Familial exudative vitreoretinopathy (FEVR) is an inheritable blinding disorder with high clinical and genetical heterogeneity. Currently, variants in fourteen genes and one locus are associated with FEVR, which accounts for only approximately 50% of the cases. This study reports three heterozygous nonsense or frameshift variants in CTNNB1 from FEVR-affected patients, which result in truncation and […]
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A polymorphic AT-repeat causes frequent allele dropout for an MME mutational hotspot exon (Contributed by Dr. Helle Høyer)
Pathogenic variants in the MME gene cause dominant and recessive late onset axonal hereditary neuropathy. In this study, we identified that a short increase in an AT-repeat close to two MME mutations is a frequent cause of allele dropout during Sanger sequencing causing false interpretation of the results in several of the patients. This may […]
Detection of copy number variants associated with late-onset conditions in ~16 200 pregnancies: parameters for disclosure and pregnancy outcome (Contributed by Dr Hagit Daum)
Copy number variants (CNVs) associated with late-onset medical conditions are rare but important secondary findings in prenatal chromosomal microarray analysis (CMA). Searching a large cohort of prenatal CMA tests (N=16,238) at two tertiary centers, we show that such CNVs are identified in 0.1% of tests and do not culminate in termination of pregnancy. We developed […]
Genotypes and phenotypes heterogeneity in PIK3CA-related overgrowth spectrum and overlapping conditions: 150 novel patients and systematic review of 1007 patients with PIK3CA pathogenetic variants (Contributed by Professor Nicoletta Resta)
Postzygotic activating PIK3CA variants cause several phenotypes within the PIK3CA-related overgrowth spectrum (PROS). Variant strength, mosaicism level, specific tissue involvement, and overlapping disorders are responsible for disease heterogeneity. Our comprehensive systematic review of more than 1,000 cases with PROS and PROS-like conditions shows that defining clear-cut genotype/phenotype correlations for all PROS entities is not possible. […]
Consolidation of the clinical and genetic definition of a SOX4-related neurodevelopmental syndrome (Contributed by Drs. Veronique Lefebvre and Rebecca Ahrens-Nicklas)
Variants in several genes encoding SOX transcription factors cause a variety of developmental disorders named SOXopathies. SOX4 variants were previously reported in four individuals with a neurodevelopmental syndrome. As with many other rare conditions, an international effort helped identify many additional patients and hence better define the clinical and genetic spectrum of the disease. The […]
Homozygous Variants in AKAP3 Induce Asthenoteratozoospermia and Male Infertility (Contributed by Prof. Feng Zhang)
As a highly specialized and evolutionarily conserved organelle, sperm flagellum provides the motile force for delivering the sperm to the egg. Fibrous sheath (FS), located in the principal piece of sperm flagella, serves as mechanical support for flagellar bending. Here, we identified two asthenoteratozoospermia-affected men carrying homozygous variants in AKAP3, encoding a FS associated protein. […]
Patient-derived cellular models of primary ciliopathies (Contributed by Dr. Virginie Sottile)
Pluripotent stem cells generated from patient samples are increasingly employed to explore disease mechanisms in the lab and test novel therapeutic strategies. Stem cells derived from patients can be cultivated in vitro to produce aggregates of cells that mimic the basic architecture of specific organs in 3D. For patients affected from complex genetic diseases such […]
Complete loss of the X-linked gene CASK causes severe cerebellar degeneration (Contributed by Dr. Konark Mukherjee)
X-linked disorders like CASK-linked pontocerebellar hypoplasia and Rett syndrome, predominantly affecting girls, are presumed to be neurodevelopmental disorders. Here, by performing a detailed analysis of a boy without CASK and genetically ablating CASK from cerebellar neurons in mice, we demonstrate that CASK loss does not affect neuronal or brain development. Instead, CASK loss results in […]
Disorders and roles of tsRNA, snoRNA, snRNA and piRNA in cancer (Contributed by Dr. Lin Xiao)
Non-coding RNAs are a large-scale and alloplasmatic family of RNAs. According to their size, small non-coding RNAs are approximately 18-200 nt. In recent years, increasing evidence has shown that small non-coding RNAs such as tsRNA, snoRNA, snRNA and piRNA play important roles in many biological processes, and their dysregulation is closely related to cancer progression. […]
RNA splicing analysis contributes to reclassifying variants of uncertain significance and improves the diagnosis of monogenic disorders (Contributed by Dr. Congling Dai)
Routinely used Whole Exome Sequencing (WES) in genetic diagnosis for monogenic disorders revealed numerous variants of uncertain significance (VUSs), which poses considerable problems for genetic counselling and clinical management. In fact, many disease-causing variants have been reported to resulting in aberrant gene splicing. Therefore, for VUSs suspected to cause aberrant splicing, additional evidence can be […]