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 […]

Read More…

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. […]

Read More…

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 […]

Read More…

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. […]

Read More…

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 […]

Read More…

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. […]

Read More…

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 […]

Read More…

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 […]

Read More…

Simplified and more sensitive criteria for identifying individuals with pathogenic CDH1 variants

Individuals carrying mutations in the CDH1 gene have a high likelihood of developing stomach cancer (lifetime risk 24-42%) and breast cancer (lifetime risk about 43-55%). Identification of these individuals through genetic testing is important because these cancers can be prevented by prophylactic surgery or detected early with endoscopy and breast imaging. Current guidelines recommend genetic testing when […]

Read More…