Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by a BKCa channel opener molecule.

International audienc

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

Néphroblastome et translocation réciproque équilibrée t(1 ; 2) (q31 ; q32) (analyse faite par cytogénétique moléculaire chez un sujet déficient mental)

TOURS-BU Médecine (372612103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

PHOX2B Genotype Allows for Prediction of Tumor Risk in Congenital Central Hypoventilation Syndrome

The Phox2b gene is necessary for autonomic nervous-system development. Phox2b(−/−) mice die in utero with absent autonomic nervous system circuits, since autonomic nervous system neurons either fail to form or degenerate. We first identified the Phox2b human ortholog, PHOX2B, as the gene underlying congenital central hypoventilation syndrome (CCHS, or Ondine curse), with an autosomal dominant mode of inheritance and de novo mutation at the first generation. We have subsequently shown that heterozygous mutations of PHOX2B may account for several combined or isolated disorders of autonomic nervous-system development—namely, tumors of the sympathetic nervous system (TSNS), such as neuroblastoma and late-onset central hypoventilation syndrome. Here, we report the clinical and molecular assessments of a cohort of 188 probands with CCHS, either isolated or associated with Hirschsprung disease and/or TSNS. The mutation-detection rate was 92.6% (174/188) in our series, and the most prevalent mutation was an in-frame duplication leading to an expansion of +5 to +13 alanines in the 20-alanine stretch at the carboxy terminal of the protein. Such findings suggest PHOX2B mutation screening as a simple and reliable tool for the diagnosis of CCHS, independent of the clinically variable phenotype. In addition, somatic mosaicism was detected in 4.5% of parents. Most interestingly, analysis of genotype-phenotype interactions strongly supports the contention that patients with CCHS who develop malignant TSNS will harbor either a missense or a frameshift heterozygous mutation of the PHOX2B gene. These data further highlight the link between congenital malformations and tumor predisposition when a master gene in development is mutated

Noradrenergic neuronal development is impaired by mutation of the proneural HASH-1 gene in congenital central hypoventilation syndrome (Ondine's curse)

International audienceCongenital central hypoventilation syndrome (CCHS, Ondine's curse) is a rare disorder of the chemical control of breathing. It is frequently associated with a broad spectrum of dysautonomic symptoms, suggesting the involvement of genes widely expressed in the autonomic nervous system. In particular, the HASH-1-PHOX2A-PHOX2B developmental cascade was proposed as a candidate pathway because it controls the development of neurons with a definitive or transient noradrenergic phenotype, upstream from the RET receptor tyrosine kinase and tyrosine hydroxylase. We recently showed that PHOX2B is the major CCHS locus, whose mutation accounts for 60% of cases. We also studied the proneural HASH-1 gene and identified a heterozygous nucleotide substitution in three CCHS patients. To analyze the functional consequences of HASH-1 mutations, we developed an in vitro model of noradrenergic differentiation in neuronal progenitors derived from the mouse vagal neural crest, reproducing in vitro the HASH-PHOX-RET pathway. All HASH-1 mutant alleles impaired noradrenergic neuronal development, when overexpressed from adenoviral constructs. Thus, HASH-1 mutations may contribute to the CCHS phenotype in rare cases, consistent with the view that the abnormal chemical control of breathing observed in CCHS patients is due to the impairment of noradrenergic neurons during early steps of brainstem development

IMPLICATION D'UN GENE DU SPLICEOSOME DANS UN CAS DE DEFICIENCE MENTALE SEVERE ?

International audienceLa déficience mentale (DM) se définit par un quotient intellectuel inférieur à 70 associé à un déficit fonctionnel du comportement adaptatif apparu avant l'âge de 18 ans (American Psychiatric Association, 1994). Sa prévalence est estimée à 1-3% de la population mondiale et ses étiologies sont extrêmement hétérogènes. Cependant, 25 à 50% des DM sévères sont d'origine génétique. Les réarrangements chromosomiques équilibrés de novo sont associés à un risque croissant de DM ou de malformations congénitales, ce qui suggère que le phénotype observé est causé par la suppression, la perturbation ou l'inactivation d'un ou plusieurs gène(s) dans les régions des points de cassure. C'est grâce à l'étude de tels remaniements chromosomiques que de nombreux gènes de DM ont été identifiés. Nous rapportons ici l'analyse moléculaire de la translocation réciproque équilibrée [46, X, t (X; 3) (p22 ; q13)] de novo portée par une fillette qui présente une déficience mentale sévère et une dysmorphie faciale. Une étude par approche « whole genome sequencing » s'est révélée non informative, le point de cassure du chromosome 3 étant situé en territoire centromérique répété. L'analyse pangénomique par puce haute résolution Affymetrix (SNP6.0 GenomeWide Human) nous a permis d'exclure l'existence de remaniements chromosomiques significatifs pouvant être à l'origine du phénotype. L'analyse transcriptomique par puce Affymetrix (Human EXON1.0) objectivait la dérégulation de l'expression de nombreux gènes. Parmi ces gènes, la baisse du taux de transcrit de gènes de déficience mentale, tels que FMR1 (syndrome de l'X fragile), CRBN (DM héréditaire), MECP2 (Syndrome de Rett) ou encore KCNMA1 (DM et autisme) expliquent le phénotype DM de la fillette porteuse du remaniement. De plus, cinq gènes se trouvent sous-exprimés dans la région de point de cassure Xp22. Parmi eux, un gène code pour une sous-unité régulatrice du complexe permettant la transcription génique, le spliceosome. Les anomalies transcriptionnelles multiples observées résultent donc probablement de cette anomalie. Cependant, à ce jour nous sommes encore dans l'incapacité de choisir entre une anomalie primaire de ce gène, liée au point de cassure Xp22, ou une anomalie secondaire ayant pour conséquence une dérégulation transcriptionnelle entrainant une déficience mentale

X-Linked Mental Retardation and Autism Are Associated with a Mutation in the NLGN4 Gene, a Member of the Neuroligin Family

A large French family including members affected by nonspecific X-linked mental retardation, with or without autism or pervasive developmental disorder in affected male patients, has been found to have a 2–base-pair deletion in the Neuroligin 4 gene (NLGN4) located at Xp22.33. This mutation leads to a premature stop codon in the middle of the sequence of the normal protein and is thought to suppress the transmembrane domain and sequences important for the dimerization of neuroligins that are required for proper cell-cell interaction through binding to β-neurexins. As the neuroligins are mostly enriched at excitatory synapses, these results suggest that a defect in synaptogenesis may lead to deficits in cognitive development and communication processes. The fact that the deletion was present in both autistic and nonautistic mentally retarded males suggests that the NLGN4 gene is not only involved in autism, as previously described, but also in mental retardation, indicating that some types of autistic disorder and mental retardation may have common genetic origins