Next‐generation sequencing (NGS) has been instrumental in solving the genetic basis of rare inherited diseases, especially neurodevelopmental syndromes. However, functional workup is essential for precise phenotype definition and to understand the underlying disease mechanisms. Using whole exome (WES) and whole genome sequencing (WGS) in four independent families with hypotonia, neurodevelopmental delay, facial dysmorphism, loss of white matter, and thinning of the corpus callosum, we identified four previously unreported homozygous truncating PPP1R21 alleles: c.347delT p.(Ile116Lysfs*25), c.2170_2171insGGTA p.(Ile724Argfs*8), c.1607dupT p.(Leu536Phefs*7), c.2063delA p.(Lys688Serfs*26) and found that PPP1R21 was absent in fibroblasts of an affected individual, supporting the allele's loss of function effect. PPP1R21 function had not been studied except that a large scale affinity proteomics approach suggested an interaction with PIBF1 defective in Joubert syndrome. Our co‐immunoprecipitation studies did not confirm this but in contrast defined the localization of PPP1R21 to the early endosome. Consistent with the subcellular expression pattern and the clinical phenotype exhibiting features of storage diseases, we found patient fibroblasts exhibited a delay in clearance of transferrin‐488 while uptake was normal. In summary, we delineate a novel neurodevelopmental syndrome caused by biallelic PPP1R21 loss of function variants, and suggest a role of PPP1R21 within the endosomal sorting process or endosome maturation pathway.

To the best our knowledge, there are variety of small molecule inhibitors to target EZH2 in cancer cells as a treatment candidate; therefore, our data in this study helps the researchers to select EZH2 for cancer therapy based on its mechanism and correlation with other markers.

Background: Esophagus cancer is the sixth most common cause of death all over the world. This type of cancer is divided into two histological subtypes: Esophagus squamous cell carcinoma and Adeno-carcinoma, the first type of this type of cancer approximately include 90% of esophageal cancers in Asian countries. While radio therapy, chemotherapy and surgery are useful in treating, few people are survived. Therefore, it is need to molecular study to predict and prevent this cancer. EZH2 gene is a member of poly comb group proteins, and with other proteins of this group act as epigenetic regulators and have principle role in cellular functions. Objectives: In this study our aim was to evaluate the impact of EZH2 silencing on TSLP gene. Materials and Methods: For constantly silencing of EZH2 gene in KYSE-30, we used shRNA in retroviral vector. After viral production in HEK293T cell line, the cells of esophagus squamous cell carcinoma were transduced with viral packages. Silencing of EZH2 gene and the expression of TSLP were evaluated with real-time PCR. Results: By using retroviral EZH2 shRNA, the expression of EZH2 reduced over 2.5 fold change in KYSE-30. TSLP gene expression reduced over 2 fold change after EZH2 gene silencing in KYSE-30. Conclusions: Regarding the stablishing of KYSE-30 cell line with EZH2 silenced gene, Our results showed that the decrease of EZH2 gene expression cause change of downstream genes expression that will be effective on molecular treatment of ESCC.

On the Front Cover: This cover image is based on the Rapid Communication Biallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function by Atteeq U. Rehman et al., Pages 267–280. DOI: https://doi.org/10.1002/humu.23694.