Mitchell-Riley Syndrome : Improving Clinical Outcomes and Searching for Functional Impact of RFX-6 Mutations

Aims/HypothesisCaused by biallelic mutations of the gene encoding the transcription factor RFX6, the rare Mitchell-Riley syndrome (MRS) comprises neonatal diabetes, pancreatic hypoplasia, gallbladder agenesis or hypoplasia, duodenal atresia, and severe chronic diarrhea. So far, sixteen cases have been reported, all with a poor prognosis. This study discusses the multidisciplinary intensive clinical management of 4 new cases of MRS that survived over the first 2 years of life. Moreover, it demonstrates how the mutations impair the RFX6 function. MethodsClinical records were analyzed and described in detail. The functional impact of two RFX6(R181W) and RFX6(V506G) variants was assessed by measuring their ability to transactivate insulin transcription and genes that encode the L-type calcium channels required for normal pancreatic beta-cell function. ResultsAll four patients were small for gestational age (SGA) and prenatally diagnosed with duodenal atresia. They presented with neonatal diabetes early in life and were treated with intravenous insulin therapy before switching to subcutaneous insulin pump therapy. All patients faced recurrent hypoglycemic episodes, exacerbated when parenteral nutrition (PN) was disconnected. A sensor-augmented insulin pump therapy with a predictive low-glucose suspension system was installed with good results. One patient had a homozygous c.1517T>G (p.Val506Gly) mutation, two patients had a homozygous p.Arg181Trp mutation, and one patient presented with new compound heterozygosity. The RFX6(V506G) and RFX6(R181W) mutations failed to transactivate the expression of insulin and genes that encode L-type calcium channel subunits required for normal pancreatic beta-cell function. Conclusions/InterpretationMultidisciplinary and intensive disease management improved the clinical outcomes in four patients with MRS, including adjustment of parenteral/oral nutrition progression and advanced diabetes technologies. A better understanding of RFX6 function, in both intestine and pancreas cells, may break ground in new therapies, particularly regarding the use of drugs that modulate the enteroendocrine system.Peer reviewe

Opposite Modulation of RAC1 by Mutations in TRIO Is Associated with Distinct, Domain-Specific Neurodevelopmental Disorders

The Rho-guanine nucleotide exchange factor (RhoGEF) TRIO acts as a key regulator of neuronal migration, axonal outgrowth, axon guidance, and synaptogenesis by activating the GTPase RAC1 and modulating actin cytoskeleton remodeling. Pathogenic variants in TRIO are associated with neurodevelopmental diseases, including intellectual disability (ID) and autism spectrum disorders (ASD). Here, we report the largest international cohort of 24 individuals with confirmed pathogenic missense or nonsense variants in TRIO. The nonsense mutations are spread along the TRIO sequence, and affected individuals show variable neurodevelopmental phenotypes. In contrast, missense variants cluster into two mutational hotspots in the TRIO sequence, one in the seventh spectrin repeat and one in the RAC1-activating GEFD1. Although all individuals in this cohort present with developmental delay and a neuro-behavioral phenotype, individuals with a pathogenic variant in the seventh spectrin repeat have a more severe ID associated with macrocephaly than do most individuals with GEFD1 variants, who display milder ID and microcephaly. Functional studies show that the spectrin and GEFD1 variants cause a TRIO-mediated hyper- or hypo-activation of RAC1, respectively, and we observe a striking correlation between RAC1 activation levels and the head size of the affected individuals. In addition, truncations in TRIO GEFD1 in the vertebrate model X. tropicalis induce defects that are concordant with the human phenotype. This work demonstrates distinct clinical and molecular disorders clustering in the GEFD1 and seventh spectrin repeat domains and highlights the importance of tight control of TRIO-RAC1 signaling in neuronal development.<br/

The phenotypic spectrum of WWOX -related disorders: 20 additional cases of WOREE syndrome and review of the literature

Purpose: Germline WWOX pathogenic variants have been associated with disorder of sex differentiation (DSD), spinocerebellar ataxia (SCA), and WWOX-related epileptic encephalopathy (WOREE syndrome). We review clinical and molecular data on WWOX-related disorders, further describing WOREE syndrome and phenotype/genotype correlations. Methods: We report clinical and molecular findings in 20 additional patients from 18 unrelated families with WOREE syndrome and biallelic pathogenic variants in the WWOX gene. Different molecular screening approaches were used (quantitative polymerase chain reaction/multiplex ligation-dependent probe amplification [qPCR/MLPA], array comparative genomic hybridization [array-CGH], Sanger sequencing, epilepsy gene panel, exome sequencing). Results: Two copy-number variations (CNVs) or two single-nucleotide variations (SNVs) were found respectively in four and nine families, with compound heterozygosity for one SNV and one CNV in five families. Eight novel missense pathogenic variants have been described. By aggregating our patients with all cases reported in the literature, 37 patients from 27 families with WOREE syndrome are known. This review suggests WOREE syndrome is a very severe epileptic encephalopathy characterized by absence of language development and acquisition of walking, early-onset drug-resistant seizures, ophthalmological involvement, and a high likelihood of premature death. The most severe clinical presentation seems to be associated with null genotypes. Conclusion: Germline pathogenic variants in WWOX are clearly associated with a severe early-onset epileptic encephalopathy. We report here the largest cohort of individuals with WOREE syndrome

Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities.

