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Purpose: Dominant variants in the retinoic acid receptor beta (RARB) gene underlie a syndromic form of microphthalmia, known as MCOPS12, which is associated with other birth anomalies and global developmental delay with spasticity and/or dystonia. Here, we report 25 affected individuals with 17 novel pathogenic or likely pathogenic variants in RARB. This study aims to characterize the functional impact of these variants and describe the clinical spectrum of MCOPS12. Methods: We used in vitro transcriptional assays and in silico structural analysis to assess the functional relevance of RARB variants in affecting the normal response to retinoids. Results: We found that all RARB variants tested in our assays exhibited either a gain-of-function or a loss-of-function activity. Loss-of-function variants disrupted RARB function through a dominant-negative effect, possibly by disrupting ligand binding and/or coactivators’ recruitment. By reviewing clinical data from 52 affected individuals, we found that disruption of RARB is associated with a more variable phenotype than initially suspected, with the absence in some individuals of cardinal features of MCOPS12, such as developmental eye anomaly or motor impairment. Conclusion: Our study indicates that pathogenic variants in RARB are functionally heterogeneous and associated with extensive clinical heterogeneity.

Disruption of any of the ocular development steps can result in ocular defects such as microphthalmia, coloboma and anterior segment dysgeneses including aniridia and cataract. All of these anomalies can be isolated or seen in association with each other. Except for aniridia (almost exclusively due to PAX6 mutations), most of these congenital ocular malformations are related to a wide genetic heterogeneity, as hundreds of genes are implied in ocular development. Here we describe a patient presenting with bilateral microphthalmia, congenital cataract, corneal dystrophy and iris hypoplasia, associated with extra-ocular features, who underwent an analysis of 119 ocular development related genes. Genetic testing revealed the presence of two truncating variants in the EPHA2 gene. While EPHA2 mutations are mainly known to be responsible for isolated dominant congenital cataract, we report here the first case of complex anterior segment dysgenesis caused by a biallelic EPHA2 mutation. This gene should be screened in case of aniridia with a negative PAX6 testing, as the ocular features of our patient clearly mimic those of PAX6 mutated patients. This observation enlarges the phenotype associated with EPHA2 variations and rise the insight of a possible PAX6-EPHA2 interaction that needs further investigations. Moreover, despite a great variability in ocular and extra-ocular phenotypes, mutations type and inheritance pattern, a possible genotype-phenotype correlation can also be drawn for this gene.

International audience; HNF1B-related disease is an emerging condition characterized by an autosomal-dominant inheritance, a 50% rate of de novo mutations, and a highly variable phenotype (renal involvement, maturity-onset diabetes of the young type 5, pancreatic hypoplasia, and urogenital tract and liver test abnormalities). Given the current lack of pathognomonic characteristics and the wide overlap with other conditions, a genetic test is the diagnostic gold standard. However, pre-genetic screening is mandatory because genetic testing has substantial costs. Our aim was to develop a HNF1B score, based on clinical, imaging, and biological variables, as a pivotal tool for rational genetic testing. A score was created using a weighted combination of the most discriminative characteristics based on the frequency and specificity in published series. The HNF1B score is calculated upon 17 items including antenatal discovery, family history, and organ involvement (kidney, pancreas, liver, and genital tract). The performance of the score was assessed by a ROC curve analysis in a 433-individual cohort containing 56 HNF1B cases. The HNF1B score efficiently and significantly discriminated between mutated and nonmutated cases (AUC 0.78). The optimal cutoff threshold for the negative predictive value to rule out HNF1B mutations in a suspected individual was 8 (sensitivity 98.2%, specificity 41.1%, and negative predictive value over 99%). Thus, the HNF1B score is a simple and accurate tool to provide a more rational approach to select patients for HNF1B screening.

Pure distal monosomy of the long arm of chromosome 10 is a rare cytogenetic abnormality. The location and size of the deletions described in this region are variable. Nevertheless, the patients share characteristic facial appearance, variable cognitive impairment and neurobehavioral manifestations. A Minimal Critical Region corresponding to a 600 kb Smallest Region of deletion Overlap (SRO) has been proposed. In this report, we describe four patients with a distal 10q26 deletion, who displayed attention-deficit/hyperactivity disorders (ADHD). One of them had a marked behavioral profile and relatively preserved cognitive functions. Interestingly, the SRO was not included in the deleted segment of this patient suggesting that this deletion could contain candidate genes involved in the control of neurobehavioral functions. One of these candidates was the CALY gene, known for its association with ADHD patients and whose expression level was shown to be correlated with neurobehavioral disturbances in varying animal models. This report emphasizes the importance of the behavioral problems as a cardinal feature of the 10q microdeletion syndrome. Haploinsufficiency of CALY could play a crucial role in the development of the behavioral troubles within these patients.

Chromosomal imbalance of the 17q12 region (which includes the HNF1B transcription factor) has recently emerged as a frequent condition. 17q12 deletion was found in patients with various renal abnormalities, diabetes mellitus (MODY type 5), genital tract or liver test abnormalities, while 17q12 duplication was identified in a subset of patients with autism, mental retardation, epilepsy and/or schizophrenia but no renal disorder. We report here two first-degree relatives carrying a 17q12 duplication and harboring various renal abnormalities (bilateral hypoplastic kidneys with vesico-ureteric reflux or multicystic dysplatic kidney with contralateral hyperechogenic kidney). Esophageal atresia (EA) type C was identified at birth in one patient while none had neurological disorder. Because EA has already been identified in patients with 17q12 duplication or HNF1B point mutation, we screened HNF1B (QMPSF and direct sequencing) in nine additional patients with EA and renal abnormalities but failed to identify any pathogenic variant. This is the second report of HNF1B mutation associated with EA. Moreover, we showed herein, that renal malformations may be part of the 17q12 duplication syndrome.

