Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative condition, predominantly affecting males with a Fragile X premutation (CGG expansion in the FMR1 gene of 55-199 repeats). Current penetrance estimates are based on data from premutation carriers with larger than average CGG repeat size (>70) and suggest up to 45% of males will develop FXTAS […]
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Delineating the genotypic and phenotypic spectrum of HECW2-related neurodevelopmental disorders
In this study, we expand and characterize the phenotypic spectrum and molecular landscape of HECW2-related neurodevelopmental disorders. Clinical characterization suggests complete penetrance for hypotonia with or without spasticity, developmental delay/intellectual disability and developmental language disorder. We also report that all pathogenic variants are missense and mainly clustered in and near the HECT domain of the […]
O’Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum
The O’Donnell-Luria-Rodan syndrome (ODLURO) is a disorder primarily affecting cognitive development and behavior. Patients often show delayed development, mild to moderate intellectual disability, a large head circumference and autism spectrum disorder. After it was first described in 2019, we now report the second systematic case series of 18 patients with ODLURO, leading to a better […]
Hypermobile Ehlers-Danlos syndrome (hEDS) phenotype in fragile X premutation carriers: case series
Although hypermobile Ehlers-Danlos syndrome (hEDS) is the most common type of EDS, its genetic etiology is unclear. This study presents 5 cases who had both a hEDS phenotype and FMR1 premutation. In premutation carriers, a possible connection between both conditions could be explained by a depletion of fragile X mental retardation protein (FMRP), a major […]
Prevalence and spectrum of DNA mismatch repair gene variation in the general Chinese population
DNA mismatch repair (MMR) genes of MLH1, MSH2, MSH6 and PMS2 play essential roles in maintaining microsatellite stability through DNA mismatch repair, pathogenic variation in MMR genes causes microsatellite instability and high cancer risk as represented by the Lynch syndrome. We identified 17,687 MMR variants from 18,844 ethnic Chinese individuals. We characterized the basic biological […]
Loss-of-function variants in DNM1 cause a specific form of developmental and epileptic encephalopathy only in bi-allelic state
The DNM1 gene encodes dynamin-1, a protein playing an important role in signal transduction from one neuron to another. This neuronal communication uses release of neurotransmitters stored in vesicles beneath the neuronal membrane. Dynamin-1 induces membrane constriction subsequently resulting in vesicle fission from the membrane. Missense variants in DNM1 were found to be associated with […]
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. Tonic seizures […]
Learning from massive testing of mitochondrial disorders: UPD explaining unorthodox transmission
Reaching a full genetic diagnosis in patients with rare diseases such as the mitochondrial disorders (MDs) is important for counseling and to prepare correct follow up and future therapies. Massive gene sequencing allow extensive investigation of potential etiologies but it is important to consider uniparental disomy (UPD) as a possible explanation for the transmission whenever […]
A protein-truncating mutation in CCNB3 in a patient with recurrent miscarriages and failure of meiosis I
Our patient suffered from 16 miscarriages and spent more than 20 years looking for treatments that could allow her to have live births but without success. She changed countries, cities, and medical centers, and sought the help of the best specialists but with no cure or satisfying answers. Her desire to understand the causes of […]
WFS1 protein expression correlates with clinical progression of optic atrophy in patients with Wolfram syndrome
Wolfram syndrome, a rare form of monogenic diabetes and neurodegeneration, currently has no cure or treatment to slow the progression. Currently we have no way of predicting progression to blindness, or how different genetic mutations may affect this progression. This paper shows that affected people who retain partial Wolfram protein expression, present with milder visual […]