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 […]
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Detection of copy number variants associated with late-onset conditions in ~16 200 pregnancies: parameters for disclosure and pregnancy outcome
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 a […]
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
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
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
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
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
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
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
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 […]
Dominant negative mutation in oxalate transporter SLC26A6 associated with enteric hyperoxaluria and nephrolithiasis
Nephrolithiasis results from interaction between genetic and environmental factors. Calcium oxalate is the most common type of kidney stone. We report a novel genetic mechanism causing hyperoxaluria and nephrolithiasis. In one family, we detected a mutation within the SLC26A6 gene that encodes an oxalate transporter. This mutation impairs SLC26A6 function, which normally secretes oxalate in […]