Wilms tumour is a childhood tumour that arises as a consequence of somatic and rare germline mutations, the characterisation of which has refined our understanding of nephrogenesis and carcinogenesis. Here we report that germline loss of function mutations in TRIM28 predispose children to Wilms tumour. Loss of function of this transcriptional co-repressor, which has a role in nephrogenesis, has not previously been associated with cancer. Inactivation of TRIM28, either germline or somatic, occurred through inactivating mutations, loss of heterozygosity or epigenetic silencing. TRIM28-mutated tumours had a monomorphic epithelial histology that is uncommon for Wilms tumour. Critically, these tumours were negative for TRIM28 immunohistochemical staining whereas the epithelial component in normal tissue and other Wilms tumours stained positively. These data, together with a characteristic gene expression profile, suggest that inactivation of TRIM28 provides the molecular basis for defining a previously described subtype of Wilms tumour, that has early age of onset and excellent prognosis.

The X-linked filaminopathies represent a diverse group of clinical conditions, all caused by variants in the gene FLNA. FLNA encodes the widely expressed actin binding protein, filamin A that has multiple roles during embryonic development including cell migration, mechanical sensing, and cell signaling. In this review, we discuss the 10 distinct X-linked filaminopathy conditions that between them affect almost all organ systems, including the brain, skeleton, heart, and skin, highlighting the critical role of this protein in human development. We review each of the phenotypes and discuss their pathogenesis, where known. Assigning pathogenicity to variants in FLNA can prove difficult, especially for missense variants and small indels, in-part because of the X-linked nature of the phenotypes, the overlap of phenotypic features between conditions, and poor understanding of the function of certain protein domains. We outline here approaches to characterize phenotypes, highlight hotspot regions within FLNA commonly mutated in these conditions, and approaches to resolving some variants of uncertain significance. K E Y W O R D S filamin A, filaminopathy, periventricular nodular heterotopia, skeletal dysplasia, X-linked disease 1 | INTRODUCTION Pathogenic variants in FLNA, the X-linked gene that encodes the cytoskeletal protein filamin A (FLNA), cause a diverse spectrum of genetic syndromes with features ranging from impaired brain development to skeletal dysplasias, gastrointestinal disorders, and compromised structure and function of the cardiac valves. To date, eight discrete syndromes are formally associated with variants in FLNA reported in OMIM (MIM# 300017). These are X-linked cardiac valvular dysplasia, congenital short bowel syndrome (also called X-linked congenital idiopathic intestinal pseudo-obstruction), frontometaphyseal dysplasia type I, periventricular nodular heterotopia (PH), Melnick -needles syndrome (MNS), otopalatodigital syndrome type 1 (OPD1), OPD2, and digitocutaneous dysplasia (DCD; formally terminal osseous dysplasia). At least two more entities should be added to this list, isolated thrombocytopenia (Nurden et al., 2011) and a disorder characterized by keloid scarring, joint contractures, and cardiac valvulopathy (Atwal et al., 2016; Lah et al., 2015). Collectively, these conditions have been termed the X-linked filaminopathies.The broad diversity of organ systems affected across this phenotypic spectrum highlight the pivotal role that FLNA plays in human development and its widespread, but not quite ubiquitous, expression (Fox et al., 1998;Robertson et al., 2003Robertson et al., , 2007. Additionally, due to the X chromosomal location of FLNA, the presentation of FLNArelated phenotypes varies between males and females. These factors conspire to make the clinical and molecular diagnosis of FLNA-related disorders challenging.Here, we review the phenotypes associated with mutations in FLNA with emphasis on those that have been newly described since the previous comprehensive review on filaminopat...

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The family of Tre2‐Bub2‐Cdc16 (TBC)‐domain containing GTPase activating proteins (RABGAPs) is not only known as key regulatorof RAB GTPase activity but also has GAP‐independent functions. Rab GTPases are implicated in membrane trafficking pathways, such as vesicular trafficking. We report biallelic loss‐of‐function variants in TBC1D2B, encoding a member of the TBC/RABGAP family with yet unknown function, as the underlying cause of cognitive impairment, seizures, and/or gingival overgrowth in three individuals from unrelated families. TBC1D2B messenger RNA amount was drastically reduced, and the protein was absent in fibroblasts of two patients. In immunofluorescence analysis, ectopically expressed TBC1D2B colocalized with vesicles positive for RAB5, a small GTPase orchestrating early endocytic vesicle trafficking. In two independent TBC1D2B CRISPR/Cas9 knockout HeLa cell lines that serve as cellular model of TBC1D2B deficiency, epidermal growth factor internalization was significantly reduced compared with the parental HeLa cell line suggesting a role of TBC1D2B in early endocytosis. Serum deprivation of TBC1D2B‐deficient HeLa cell lines caused a decrease in cell viability and an increase in apoptosis. Our data reveal that loss of TBC1D2B causes a neurodevelopmental disorder with gingival overgrowth, possibly by deficits in vesicle trafficking and/or cell survival.

Pathogenic variants in the Golgi localised alpha 1,6 fucosyltransferase, FUT8, cause a rare inherited metabolic disorder known as FUT8‐CDG. To date, only three affected individuals have been reported presenting with a constellation of symptoms including intrauterine growth restriction, severe delays in growth and development, other neurological impairments, significantly shortened limbs, respiratory complications, and shortened lifespan. Here, we report an additional four unrelated affected individuals homozygous for novel pathogenic variants in FUT8. Analysis of serum N‐glycans revealed a complete lack of core fucosylation, an important diagnostic biomarker of FUT8‐CDG. Our data expands both the molecular and clinical phenotypes of FUT8‐CDG and highlights the importance of identifying a reliable biomarker for confirming potentially pathogenic variants.