SLC6A1 encodes GAT-1, a gamma-aminobutyric acid (GABA) transporter in the brain. We describe 28 individuals recruited through Simons Searchlight with heterozygous pathogenic or likely pathogenic SLC6A1 variants to better understand the associated neurobehavioral phenotype. Individuals all have some combination of developmental delay, intellectual disability, speech delay, language disorder, seizures, autism, hypotonia, and/or movement/coordination disorders. We […]
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Development and evaluation of an online, patient-driven, family outreach intervention to facilitate sharing of genetic risk information in families with Lynch syndrome
Cancer patients with a genetic mutation for hereditary cancer are largely responsible for sharing genetic risk information with relatives and encouraging them to have predictive genetic testing. Genetic risk communication within families is incomplete and limited to close relatives. To address this gap, we developed FamilyCONNECT, a provider-mediated, patient-navigated online tool to facilitate family outreach […]
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 […]
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 […]
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 […]
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 […]
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 […]
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. […]
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, […]
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 […]