RESUMO
Neurodevelopmental disorders are major indications for genetic referral and have been linked to more than 1,500 loci including genes encoding transcriptional regulators. The dysfunction of transcription factors often results in characteristic syndromic presentations, however, at least half of these patients lack a genetic diagnosis. The implementation of machine learning approaches has the potential to aid in the identification of new disease genes and delineate associated phenotypes. Next generation sequencing was performed in seven affected individuals with neurodevelopmental delay and dysmorphic features. Clinical characterization included reanalysis of available neuroimaging datasets and 2D portrait image analysis with GestaltMatcher. The functional consequences of ZSCAN10 loss were modelled in mouse embryonic stem cells (mESC), including a knock-out and a representative ZSCAN10 protein truncating variant. These models were characterized by gene expression and Western blot analyses, chromatin immunoprecipitation and quantitative PCR (ChIP-qPCR), and immunofluorescence staining. Zscan10 knockout mouse embryos were generated and phenotyped. We prioritized bi-allelic ZSCAN10 loss-of-function variants in seven affected individuals from five unrelated families as the underlying molecular cause. RNA-Seq analyses in Zscan10-/- mESCs indicated dysregulation of genes related to stem cell pluripotency. In addition, we established in mESCs the loss-of-function mechanism for a representative human ZSCAN10 protein truncating variant by showing alteration of its expression levels and subcellular localization, interfering with its binding to DNA enhancer targets. Deep phenotyping revealed global developmental delay, facial asymmetry, and malformations of the outer ear as consistent clinical features. Cerebral MRI showed dysplasia of the semicircular canals as an anatomical correlate of sensorineural hearing loss. Facial asymmetry was confirmed as a clinical feature by GestaltMatcher and was recapitulated in the Zscan10 mouse model along with inner and outer ear malformations. Our findings provide evidence of a novel syndromic neurodevelopmental disorder caused by bi-allelic loss-of-function variants in ZSCAN10.
RESUMO
Advances in endoscopy and anesthesia have enabled gastrointestinal endoscopy for children since 1960. Over the past decades, the number of endoscopies has increased rapidly. As specialized teams of pediatric gastroenterologists, pediatric intensive care physicians and pediatric endoscopy nurses are available in many medical centers, safe and effective procedures have been established. Therefore, diagnostic endoscopies in children are routine clinical procedures. The most frequently performed endoscopies are esophagogastroduodenoscopy (EGD), colonoscopy and endoscopic retrograde cholangiopancreaticography (ERCP). Therapeutic interventions include variceal bleeding ligation, foreign body retrieval and percutaneous endoscopic gastrostomy. New advances in pediatric endoscopy have led to more sensitive diagnostics of common pediatric gastrointestinal disorders, such as Crohn's disease, ulcerative colitis and celiac disease; likewise, new diseases, such as eosinophilic esophagitis, have been brought to light.Upcoming modalities, such as capsule endoscopy, double balloon enteroscopy and narrow band imaging, are being established and may contribute to diagnostics in pediatric gastroenterology in the future.
