Successful Treatment with Dabrafenib/Trametinib of a Malignantly Transformed and Metastasized BRAF V600E Mutant Pleiomorphic Xanthoastrocytoma: A Case Report and Review of the Literature

Introduction: Pleiomorphic xanthoastrocytoma (PXA) is considered a low-grade glioma with a favorable prognosis following surgical resection. We present a case report of a BRAFV600E mutant malignantly transformed and disseminated PXA that was successfully treated with BRAF-/MEK-targeted therapy (dabrafenib/trametinib). Case Presentation: At the age of 16 years, our patient underwent an initial subtotal resection of a right occipital PXA. Six months later, a reintervention for an asymptomatic tumor recurrence was performed and complete resection was achieved. The patient has been followed up by MRI for 14 years without arguments for recurrence but was lost to follow-up thereafter. At 38 years of age, he presented with a symptomatic local recurrence with extra-cerebral soft tissue extension, for which a third surgical resection was performed. Anatomopathological examination reported a grade 3 anaplastic PXA (aPXA); molecular analysis detected a BRAFV600E mutation. Three months later, before the initiation of radiotherapy, a local tumor recurrence was diagnosed, for which he underwent a fourth surgical resection. Radiotherapy was performed following the surgical debulking. One month after completion of radiotherapy, disease progression was documented including multiple sites of extracranial metastases (skeletal, lung, cervical lymph node, and subcutaneous metastases). Systemic treatment with a combination of BRAF-/MEK-inhibitors (dabrafenib/trametinib) was initiated and resulted in a rapid and deep tumor response (partial response according to RECISTv1.1) and absence of BRAFV600E mutant ctDNA in plasma at 6 weeks after treatment initiation. A near-complete metabolic remission was documented on [18F]FDG-PET/CT 3 months after starting systemic therapy. Conclusion: We present a rare case of malignant transformation and systemic dissemination of a BRAFV600E mutant PXA, occurring 20 years after the initial diagnosis. This case highlights the importance of long-term follow-up of patients diagnosed with these rare central nervous system tumors that initially are considered benign and also illustrates that BRAF/MEK inhibition can be an effective therapy for BRAFV600E mutated PXA, underscoring the importance of performing molecular genetic profiling of these tumors

A nutrient control on marine anoxia during the end-Permian mass extinction

Oxygen deprivation and hydrogen sulfide toxicity are considered potent kill mechanisms during the mass extinction just before the Permian–Triassic boundary (~251.9 million years ago). However, the mechanism that drove vast stretches of the ocean to an anoxic state is unclear. Here, we present palaeoredox and phosphorus speciation data for a marine bathymetric transect from Svalbard. This shows that, before the extinction, enhanced weathering driven by Siberian Traps volcanism increased the influx of phosphorus, thus enhancing marine primary productivity and oxygen depletion in proximal shelf settings. However, this non-sulfidic state efficiently sequestered phosphorus in the sediment in association with iron minerals, thus restricting the intensity and spatial extent of oxygen-depleted waters. The collapse of vegetation on land immediately before the marine extinction changed the relative weathering influx of iron and sulfate. The resulting transition to euxinic (sulfidic) conditions led to enhanced remobilization of bioavailable phosphorus, initiating a feedback that caused the spread of anoxic waters across large portions of the shelf. This reconciles a lag of >0.3 million years between the onset of enhanced weathering and the development of widespread, but geographically variable, ocean anoxia, with major implications for extinction selectivity

De novo variants in ATXN7L3 lead to developmental delay, hypotonia and distinctive facial features

Deubiquitination is critical for the proper functioning of numerous biological pathways such as DNA repair, cell cycle progression, transcription, signal transduction, and autophagy. Accordingly, pathogenic variants in deubiquitinating enzymes (DUBs) have been implicated in neurodevelopmental disorders (ND) and congenital abnormalities. ATXN7L3 is a component of the DUB module of the SAGA complex, and two other related DUB modules, and serves as an obligate adaptor protein of 3 ubiquitin-specific proteases (USP22, USP27X or USP51). Through exome sequencing and GeneMatching, we identified nine individuals with heterozygous variants in ATXN7L3. The core phenotype included global motor and language developmental delay, hypotonia, and distinctive facial characteristics including hypertelorism, epicanthal folds, blepharoptosis, a small nose and mouth, and low-set posteriorly rotated ears. In order to assess pathogenicity, we investigated the effects of a recurrent nonsense variant [c.340C>T; p.(Arg114Ter)] in fibroblasts of an affected individual. ATXN7L3 protein levels were reduced, and deubiquitylation was impaired, as indicated by an increase in histone H2Bub1 levels. This is consistent with the previous observation of increased H2Bub1 levels in Atxn7l3-null mouse embryos, which have developmental delay and embryonic lethality. In conclusion, we present clinical information and biochemical characterization supporting ATXN7L3 variants in the pathogenesis of a rare syndromic ND

ISL1 is a major susceptibility gene for classic bladder exstrophy and a regulator of urinary tract development.

