We studied a family where a mother passed on two different genetic variants at the same nucleotide in the GRIN2A gene to her children. Both variants disrupt the gene function. The son manifest epilepsy and intellectual disability, while the daughter and the mother exhibit language impairment and learning difficulties. The mother carries both variants, with […]
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Germline testing for breast cancer patients in England: illogical to prioritise grade 1 breast cancer aged 30–39 over grade 3 aged 40–49 years?
Genetic testing for inherited disease-causing changes in breast cancer genes is currently limited by guidelines that determine who is eligible. Testing breast cancer patients in England was updated in April-2022 making it more widely available, including all women diagnosed under 40years, except those with low grade cancers-(grade-1). However, this exception was recently dropped, apparently to […]
IFIH1 variants are associated with generalised epilepsy preceded by febrile seizures
Generalized epilepsy is the most common epilepsy with a prominent genetic etiology. Currently, a substantial number of genes related to generalized epilepsy have not been identified. In this study, we report two de novo heterozygous and three biallelic IFIH1 variants in five unrelated patients with generalized epilepsy with antecedent febrile seizures. Patients showed an early […]
Arterial aneurysm and dissection: toward the evolving phenotype of Tatton-Brown-Rahman syndrome
Tatton-Brown Rahman syndrome (TBRS) is a recently described rare disease. The knowledge contributed by new patients is crucial for enhancing our understanding of the condition and, consequently, improving its management and follow-up. The prevalence of aortic disease in TBRS individuals is far in excess of that expected in the general population. This cohort, together with […]
Long-read sequencing identifies an SVA_D retrotransposon insertion deep within the intron of ATP7A as a novel cause of occipital horn syndrome
Retrotransposons, known as “jumping genes,” move from one location to another across the human genome in a “copy-and-paste” manner and sometimes cause genetic diseases. We used long-read genome sequencing to show that an evolutionarily old SVA_D retrotransposon inserted deep in the intron of ATP7A caused occipital horn syndrome, a rare hereditary copper deficiency. A pedigree analysis indicated […]
Large TRAPPC11 gene deletions as a cause of muscular dystrophy and their estimated genesis
Causative variants in the TRAPPC11 gene are associated with muscular dystrophy and a broad spectrum of other clinical features. We present clinical and molecular genetic findings in three patients who are compound heterozygotes for a missense variant and a multiexon deletion in the TRAPPC11 gene. These are the first structural variants identified in this gene […]
NF2-related schwannomatosis and other schwannomatosis: an updated genetic and epidemiological study
Schwannomatosis is a rare tumour predisposition condition. Using a large UK-wide database we have studied the epidemiology of both NF2 and other genetic (LZTR1 and SMARCB1-related) schwannomatoses. We confirm an evenly distributed prevalence of 1 in 58,000 for NF2. A high proportion of cases (72% in England) are de novo (present new in an individual). This is higher than […]
De novo variants in KCNJ3 are associated with early-onset epilepsy
Epilepsy is a common chronic neurological disorder characterized by recurring spontaneous seizures with cognitive and psychosocial comorbidities. Genetic factors play a crucial role in the cause of epilepsy. We report two patients with epilepsy carrying the variants in KCNJ3 gene, which encodes a potassium channel. For the patients, the seizures occurred at a young age […]
Novel TFG mutation causes autosomal-dominant spastic paraplegia and defects in autophagy
Mutations in the tropomyosin receptor kinase fused (TFG) have been identified as contributing to several neurological disorders: hereditary spastic paraplegia (HSP), hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P), and Charcot-Marie-Tooth disease type 2 (CMT2). Here, we describe a novel heterozygous TFG variant (p.R42Q) responsible for pure HSP. We have further confirmed that […]
Intellectual disability syndrome associated with a homozygous founder variant in SGSM3 in Ashkenazi Jews
Neurodevelopmental disorders (NDDs) affect brain development and function, with varying symptoms and genetic causes. While some RAS superfamily proteins are known to contribute to NDDs, the role of SGSM (small G protein signaling modulator) remained unexplored. A recent study changed that, identifying an SGSM3 gene founder variant in 13 patients from 8 Ashkenazi Jewish families. […]