Constitutional Mismatch Repair Deficiency (CMMRD) is a rare and devastating childhood-onset cancer predisposition syndrome caused by biallelic germline mutations in mismatch repair (MMR) genes. This inherited MMR deficiency causes an accumulation of errors mainly in repetitive regions of the DNA known as microsatellite instability (MSI). We have developed a valuable diagnostic tool that can detect MSI at […]
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Open questions on the nature of Parkinson’s disease: from triggers to spreading pathology
Parkinson’s disease (PD) is a late onset neurological condition characterized by impaired movements: tremors, rigidity, slow movements, and abnormal posture. In recent years, numerous non-motor symptoms, including psychiatric, sleep, smell, and digestive alterations, have been identified as integral components of the disease. Loss of smell and constipation can appear a decade before the full motor […]
Predictability and inconsistencies of cognitive outcome in patients with phenylketonuria and personalized therapy: the challenge for the future guidelines
Precision medicin requires the knowledge of constitutive factors of idiosyncratic resilience/vulnerability of a subject to a disease as a prerequisite for a tailored treatment. Phenylketonuria (PKU), a prototypical model of a treatable genetic disorder, has taught us how variable may be the clinical phenotype caused by a monogenic lesion. We are now aware that the […]
Differential disruption of autoinhibition and defect in assembly of cytoskeleton during cell division decide the fate of human DIAPH1-related cytoskeletopathy
Diaphanous-related formins1 (DIA1) is a protein, encoded by DIAPH1 and it assembles the unbranched actin microfilament and microtubule cytoskeleton. As it functions in blood cell as well as hair cell in the cochlea, constitutive activation by the disruption of autoinhibitory interactions between the diaphanous inhibitory domain (DID) and diaphanous auto regulatory domain (DAD) caused by […]
De novo SCAMP5 mutation causes a neurodevelopmental disorder with autistic features and seizures
Our objective was to identify and characterize pathogenic variants in individuals with autistic spectrum disorders (ASD) with developmental delay and seizures. These features are a group of diseases caused by at least 700 different genes. A number of cases remain genetically undiagnosed. We performed exome (protein coding sequences from all genes) sequencing to identify pathogenic […]
New insights into 5α-reductase type 2 deficiency based on a multi-centre study: regional distribution and genotype–phenotype profiling of SRD5A2 in 190 Chinese patients
The 5α-reductase type 2 (5α-RD2) deficiency caused by mutations in the steroid 5α-reductase 2 (SRD5A2) gene results in variable degrees of undervirilization in patients with 46,XY disorders of sex development. Through a multi-center cooperative effort, 190 Chinese subjects diagnosed with 5α-RD2 deficiency were consecutively enrolled, representing the largest case number so far. Based on this, […]
Addition of a 161-SNP polygenic risk score to family history-based risk prediction: impact on clinical management in non-BRCA1/2 breast cancer families
At this moment, risk management for non-BRCA1/2 breast cancer families is mainly based on family history, calculated by risk prediction algorithms such as BOADICEA. Here, we use a Polygenic Risk Score based on 161 breast cancer associated SNPs, to show the potential clinical utility of this PRS within non-BRCA1/2 high risk breast cancer families including […]
Genetic factors contributing to autism spectrum disorder in Williams-Beuren syndrome
Williams-Beuren syndrome is a neurodevelopmental disorder caused by a deletion at chromosome 7q11.23. It is characterised by a hypersocial neurocognitive profile, often defined as a “cocktail party” personality. However, the prevalence of Autism Spectrum Disorder is higher among patients with Williams-Beuren syndrome, a striking finding considering their opposite phenotype. Here, we study eight individuals with […]
‘Metaphyseal dysplasia without hypotrichosis’ can present with late-onset extraskeletal manifestations
Changes in the RMRP gene result in rare skeletal disorders: metaphyseal dysplasia without hypotrichosis (MDWH) and cartilage-hair hypoplasia (CHH). We hypothesized that MDWH may, similar to CHH, associate with immune deficiency and cancer. We collected data for 80 patients with RMRP mutations followed for over 30 years, and among them we identified 10 patients with features consistent with MDWH […]
Biallelic mutations in CFAP65 lead to severe asthenoteratospermia due to acrosome hypoplasia and flagellum malformations
Accurate acrosome formation and flagellum assembly during spermiogenesis are important prerequisites to ensure the fertilization of sperm and eggs. However, no spermiogenesis related gene mutation was reported to directly result in disorders of acrosome formation and flagellum assembly. In this manuscript, by whole exome sequencing of 47 individuals with severe asthenozoospermia from 45 unrelated Chinese […]