Recessive mutations in the RMND1 gene, encoding the Required for Meiotic Nuclear Division protein 1, can cause defects in mitochondrial translation and oxidative phosphorylation, resulting in multi-system mitochondrial disease. In this multi-centre international study, we identified 14 new cases from 11 pedigrees with recessive RMND1 mutations including six novel, pathogenic variants. Hypotonia, developmental delay, congenital […]
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De novo mutations of KIAA2022 in females cause intellectual disability and intractable epilepsy
Pathogenic variants in the X-linked KIAA2022 gene are known to cause severe intellectual disability in males. Until now, all reported related female carriers of these KIAA2022 disruptions were unaffected and only 3 affected female patients have been described so far. We now report 14 female patients with heterozygous de novo loss of function mutations of […]
Specifying the ovarian cancer risk threshold of ‘premenopausal risk-reducing salpingo-oophorectomy’ for ovarian cancer prevention: a cost-effectiveness analysis
Risk-reducing surgery to prevent ovarian cancer involves removal of tubes and ovaries. This has traditionally been performed in women at high risk (>1-in-10 chance) of getting ovarian cancer (e.g. BRCA1/BRCA2 carriers). However, the ovarian cancer risk level at which surgical prevention should be offered has not been previously defined. We undertook a health economic analysis […]
Identification of bi-allelicLRRK1mutations inosteosclerotic metaphyseal dysplasiaand evidence for locus heterogeneity
Osteosclerotic metaphyseal dysplasia is a unique form of osteopetrosis characterized by dysplasiaof metaphyses of tubular bones with increased bone density. By exome sequencing, we found a homozygous mutation, c.5938_5944del[p.E1980Afs*66]in LRRK1 (Leucin-rich repeat kinase 1). LRRK1 was highly expressed in differentiated osteoclast. The patient’s phenotype was very similar to that of Lrrk1 knockout mice that we […]
Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head
Osteonecrosis of the femoral head is a painful and debilitating bone disease that causes bone death at the hip leading to its collapse and subsequent end-stage osteoarthritis. The disease is poorly understood limiting treatment options to invasive surgical procedures such as total hip replacement. We have identified a Canadian family of Greek origin with osteonecrosis […]
Mutations in TUBB8 cause a multiplicity of phenotypes in human oocytes and early embryos
An essential feature of successful mammalian reproduction is the fusion of a sperm with a mature oocyte. We previously found that heterozygous mutations in TUBB8 caused oocyte maturation arrest. In this study, we identified novel heterozygous and homozygous mutations in TUBB8 that cause variability in the corresponding phenotypes of human oocytes and early embryos. For […]
Genes associated with common variable immunodeficiency: one diagnosis to rule them all?
Common variable immunodeficiency (CVID) is an immune disorder characterized by low antibody levels and an increased susceptibility to infections and immune-related complications. It is a heterogeneous disorder with a variable clinical presentation and severity. Thus far, single gene defects have been identified in about 2-10% of patients. As more disease genes are being identified, it […]
A Splicing Mutation in VPS4B Causes Dentin Dysplasia I
Dentin dysplasia I (DDI) is an autosomal dominant disorder characterized by rootless teeth with abnormal pulpal morphology. The etiology of DDI still remains largely unclear. Here, we identified VPS4B as a disease-causing gene for DDI by linkage analysis followed by deep sequencing of the candidate genes in a large Chinese family with DDI. A splicing mutation (IVS7+46C>G) […]
GATOR1 complex: the common genetic actor in focal epilepsies
mTOR is a critical effector of cell signaling, playing a pivotal role in regulating physiology of the whole body, including the brain. Mutations in genes encoding GATOR1 complex, an inhibitor of mTOR activity, have been recently implicated in the pathogenesis of a wide spectrum of focal epilepsies (FEs), occasionally associated with malformations of cortical development. […]
New paradigms for BRCA1/BRCA2 testing in women with ovarian cancer: results of the Genetic Testing in Epithelial Ovarian Cancer (GTEOC) study
Many women diagnosed with epithelial ovarian cancer do not access genetic testing for BRCA1/2 mutations. The reasons for this are complex but may in part be due to lack of awareness or an over-complicated referral pathway. The Genetic Testing in Epithelial Ovarian Cancer (GTEOC) study looked at a streamlined approach led by Oncology and coordinated […]