We report here a 44 years-old patient with late-onset partial lipodystrophy, mental retardation, epilepsy, ichtyosis and glomerulonephritis, carrying a 10 Mb duplication of the chromosome 5q31.3–5q32.1 region detected by array-CGH.

The eye is a complex organ whose embryonic origin and developmental dynamics are now better known. The genetic basis of eye development is interesting with respect to both fundamental notions and medical implications. They are reviewed here in the light of the latest anatomical and molecular knowledge. Anomalies of the master control pathways and differentiation cascades are described, with reference to human cases and animal models. New knowledge of the pathophysiology of inherited defects sometimes challenges old classifications, provides new diagnostic tools, and may soon lead to novel treatments.

International audience; The aim of this work was to analyse genetic influences on ocular refractive value and axial length using the hypothesis of a polygenic control. The genealogical records of 55 families were used in the analyses. The cohort included 723 individuals and clinical data were collected for 445 individuals with a mean age of 37.86 years. Ocular refraction was determined by standard autorefractometry. Axial length was evaluated by scan ultrasonography. Gender, age and ethnic origin were included as covariates in the statistical analyses. Using variance component analysis via a Markov Chain Monte Carlo (MCMC) method, we estimated the heritability of refractive value and axial length in the pedigree. We then performed a segregation analysis, using Loki, a (MCMC) linkage analysis program for multilocus inheritance models, examining different inheritance models with polygenic components. Polygenic control was modelled under an additive infinitesimal model (which assumes infinite loci with small effects, with additive actions) and under a finite locus model (i.e. several causal loci). The estimates of heritability were 0.20 (95% confidence interval (CI) 0.04e0.36) for refractive value and 0.20 (95% CI 0.03e0.43) for axial length. Segregation analyses suggested that ocular refraction and axial length are under a polygenic control. A finite number of genes were identified with or without a polygenic, infinitesimal component. Ocular refraction is mildly-moderately heritable in the studied population.

Pseudoxanthoma elasticum (PXE) is a heritable connective tissue disorder caused by mutations in an ABC (ATP-Binding Cassette) transporter gene (ABCC6), which manifests with cutaneous, ophthalmologic, and cardiovascular findings. We studied a cohort of 19 families with PXE, and identified 16 different mutations, nine of which were novel variants. The mutation detection rate was about 77%. We found that arginine codon 518 was, with the previously described R1141X and EX23_29del, a recurrently mutated amino acid (11.5% of the mutations detected for each variant R518Q and R518X). No clear delineation of genotype/phenotype correlation was identified, and marked intra-familial variability of the disease was seen in one family. One family with pseudodominant inheritance displayed three distinct ABCC6 mutations, providing further evidence for the probable exclusive recessive transmission of PXE. These data contribute to the expanding database of ABCC6 mutations, to the description of phenotypic variability, and inheritance in PXE, and should be helpful for genetic counselling.

Introduction Bien que l’utilite du sequencage d’exome (ES) dans le diagnostic des ataxies semble etre etablie, le rendement diagnostique est variable (18–46 %) ; les populations ciblees et les techniques utilisees different d’une etude a l’autre. Objectifs Evaluer le rendement diagnostique d’une strategie associant ES cible (117 genes d’ataxie) a l’etude d’autres genes de maladies neurodegeneratives disponibles dans un mini-exome. Patients et methodes Trente-trois patients avec ataxie cerebelleuse d’origine genetique possible avec âge de debut inferieur a 50 ans (negatifs pour l’ataxie de Friedreich) ont ete analyses par sequencage de mini-exome (4813 genes) avec le kit Illumina « TruSight One » (sequenceur Illumina MiSeq–Plateforme CHRU Montpellier). Une analyse bio-informatique complementaire a ete realisee pour la recherche des grands rearrangements. Resultats Un rendement diagnostique de 42 % a ete obtenu avec une implication majoritaire des genes SETX (AOA2), NPC1 (Niemann Pick C), et PRKGC (SCA14). Cette approche a permis la detection de presentations atypiques de maladies connues (Niemann Pick C, ataxie telangiectasie, SCA23) et mis en evidence l’implication de genes plus rarement associes a une ataxie (HSD17B4, ERCC4). Vingt et un pour cent des patients presentaient des variants de signification inconnue et 33 % n’avaient aucun variant candidat. Discussion Le rendement diagnostique de l’approche « mini-exome » est comparable aux analyses d’exomes complets. Aucune caracteristique systematiquement associee aux resultats negatifs ne permet de formuler des recommandations quant a la prescription d’ES. L’ES devrait etre propose aux patients bien caracterises et suivis, car des analyses complementaires (genetiques, cliniques et metaboliques) sont souvent necessaires pour valider les resultats. Conclusion Cette etude confirme l’interet diagnostique de l’analyse de mini-exome pour les ataxies cerebelleuses et souligne la necessite d’une collaboration multidisciplinaire pour interpreter et valider correctement les donnees d’ES.

We report on a boy with a BMD phenotype presenting with a deletion of exons 45-49 in the DMD gene. Immunofluorescence and Western blot analysis of a skeletal muscle sample revealed, as expected, truncated dystrophin with loss in the central rod domain, but with an unusual severe deficiency in the sarcoglycan complex, as in severe DMD. We discuss possible neighboring between dystrophin and associated proteins within their complex organization at the muscle membrane.