We aimed to provide a survey of the skeletal, neurological and immune manifestations of this disease in a cohort of molecularly confirmed cases. Methods: We compiled clinical, genetic and serological data from a total of 26 patients from 18 pedigrees, all with biallelic ACP5 mutations. Results: We observed a variability in skeletal, neurological and immune phenotypes, which was sometimes marked even between affected siblings. In total, 22 of 26 patients manifested autoimmune disease, most frequently autoimmune thrombocytopenia and systemic lupus erythematosus. Four patients were considered to demonstrate no clinical autoimmune disease, although two were positive for autoantibodies. In the majority of patients tested we detected upregulated expression of interferon-stimulated genes (ISGs), in keeping with the autoimmune phenotype and the likely immune-regulatory function of the deficient protein tartrate resistant acid phosphatase (TRAP). Two mutation positive patients did not demonstrate an upregulation of ISGs, including one patient with significant autoimmune disease controlled by immunosuppressive therapy. Conclusions: Our data expand the known phenotype of SPENCD. We propose that the OMIM differentiation between spondyloenchondrodysplasia and spondyloenchondrodysplasia with immune dysregulation is no longer appropriate, since the molecular evidence that we provide suggests that these phenotypes represent a continuum of the same disorder. In addition, the absence of an interferon signature following immunomodulatory treatments in a patient with significant autoimmune disease may indicate a therapeutic response important for the immune manifestations of spondyloenchondrodysplasia

PEDIA: prioritization of exome data by image analysis.

PURPOSE: Phenotype information is crucial for the interpretation of genomic variants. So far it has only been accessible for bioinformatics workflows after encoding into clinical terms by expert dysmorphologists. METHODS: Here, we introduce an approach driven by artificial intelligence that uses portrait photographs for the interpretation of clinical exome data. We measured the value added by computer-assisted image analysis to the diagnostic yield on a cohort consisting of 679 individuals with 105 different monogenic disorders. For each case in the cohort we compiled frontal photos, clinical features, and the disease-causing variants, and simulated multiple exomes of different ethnic backgrounds. RESULTS: The additional use of similarity scores from computer-assisted analysis of frontal photos improved the top 1 accuracy rate by more than 20-89% and the top 10 accuracy rate by more than 5-99% for the disease-causing gene. CONCLUSION: Image analysis by deep-learning algorithms can be used to quantify the phenotypic similarity (PP4 criterion of the American College of Medical Genetics and Genomics guidelines) and to advance the performance of bioinformatics pipelines for exome analysis

Correction:FOXP1-related intellectual disability syndrome: a recognisable entity

Meerschaut I, Rochefort D, Revençu N, et al. FOXP1-related intellectual disability syndrome: a recognisable entity. Journal of Medical Genetics 2017;54:613-623. In the original article, the authors noted four mutation annotation errors in figure 1B and supplementary table 1. Correction of the mistakes in the annotations have no impact on the results and conclusions of this article. The authors apologise for all possible inconveniences due to these error

RASA1-related phenotypes and possible pathophysiological mechanism

The capillary malformation (CM) represents the most frequent vascular malformation. Usually considered sporadic, families in which these lesions segregate in a dominant manner have been reported. In 2003, our lab identified heterozygous germline mutations in the RASA1 gene in 6 families with inherited CMs. The analysis of the phenotype revealed atypical, multifocal, CMs, and a predisposition to arteriovenous malformations (AVMs) or arteriovenous fistulas (AVFs). The disorder was named capillary malformation – arteriovenous malformation (CM-AVM). The aim of the work presented in this thesis was to define the phenotypic spectrum associated with RASA1 mutations. An additional aim was to address the question of the pathophysiological mechanism. Since 2003, we have recruited DNA samples and clinical data from 156 families with multifocal CMs with or without AVMs. We identified 89 distinct mutations in 113 families (241 individuals). The penetrance and de novo occurrence were high and the intra-familial clinical variability important. The affected individuals had distinct, multifocal CMs. In addition, one third of patients had fast-flow lesions, located in extremities (including Parkes Weber syndrome), intra-cranially, intra-spinally, and in the head and neck region. Importantly, the intra-cranial and intra-spinal fast-flow lesions were often associated with severe outcome. No mutation was identified in 43 families with indistinguishable phenotype. This could be explained by deletion/duplication of one or more exons, sensitivity of the screening techniques, mutations in regulatory regions or deep in introns. Additional gene(s) could also be involved. We hypothesised that a somatic second-hit could be the pathophysiological mechanism of CM-AVM disorder. It would explain the multifocality of the lesions and the intra-familial variability. Tissues from CM-AVM patients are scarcely available, as the lesions rarely require removal. Nevertheless, we could show a somatic RASA1 second-hit in one patient. In parallel, RASA1 was screened for germline mutation in patients with possibly related phenotypes, such as common capillary malformation (n=100), isolated arteriovenous malformation (n=24), Sturge-Weber syndrome (n=37), Klippel-Trenaunay syndrome (n=13), and capillary malformation on a limb with overgrowth (n=17). No mutation was identified. Our findings and the animal models, suggest an important role for RASA1 in vascular development. An additional hint comes from our preliminary by in-situ RNA hybridisation studies which showed a Rasa1 prevalent expression in arteries during murine development. Overall, this work represents a breakthrough into the characterisation of the CM-AVM phenotype and the associated RASA1 mutations, essential steps for the correct management of the patients. Currently, there is a significant body of evidence supporting the involvement of RASA1 specifically in vascular development. Hopefully, these findings will contribute to the understanding of the mechanisms that governs the neo(angiogenesis) and the development of targeted therapies.(SBIM 3) -- UCL, 201