Three cases of molecularly confirmed Knobloch syndrome

Background: Knobloch syndrome (OMIM 267750) is a rare autosomal recessive disorder due to genetic defects in the COL18A1 gene. The triad of high myopia, occipital defect, vitreoretinal degeneration has been described as pathognomonic for this condition. Patients with Knobloch syndrome have also extraocular problems as brain and kidney malformations. High genetic and phenotypic variation has been reported in the affected patients. Materials and Methods: Here we provide detailed clinical description of 3 individuals with Knobloch syndrome. Ocular examination and fundus imaging have been performed. Detailed information about systemic conditions has been provided. Results: Mutations in COL18A1 were identified in all three patients. Patient 1 had congenital hip dislocation and patient 2 had renal atrophy, cardiac insufficiency and difficult skin healing. Conclusions: With this report we add to the clinical and genetic knowledge of this rare condition

Congenital hydrocephalus : new Mendelian mutations and evidence for oligogenic inheritance

Peer reviewe

Activating TIE2 mutations with distinct features cause a spectrum of venous malformations

Venous malformations (VMs) are localized defects of angiogenesis consisting of abnormally enlarged venous channels with disorganized surrounding smooth muscle cells (SMCs). VMs can cause pain and diminish quality of life. While mostly sporadic, 1-2% of venous malformations occur as an autosomal dominant inherited trait, cutaneomucosal venous malformation (VMCM). Earlier studies demonstrated that TIE2 germline mutations cause VMCM (Vikkula et al., 1996), while somatic mutations in the same gene cause common sporadic unifocal venous malformation (Limaye et al., 2009). In the frame of this thesis, we have expanded the number of mutations identified in VMCM and in unifocal VMs. In addition, we have shown that TIE2 mutations are also responsible for multifocal forms of venous malformation (BRBN and sporadically occurring multifocal venous malformations). Interestingly, in contrast to unifocal VMs, most multifocal VMs are caused by TIE2 double cis mutations. Thus, TIE2 mutations have been identified in patients with a variety of venous malformations, illustrating the extensive phenotypic heterogeneity of TIE2-mediated venous anomalies. However, distinct mutations are enriched in the different clinical subtypes, and different venous entities also differ in terms of mutational mechanisms (germline, mosaic, or somatic events that occursimultaneously or serially). In cultured endothelial cells (HUVECs), we show that different TIE2 mutations have both common and mutation-specific effects. All mutations identified in these studies (including those that truncate the TIE2 C-terminal tail) induce ligand-independent phosphorylation of the receptor. We also show that the activation of PI3K/AKT is common in cells expressing mutated TIE2. Another common feature is the disruption of the normal EC cobblestone morphology. On the other hand, we also show genotype-phenotype correlation of mutations with distinct cellular effects, with clinically different venous phenotypes. In collaborative works, we also show that we are able to recapitulate the pathognomonic features of human VMs in a mouse xenograft model, using TIE2-mutant human ECs. This allowed us to better characterize the different mutants and to test molecular therapies. This led to a therapeutic pilot study in which rapamycin shows improvement of the symptoms of affected patients.(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 201

Novel pathogenic variants in GLE-1 as cause of congenital, AR motorneuron disease with extremely poor prognosis: contribution of WES

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Compound heterozygous null mutations of NOBOX in sisters with delayed puberty and primary amenorrhea

Background: Premature ovarian insufficiency (POI) is a heterogeneous clinical syndrome defined by a premature loss of ovarian function that associates menstrual disturbances and hypergonatropic hypogonadism. POI is a major cause of female infertility affecting 1% of women before the age of 40 and up to 0.01% before the age of 20. The etiology of POI may be iatrogenic, auto-immune or genetic but remains however undetermined in a large majority of cases. An underlying genetic etiology has to be searched in idiopathic cases, particularly in the context of a family history of POI. Methods: Whole exome sequencing (WES) was performed in trio in a Belgian patient presenting POI and in her two parents. The patient presented delayed puberty and primary amenorrhea with hypergonadotropic hypogonadism. Results: WES identified two novel compound heterozygous truncating mutations in the Newborn oogenesis homeobox (NOBOX) gene, c.826C>T (p.(Arg276Ter)) and c.1421del (p.(Gly474AlafsTer76)). Both mutations were confirmed by Sanger sequencing in the proband's sister who presented the same phenotype. Both variants were pathogenic and very likely responsible for the severe POI in this family. Conclusion: We report here for the first time compound heterozygous truncating mutations of NOBOX in outbred patients, generalizing biallelic NOBOX null mutations as a cause of severe POI with primary amenorrhea. In addition, our findings also suggest that NOBOX haploinsufficiency is tolerated.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Variable somatic TIE2 mutations in half of sporadic venous malformations

