NF2-related-schwannomatosis is characterised by the development of benign tumours of nerve sheaths (schwannomas) and lining of the brain (meningiomas). Around 50—60% of affected people are the first in their family and half of these have genetic faults that change an amino acid to an instruction to stop making protein (nonsense). Although there are 60 positions […]
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Biallelic mutations in CFAP54 cause male infertility with severe MMAF and NOA
As important pathogenic factors of male infertility, severe multiple morphological abnormalities of the sperm flagella (MMAF) and nonobstructive azoospermia (NOA) are mostly considered to be of genetic origin. Here, we identified biallelic deleterious variants of CFAP54 from three unrelated men with severe MMAF or NOA. CFAP54 deficiency could cause various morphological and ultrastructural abnormalities in […]
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 […]
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 […]
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 […]
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 […]
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 […]
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 […]
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 […]
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 […]