A new platform for RNA-based diagnosis of cancer predisposition syndromes

A large fraction of disease causing DNA variants are known to disrupt mRNA structure or expression. Whereas, long-read RNA sequencing is a powerful tool to assess mRNA structure, its sensitivity is limited. Here, we developed CAPLRseq as an adaptable workflow for effective transcriptome-based disease diagnosis. CAPLRseq can evaluate a wide range of simple and complex […]

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Development of a comprehensive approach to adult hereditary cancer testing in Ontario

There has been a rapid expansion of genetic testing for hereditary cancer syndromes in oncology.  In Ontario’s publicly funded health care system, a standardized approach to testing across the province supports equitable access.  This study describes an method for establishing consensus on hereditary cancer testing across a broad spectrum of tumour types.  This framework can […]

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Craniosynostosis, inner ear, and renal anomalies in a child with complete loss of SPRY1 (sprouty homolog 1) function

We describe the first bona fide case of a patient with craniosynostosis (the premature fusion of the gaps in our skull plates known as sutures) and a homozygous variant in SPRY1. The variant results in complete loss of the protein in the child, and reduced levels of the protein in both heterozygous parents. The child […]

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A novel causative gene of epilepsy: Variants in BSN gene associated with epilepsy with favorable outcome

Epilepsy is a common neurological disorder featured by the recurrence of unprovoked seizures. The etiologies in the majority of patients with epilepsy still keep unknown. This study identified a novel causative gene of epilepsy—BSN gene. BSN gene encodes Bassoon, an essential protein to assemble the cytomatrix at the active zone of neurotransmitter release. In this […]

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Optimising clinical care through CDH1-specific germline variant curation: improvement of clinical assertions and updated curation guidelines

Accurate interpretation of CDH1 germline variants is critical for physicians and individuals with pathogenic or likely pathogenic variants in CDH1 who are faced with consideration of potentially morbid risk-reduction strategies including total gastrectomy and bilateral mastectomy in females. CDH1-specific variant classification guidelines have been developed by the Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert […]

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Single amino acid variation in MAB21L1 is dominantly associated with congenital eye defects

Microphthalmia is a congenital eye defect caused by the underdevelopment of the optical structures typically bearing small eyeballs and cornea. We identified a novel missense variant in MAB21L1, which was dominantly inherited in a family with microphthalmia. We analyzed 3D structures of several mutant proteins predicted by AlphaFold2, and observed the effects of the mutant proteins […]

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Clinical and psychological implications of secondary and incidental findings in cancer susceptibility genes after exome sequencing in patients with rare disorders

In this work we analyzed the frequency, actionability and psychological impact of disclosing pathogenic variants in cancer susceptibility genes (CSG) as a secondary or incidental finding (SF/IF) mainly in pediatric patients. In a total of 533 exomes examined for non-cancer indications, we found a pathogenic variant in a CSG as a SF/IF in 2%. Around […]

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Experience of a 2-year spinal muscular atrophy NBS pilot study in Italy: towards specific guidelines and standard operating procedures for the molecular diagnosis

In the present article we report the results of the first Italian newborn screening project for Spinal Muscular Atrophy (SMA). The scenario of the disease has been revolutionized by three different effective treatments, acting at the molecular defect level, that, even if are not the cure, have radically changed the course of the disease, especially […]

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UK consensus recommendations for clinical management of cancer risk for women with germline pathogenic variants in cancer predisposition genes: RAD51C, RAD51D, BRIP1 and PALB2

Pathogenic variants in RAD51C, RAD51D, BRIP1 are established ovarian cancer predisposition genes. PALB2 is firmly recognised as a breast cancer predisposition gene and more recently associated with ovarian cancer.  An association of RAD51C and RAD51D with breast cancer predisposition was recently confirmed. Whilst improved cancer risks estimates for these genes are available, to date no […]

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Conclusion of diagnostic odysseys due to inversions disrupting GLI3 and FBN1

As common genetic testing methodologies cannot detect copy-neutral rearrangements such as inversions, this category of variant suffers from under-ascertainment. Pagnamenta and colleagues scanned data from the 100KGP (#genomes100k) for 43 genes linked to skeletal disorders. Ten individuals from 3 families harboured diagnostic inversions. In two families, GLI3-disrupting inversions segregated with skeletal features consistent with Greig […]

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