Pathogenic copy number variants (CNVs) are deletions or duplications of large stretches of chromosomes, that have been shown to cause developmental delay, autism spectrum disorders and schizophrenia. The UK Biobank, with half a million well-phenotyped participants, provides an unprecedented opportunity to examine whether these CNVs increase risk to develop other medical disorders. We analysed the […]
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De novo pathogenic variants in neuronal differentiation factor 2 (NEUROD2) cause a form of early infantile epileptic encephalopathy
Early infantile epileptic encephalopathies (EIEEs) are severe disorders characterized by drug-resistant seizures and developmental delay. More than 100 genes have been associated with EIEEs, with genetic and phenotypic heterogeneity. Two unrelated patients with EIEE presented with de novo mutations in Neuronal Differentiation Factor 2 (NEUROD2), which had not been previously reported in any human disease. […]
Efficacy of novel immunotherapy regimens in patients with metastatic melanoma with germline CDKN2A mutations
Inherited mutation in the tumor suppressor gene CDKN2A is one of the strongest known risk factors for melanoma of the skin. Moreover, carriers have been found to have poor melanoma-specific survival. In this study, responses to novel immunotherapy agents (PD-1 and CTLA-4 inhibitors) in CDKN2A mutation carriers with metastatic melanoma were evaluated. Eleven of nineteen affected carriers (58%) responded […]
Progression from islet autoimmunity to clinical type 1 diabetes is influenced by genetic factors: results from the prospective TEDDY study
Type 1 diabetes, which is the most common metabolic disease in children and adolescents, begins with a pre-clinical phase which is defined by the presence of islet autoantibodies. This pre-clinical phase is variable in duration with onset of clinical diabetes occurring months to decades after the appearance of islet autoantibodies. In this study, we found […]
Investigation of clinically relevant germline variants detected by next-generation sequencing in patients with childhood cancer: a review of the literature
Genomic technologies have enabled the sequencing of childhood cancer patients to investigate genetic predisposition. This review compares 6 studies of selected cohorts of childhood cancer patients reporting clinically relevant pathogenic germline variants in a broad spectrum of genes associated with susceptibility to both adult and paediatric cancers. We identified differences in the reported incidence of […]
Mosaicism and incomplete penetrance of PCDH19 mutations
Point mutations or rearrangements involving the PCDH19 gene located on Xq22.1 cause epilepsy and mental retardation mainly in females. However, affected males with mosaic PCDH19 mutations have also been reported. It is hypothesized that cellular interference mechanism is the main pathogenic mechanism. In our 42 PCDH19-related epilepsy families, five mosaic individuals, four males and one female, […]
Leveraging the Power of New Molecular Technologies in the Clinical Setting Requires Unprecedented Awareness of Limitations and Drawbacks: Experience of One Diagnostic Laboratory
Although new molecular technologies and computational prediction tools offer wide-raging opportunities in genetic diagnostic settings, they have many limitations. We contextualize these limitations by investigating incorrect variant detection in genomic regions of high sequence similarities and from inappropriate computational analysis. For instance, we observed a 5% false positive rate in MYH7 variant detection due to […]
Long-read sequencing identified intronic repeat expansions in SAMD12 from Chinese pedigrees affected with familial cortical myoclonic tremor with epilepsy
Familial cortical myoclonic tremor with epilepsy (FCMTE) is an autosomal inherited disease mainly characterized by adult-onset cortical myoclonus and infrequent epilepsy. Over the past a few decades, we have used a number of genomic technologies to examine its genetic etiology but failed to identify likely pathogenic mutations. In the current study, we used long-read sequencing […]
Non-HFE mutations in haemochromatosis in China: combination of heterozygous mutations involving HJV signal peptide variants
Hereditary hemochromatosis (HH) caused by a homozygous p.C282Y mutation in hemochromatosis (HFE) gene has been well-documented in Caucasian patients with HH. However, the morbidity of HH is less reported in Asian countries. Little is known about the general patterns of mutation of HH-related gene in Chinese patients. The present study by Lv et al. provided […]
Perturbations of BMP/TGF-β and VEGF/VEGFR signalling pathways in non-syndromic sporadic brain arteriovenous malformations (BAVM)
Brain arteriovenous malformations (BAVM) represent a congenital anomaly of the cerebral vessels with a prevalence of 10–18/100,000. BAVM is the leading etiology of intracranial hemorrhage in children. To identify gene variants potentially contributing to disease, we sequenced the DNA of 100 families with a BAVM phenotype. Pathogenic variants were then studied in vivo using a […]