Venous malformations (VMs) are the most frequent vascular malformations referred to specialized vascular anomaly cen- ters. A rare (1–2%) familial form, termed cutaneomucosal ve- nous malformation (VMCM), is caused by gain-of-function mutations in TIE2. More recently, sporadic VMs, character- ized by the presence of large unifocal lesions, were shown to be caused by somatic mutations in TIE2. These include a fre- quent L914F change, and a series of double mutations in cis. All of which cause ligand-independent receptor hyperphos- phorylation in vitro. Here, we expanded our study to assess the range of mutations that cause sporadic VM. To test for somatic changes, we screened the entire coding region of TIE2 in cDNA from resected VMs by direct sequencing. We detected TIE2 mutations in 17/30 (56.7%) of the samples. In addition to previously detected mutations, we identified 7 novel somatic intracellular TIE2 mutations in sporadic VMs, including 3 that cause premature protein truncation

Carbamazepine efficacy in a severe electro-clinical presentation of SLC13A5-epilepsy.

Recessive mutations in the SLC13A5 gene encoding the sodium-dependent citrate transporter are a recently identified cause of developmental and epileptic encephalopathy. Here, we describe a child harboring a novel homozygous loss-of-function mutation in the SLC13A5 gene (c.1496C>T-p.Ser499Phe) and exhibiting an unusual extremely severe neonatal presentation with drug-resistant seizures and burst-suppression EEG pattern. Early carbamazepine use resulted in dramatic improvement both clinically and on EEG features. Follow-up from the neonatal period to the age of 4 years is documented. This case expands the electro-clinical phenotype associated with SLC13A5-related disease and confirms the efficacy and safety of carbamazepine in nonstructural early-onset epilepsies

Common and specific effects of TIE2 mutations causing venous malformations.

Venous malformations (VMs) are localized defects in vascular morphogenesis frequently caused by mutations in the gene for the endothelial tyrosine kinase receptor TIE2. Here, we report the analysis of a comprehensive collection of 22 TIE2 mutations identified in patients with VM, either as single amino acid substitutions or as double-mutations on the same allele. Using endothelial cell (EC) cultures, mouse models and ultrastructural analysis of tissue biopsies from patients, we demonstrate common as well as mutation-specific cellular and molecular features, on the basis of which mutations cluster into categories that correlate with data from genetic studies. Comparisons of double-mutants with their constituent single-mutant forms identified the pathogenic contributions of individual changes, and their compound effects. We find that defective receptor trafficking and subcellular localization of different TIE2 mutant forms occur via a variety of mechanisms, resulting in attenuated response to ligand. We also demonstrate, for the first time, that TIE2 mutations cause chronic activation of the MAPK pathway resulting in loss of normal EC monolayer due to extracellular matrix (ECM) fibronectin deficiency and leading to upregulation of plasminogen/plasmin proteolytic pathway. Corresponding EC and ECM irregularities are observed in affected tissues from mouse models and patients. Importantly, an imbalance between plasminogen activators versus inhibitors would also account for high d-dimer levels, a major feature of unknown cause that distinguishes VMs from other vascular anomalies

Digestive involvement in a severe form of Snyder-Robinson syndrome: Possible expansion of the phenotype

International audienceSnyder-Robinson syndrome (OMIM #309583) is a rare X-linked condition, caused by mutation in the SMS gene (MIM *300105), characterized by a wide spectrum of clinical signs including developmental delay, epilepsy, asthenic habitus, dysmorphism, osteopenia, and renal or genital anomalies. Here we describe two maternal half-brothers who both presented with severe neurodevelopmental delay, seizures, hearing loss, facial dysmorphism, renal and ophthalmologic anomalies, failure to thrive and premature death. A novel p.(Gly203Asp) variant was found at the hemizygous state in the two boys, and an elevated Spermidine/Spermine ratio confirmed the diagnosis of Snyder-Robinson syndrome. One of the brothers presented with gastrointestinal symptoms, with jejunal stenosis, enteral feeding intolerance, failure to thrive due to a dysfunctional gastrointestinal system, cholestasis and exocrine pancreatic insufficiency. Although more studies will be needed to understand its mechanisms, this observation lends further support to the possibility of severe digestive involvement in Snyder Robinson syndrome

New variant in deficiency of interleukin‐36 receptor antagonist syndrome (DITRA)

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