Previously genome-wide association methods in patients with classic bladder exstrophy (CBE) found association with ISL1, a master control gene expressed in pericloacal mesenchyme. This study sought to further explore the genetics in a larger set of patients following-up on the most promising genomic regions previously reported. Genotypes of 12 markers obtained from 268 CBE patients of Australian, British, German Italian, Spanish and Swedish origin and 1,354 ethnically matched controls and from 92 CBE case-parent trios from North America were analysed. Only marker rs6874700 at the ISL1 locus showed association (p = 2.22 × 10-08). A meta-analysis of rs6874700 of our previous and present study showed a p value of 9.2 × 10-19. Developmental biology models were used to clarify the location of ISL1 activity in the forming urinary tract. Genetic lineage analysis of Isl1-expressing cells by the lineage tracer mouse model showed Isl1-expressing cells in the urinary tract of mouse embryos at E10.5 and distributed in the bladder at E15.5. Expression of isl1 in zebrafish larvae staged 48 hpf was detected in a small region of the developing pronephros. Our study supports ISL1 as a major susceptibility gene for CBE and as a regulator of urinary tract development

De novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus

Subcellular membrane systems are highly enriched in dolichol, whose role in organelle homeostasis and endosomal-lysosomal pathway remains largely unclear besides being involved in protein glycosylation. DHDDS encodes for the catalytic subunit (DHDDS) of the enzyme cis-prenyltransferase (cis-PTase), involved in dolichol biosynthesis and dolichol-dependent protein glycosylation in the endoplasmic reticulum. An autosomal recessive form of retinitis pigmentosa (retinitis pigmentosa 59) has been associated with a recurrent DHDDS variant. Moreover, two recurring de novo substitutions were detected in a few cases presenting with neurodevelopmental disorder, epilepsy, and movement disorder. We evaluated a large cohort of patients (n=25) with de novo pathogenic variants in DHDDS and provided the first systematic description of the clinical features and long-term outcome of this new neurodevelopmental and neurodegenerative disorder. The functional impact of the identified variants was explored by yeast complementation system and enzymatic assay. Patients presented during infancy or childhood with a variable association of neurodevelopmental disorder, generalized epilepsy, action myoclonus/cortical tremor, and ataxia. Later in the disease course they experienced a slow neurological decline with the emergence of hyperkinetic and/or hypokinetic movement disorder, cognitive deterioration, and psychiatric disturbances. Storage of lipidic material and altered lysosomes were detected in myelinated fibers and fibroblasts, suggesting a dysfunction of the lysosomal enzymatic scavenger machinery. Serum glycoprotein hypoglycosylation was not detected and, in contrast to retinitis pigmentosa and other congenital disorders of glycosylation involving dolichol metabolism, the urinary dolichol D18/D19 ratio was normal. Mapping the disease-causing variants into the protein structure revealed that most of them clustered around the active site of the DHDDS subunit. Functional studies using yeast complementation assay and in vitro activity measurements confirmed that these changes affected the catalytic activity of the cis-PTase and showed growth defect in yeast complementation system as compared with the wild-type enzyme and retinitis pigmentosa-associated protein. In conclusion, we characterized a distinctive neurodegenerative disorder due to de novo DHDDS variants, which clinically belongs to the spectrum of genetic progressive encephalopathies with myoclonus. Clinical and biochemical data from this cohort depicted a condition at the intersection of congenital disorders of glycosylation and inherited storage diseases with several features akin to of progressive myoclonus epilepsy such as neuronal ceroid lipofuscinosis and other lysosomal disorders

The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology

De novo variants in ATXN7L3 lead to developmental delay, hypotonia and distinctive facial features: ATXN7L3 variants in developmental delay