PURPOSE: Hypomelanosis of Ito (HI) is a skin marker of somatic mosaicism. Mosaic MTOR pathogenic variants have been reported in HI with brain overgrowth. We sought to delineate further the pigmentary skin phenotype and clinical spectrum of neurodevelopmental manifestations of MTOR-related HI. METHODS: From two cohorts totaling 71 patients with pigmentary mosaicism, we identified 14 patients with Blaschko-linear and one with flag-like pigmentation abnormalities, psychomotor impairment or seizures, and a postzygotic MTOR variant in skin. Patient records, including brain magnetic resonance image (MRI) were reviewed. Immunostaining (n = 3) for melanocyte markers and ultrastructural studies (n = 2) were performed on skin biopsies. RESULTS: MTOR variants were present in skin, but absent from blood in half of cases. In a patient (p.[Glu2419Lys] variant), phosphorylation of p70S6K was constitutively increased. In hypopigmented skin of two patients, we found a decrease in stage 4 melanosomes in melanocytes and keratinocytes. Most patients (80%) had macrocephaly or (hemi)megalencephaly on MRI. CONCLUSION: MTOR-related HI is a recognizable neurocutaneous phenotype of patterned dyspigmentation, epilepsy, intellectual deficiency, and brain overgrowth, and a distinct subtype of hypomelanosis related to somatic mosaicism. Hypopigmentation may be due to a defect in melanogenesis, through mTORC1 activation, similar to hypochromic patches in tuberous sclerosis complex

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Retards mentaux et dysmyélinisation liés à l'X par mutation du transporteur des hormones thyroïdiennes MCT8 (étude bibliographique, présentation de 2 observations et test fonctionnel sur fibroblastes de patients)

Le gène monocarboxylate transporteur 8 (MCT8)? EN Xq13, produit une protéine transporteur les hormones thyroïdiennes (HT) à l'intérieur des cellules. Chez l'homme, la perte de fonction de MCT8 entraîne un retard mental lié à l'X associé à un retard de myélinisation pouvant initialement s'apparenter à une maladie de Pelizeus-Mezbacher. Le tableau clinique associe une hypotonie, un syndrome pyramidal, une spasticité, des mouvements anormaux et un trouble de l'acquisition du langage mais l'élément caractéristique est la perturbation du bilan thyroïdien. Nous décrirons 2 patients porteurs de ce syndrome, dont la sévérité de la maladie est différente. L'analyse moléculaire de MCT8 fut réalisée après la découverte des perturbations caractéristiques du bilan thyroïdien et elle mis en évidence 2 nouvelles mutations. Afin de prouver le caractère délétère de ces mutations, nous avons effectué un test fonctionnel de transport de T3 sur les fibroblastes de patients. Devant le retard de myélinisation de ce syndrome, nous avons tenté d'étudier le rôle de MCT8 dans les oligodendrocytes, cellules responsables de la myélinisation du système nerveux central. Les résultats obtenus suggèrent un rôle direct de MCT8 dans le transport des HT dans les oligodendrocytes.The monocarboxylate transporter 8 (MCT8) gene, located on the X chromosome, encodes an efficient thyroid hormone (TH) transporter able to uptake TH in cells. In human, MCT8 loss of fonction involves an X-linked mental retardation with various severity. When associated with myelination delay, this syndrome can be misdiagnosed with a Pelizeus-Merzbacher-like disease. Hallmarks of the syndrome are hypotonia, pyramidal syndrome, spasticity, abnormal mouvements and sever language impairment, but the most specific element is an abnormal thyroid hormone test. We report 2 cases of this syndrome whose clinical presentations are very different. Thyroid hormone test showed the caracteristic disturbances and molecular analysis of those patients's MCT8 gene revealed 2 new mutations. In order to demonstrate the negative effect of those mutations, we proceeded to a functional T3 uptake test on patients' fibroblasts. Because of the myelination observed in this syndrome, we tried to understand if MCT8 could play a role in oligodendrocytes : cells that are in charge of myelination in central nervous system. As a results, MCT8 expression and functional test on oligodendrocyte showed that MCT8 could play a direct role in TH uptake in this cell line.CLERMONT FD-BCIU-Santé (631132104) / SudocSudocFranceF

Phenotype associated with TAF2 biallelic mutations: a clinical description of four individuals and review of the literature

International audienceTranscription factor IID is a multimeric protein complex that is essential for the initiation of transcription by RNA polymerase II. One of its critical components, the TATA-binding protein-associated factor 2, is encoded by the gene TAF2. Pathogenic variants of this gene have been shown to be responsible for the Mental retardation, autosomal recessive 40 syndrome. This syndrome is characterized by severe intellectual disability, postnatal microcephaly, pyramidal signs and thin corpus callosum. Until now, only three families have been reported separately. Here we report four individuals, from two unrelated families, who present with severe intellectual disability and global developmental delay, postnatal microcephaly, feet deformities and thin corpus callosum and who carry homozygous TAF2 missense variants detected by Exome Sequencing. Taken together, our findings and those of previously reported subjects allow us to further delineate the clinical phenotype associated with TAF2 biallelic mutations

LEF1 haploinsufficiency causes ectodermal dysplasia

Ectodermal dysplasias are a family of genodermatoses commonly associated with variants in the ectodysplasin/NF-κB or the Wnt/β-catenin pathways. Both pathways are involved in signal transduction from ectoderm to mesenchyme during the development of ectoderm-derived structures. Wnt/β-catenin pathway requires the lymphoid enhancer-binding factor 1 (LEF1), a nuclear mediator, to activate target gene expression. In mice, targeted inactivation of the LEF1 gene results in a complete block of development of multiple ectodermal appendages. We report two unrelated patients with 4q25 de novo deletion encompassing LEF1, associated with severe oligodontia of primary and permanent dentition, hypotrichosis and hypohidrosis compatible with hypohidrotic ectodermal dysplasia. Taurodontism and a particular alveolar bone defect were also observed in both patients. So far, no pathogenic variants or variations involving the LEF1 gene have been reported in human. We provide further evidence for LEF1 haploinsufficiency role in ectodermal dysplasia and delineate its clinical phenotype.status: publishe