Genetic testing in motor neuron disease and frontotemporal dementia: a 5-year multicentre evaluation

Motor neurone disease (MND) is a neurodegenerative disorder that forms a disease spectrum with frontotemporal dementia (FTD). Affected MND/FTD patients and their unaffected relatives are often referred to clinical genetics for genetic testing. Our service evaluation explored genetics testing practices over a five-year period and across ten UK genetics centres. 301 referrals were included, 70 […]

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Analysis of 200,000 exome-sequenced UK Biobank subjects illustrates the contribution of rare genetic variants to hyperlipidaemia

A number of genes have previously been identified in which extremely rare variants with a large impact on gene function can produce marked abnormalities in lipid metabolism. Here we show that much larger numbers of protein-altering variants in these genes can have moderate effects on increasing or reducing the risk of clinically relevant hyperlipidaemia in […]

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BBS1 branchpoint variant is associated with non-syndromic retinitis pigmentosa

In our study, we have identified a pathogenic splice defect caused by a branchpoint variant in BBS1 gene in four unrelated individuals with non-syndromic retinitis pigmentosa. Splicing is the process in which the pre-mRNA is transformed into mature mRNA by removing the introns and joining the exons. The branchpoint nucleotide ‘A’, plays a crucial step […]

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Haploinsufficiency in non-homologous end joining factor 1 induces ovarian dysfunction in humans and mice

Premature ovarian insufficiency (POI) is a common disease in women that leads to a reduced reproductive lifespan. By utilizing whole-exome sequencing, we identified a rare heterozygous loss-of-function variant of non-homologous end joining factor 1 (NHEJ1) co-segregating with POI in a three-generation Chinese family. The loss-of-function variant caused an approximately 50% reduction in NHEJ1 protein amount […]

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Data sharing to improve concordance in variant interpretation across laboratories: results from the Canadian Open Genetics Repository

Genetic diagnostic laboratories classify DNA sequence variants based on available evidence, following guidelines for variant interpretation. Despite guidelines, laboratories may differ in how they classify the same variant, for example because of differences in how they apply the interpretation criteria. The Canadian Open Genetics Repository (COGR) is an online collaborative effort for data sharing and […]

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Adult phenotype of KCNQ2 encephalopathy

In this study, we describe the disease evolution and adult phenotype of KCNQ2 encephalopathy through retrospective study of 13 patients (18-45 years of age). We show that seizure frequency declines over the years and that most patients are seizure-free in adulthood. Longer seizure-free periods followed by seizure recurrence are however common during childhood and adolescence. […]

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Mutations in Phospholipase C eta-1 (PLCH1) are associated with Holoprosencephaly

Holoprosencephaly is a rare neurodevelopmental syndrome in which the brain doesn’t properly divide into the right and the left hemispheres. The condition can be caused by mutations in different genes. Our study descrides two families in which offspring had holoprosencephaly with mutations in a new gene called phospholipase C eta-1 (PLCH1). In the physiological condition, […]

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Clinical and subclinical findings in heterozygous ABCC6 carriers: results from a Belgian cohort and clinical practice guidelines

Hereditary defects in the ABCC6 gene are common in the general population with an estimated 1% of individuals having such a defect in their genetic material. In this study, we examined the physical signs and symptoms in a group of 56 individuals having 1 ABCC6 defect, called ‘carriers’. We found that 24% of carriers have […]

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Characterisation of protein-truncating and missense variants in PALB2 in 15 768 women from Malaysia and Singapore

Pathogenic variants in PALB2 is associated with an increased risk of breast, ovarian and pancreatic cancer. In our case-control study of more than 15,000 women from two multi-ethnic South East Asian populations (Malaysia and Singapore), we found that PALB2 carriers have a 5 fold increased risk of breast cancer compared to healthy individuals. Notably, many of the variants identified in this […]

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High cumulative risk of colorectal cancers and desmoid tumours and fibromatosis in South Asian APC mutation carriers

Familial Adenomatous Polyposis (FAP) is a rare inherited syndrome due to APC gene mutation. The extensive colorectal polyps and cancer risk requires lifelong endoscopic surveillance, often with preventive colorectal surgery before cancer development. FAP manifestation depend on the location of APC mutation which could vary in different populations. We report several novel mutations and a […]

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