International audienceAbstract Deubiquitination is critical for the proper functioning of numerous biological pathways such as DNA repair, cell cycle progression, transcription, signal transduction, and autophagy. Accordingly, pathogenic variants in deubiquitinating enzymes (DUBs) have been implicated in neurodevelopmental disorders (ND) and congenital abnormalities. ATXN7L3 is a component of the DUB module of the SAGA complex, and two other related DUB modules, and serves as an obligate adaptor protein of 3 ubiquitin-specific proteases (USP22, USP27X or USP51). Through exome sequencing and GeneMatching, we identified nine individuals with heterozygous variants in ATXN7L3. The core phenotype included global motor and language developmental delay, hypotonia, and distinctive facial characteristics including hypertelorism, epicanthal folds, blepharoptosis, a small nose and mouth, and low-set posteriorly rotated ears. In order to assess pathogenicity, we investigated the effects of a recurrent nonsense variant [c.340C>T; p.(Arg114Ter)] in fibroblasts of an affected individual. ATXN7L3 protein levels were reduced, and deubiquitylation was impaired, as indicated by an increase in histone H2Bub1 levels. This is consistent with the previous observation of increased H2Bub1 levels in Atxn7l3-null mouse embryos, which have developmental delay and embryonic lethality. In conclusion, we present clinical information and biochemical characterization supporting ATXN7L3 variants in the pathogenesis of a rare syndromic ND

De novo variants in ATXN7L3 lead to developmental delay, hypotonia and distinctive facial features

Deubiquitination is critical for the proper functioning of numerous biological pathways such as DNA repair, cell cycle progression, transcription, signal transduction, and autophagy. Accordingly, pathogenic variants in deubiquitinating enzymes (DUBs) have been implicated in neurodevelopmental disorders (ND) and congenital abnormalities. ATXN7L3 is a component of the DUB module of the SAGA complex, and two other related DUB modules, and serves as an obligate adaptor protein of 3 ubiquitin-specific proteases (USP22, USP27X or USP51). Through exome sequencing and GeneMatching, we identified nine individuals with heterozygous variants in ATXN7L3. The core phenotype included global motor and language developmental delay, hypotonia, and distinctive facial characteristics including hypertelorism, epicanthal folds, blepharoptosis, a small nose and mouth, and low-set posteriorly rotated ears. In order to assess pathogenicity, we investigated the effects of a recurrent nonsense variant [c.340C>T; p.(Arg114Ter)] in fibroblasts of an affected individual. ATXN7L3 protein levels were reduced, and deubiquitylation was impaired, as indicated by an increase in histone H2Bub1 levels. This is consistent with the previous observation of increased H2Bub1 levels in Atxn7l3-null mouse embryos, which have developmental delay and embryonic lethality. In conclusion, we present clinical information and biochemical characterization supporting ATXN7L3 variants in the pathogenesis of a rare syndromic ND

SLC20A1Is Involved in Urinary Tract and Urorectal Development

Previous studies in developingXenopusand zebrafish reported that the phosphate transporterslc20a1ais expressed in pronephric kidneys. The recent identification ofSLC20A1as a monoallelic candidate gene for cloacal exstrophy further suggests its involvement in the urinary tract and urorectal development. However, little is known of the functional role ofSLC20A1in urinary tract development. Here, we investigated this using morpholino oligonucleotide knockdown of the zebrafish orthologslc20a1a. This caused kidney cysts and malformations of the cloaca. Moreover, in morphants we demonstrated dysfunctional voiding and hindgut opening defects mimicking imperforate anus in human cloacal exstrophy. Furthermore, we performed immunohistochemistry of an unaffected 6-week-old human embryo and detectedSLC20A1in the urinary tract and the abdominal midline, structures implicated in the pathogenesis of cloacal exstrophy. Additionally, we resequencedSLC20A1in 690 individuals with bladder exstrophy-epispadias complex (BEEC) including 84 individuals with cloacal exstrophy. We identified two additional monoallelicde novovariants. One was identified in a case-parent trio with classic bladder exstrophy, and one additional novelde novovariant was detected in an affected mother who transmitted this variant to her affected son. To study the potential cellular impact ofSLC20A1variants, we expressed them in HEK293 cells. Here, phosphate transport was not compromised, suggesting that it is not a disease mechanism. However, there was a tendency for lower levels of cleaved caspase-3, perhaps implicating apoptosis pathways in the disease. Our results suggestSLC20A1is involved in urinary tract and urorectal development and implicateSLC20A1as a disease-gene for BEEC