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. […]
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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 […]
Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes
Ciliopathies are an extensive group of disorders with considerable genetic and clinical overlap, which collectively share multiple organ involvement and may result in lethal or viable phenotypes. In large numbers of cases the genetic defect remains yet to be determined. Our study resulted in the identification of six probands carrying nine distinct mutations (of which […]
When chromatin organisation floats astray: the Srcap gene and Floating–Harbor syndrome
Floating-Harbor syndrome (FHS) is a rare human disease characterized by developmental defects, often associated with mental retardation. FHS was first described at Boston’s Floating Hospital in 1973, but the causative gene, called Srcap, was identified only recently. Srcap encodes a protein with a key role in control of gene expression, however, the underlying molecular bases […]
A recurrent mitochondrial p.Trp22Arg NDUFB3 variant causes a distinctive facial appearance, short stature and a mild biochemical and clinical phenotype
Mitochondrial diseases occur when insufficient energy is produced, affect both adults and children and often require a muscle biopsy to help the investigation and diagnosis. We have identified the same genetic defect – a mutation within the NDUFB3 gene – in ten children from eight families with identical physical features; affected children are short, have […]
Microduplications at the Pseudoautosomal SHOX Locus in Autism Spectrum Disorders and Related Neurodevelopmental Conditions
SHOX encodes a transcription factor involved in cell-cycle and growth regulation. Here, we report the association between microduplications at the SHOX locus and autism spectrum disorders (ASD) and related neurodevelopmental conditions (NDD). The study was triggered by observations in a discovery series of 90 ASD cases, who underwent clinical genetic testing by array-comparative genomic hybridisation. […]
Functional and genetic epidemiological characterisation of the FFAR4 (GPR120) p.R270H variant in the Danish population
The 7TM receptor for long chain fatty acids FFAR4 (GPR120) currently attracts great attention as a therapeutic target to treat metabolic diseases. A low-frequency missense variant (p.R270H, rs116454156) in FFAR4 has previously been reported to associate with obesity in European populations and to impair signaling of the receptor. Here we further examine the functional consequences […]
Mutations in LTBP3 cause acromicric dysplasia and geleophysic dysplasia
Acromicric dysplasia and geleophysic dysplasia are both forms of acromelic dysplasia. Several causative genes have been identified for the acromelic dysplasias, all of which affect TGF-β signalling and/or interactions with fibrillin. Here, we have used massive parallel sequencing to identify a dominant mutation in latent TGF-β binding protein-3 (LTBP3) in a family with acromicric dysplasia, […]
Naturally occurring BRCA2 alternate mRNA splicing events in clinically relevant samples
Genetic testing of BRCA1 and BRCA2 genes in cancer patients frequently reveals gene variations with unknown clinical effects. Some of these variations might affect mRNA splicing, an important step in gene expression. Aberrant splicing is typically determined by looking for novel mRNA molecules. We wanted to know if these molecules could also occur at random. […]
Germline RRAS2 Mutations are not associated with Noonan Syndrome
Mutations in a variety of Ras-MAPK pathway genes are detected in 70-80% of patients with Noonan Syndrome (NS) and related disorders, collectively referred to as RASopathies. Certain patients with RASopathies are predisposed to developing juvenile myelomonocytic leukemia (JMML), a myeloproliferative disorder of early childhood. We recently identified somatic mutations in RRAS2 in JMML and hypothesized […]