Finger creases lend a hand in Kabuki syndrome.

International audienceKabuki syndrome (KS) is a rare syndrome associating malformations with intellectual deficiency and numerous visceral, orthopedic, endocrinological, immune and autoimmune complications. The early establishment of a diagnostic of KS leads to better care of the patients and therefore prevents complications such as perception deafness, severe complications of auto-immune diseases or obesity. However, the diagnosis of KS remains difficult because based on the appreciation of facial features combined with other highly variable features. We describe a novel sign, namely the attenuation and/or congenital absence of the IPD crease of the third and fourth fingers associated with limitation of flexion of the corresponding joints, which seems to be specific of KS and could help the clinician to diagnose KS

Whole exome sequencing coupled with unbiased functional analysis reveals new Hirschsprung disease genes

Background: Hirschsprung disease (HSCR), which is congenital obstruction of the bowel, results from a failure of enteric nervous system (ENS) progenitors to migrate, proliferate, differentiate, or survive within the distal intestine. Previous studies that have searched for genes underlying HSCR have focused on ENS-related pathways and genes not fitting the current knowledge have thus often been ignored. We identify and validate novel HSCR genes using whole exome sequencing (WES), burden tests, in silico prediction, unbiased in vivo analyses of the mutated genes in zebrafish, and expression analyses in zebrafish, mouse, and human. Results: We performed de novo mutation (DNM) screening on 24 HSCR trios. We identify 28 DNMs in 21 different genes. Eight of the DNMs we identified occur in RET, the main HSCR gene, and the remaining 20 DNMs reside in genes not reported in the ENS. Knockdown of all 12 genes with missense or loss-of-function DNMs showed that the orthologs of four genes (DENND3, NCLN, NUP98, and TBATA) are indispensable for ENS development in zebrafish, and these results were confirmed by CRISPR knockout. These genes are also expressed in human and mouse gut and/or ENS progenitors. Importantly, the encoded proteins are linked to neuronal processes shared by the central nervous system and the ENS. Conclusions: Our data open new fields of investigation into HSCR pathology and provide novel insights into the development of the ENS. Moreover, the study demonstrates that functional analyses of genes carrying DNMs are warranted to delineate the full genetic architecture of rare complex diseases

Interaction Between a Chromosome 10 RET Enhancer and Chromosome 21 in the Down Syndrome-Hirschsprung Disease Association

Individuals with Down syndrome display a 40-fold greater risk of Hirschsprung disease (HSCR) than the general population of newborns implicating chromosome 21 in HSCR etiology. Here we demonstrate that the RET enhancer polymorphism RET + 9.7 (rs2435357:C > T) at chromosome 10q11.2 is associated with HSCR in DS individuals both by transmission disequilibrium (P = 0.0015) and case-control (P = 0.0115) analysis of matched cases. Interestingly, the RET+9.7 T allele frequency is significantly different between individuals with DS alone (0.26 +/- 0.04), HSCR alone (0.61 +/- 0.04), and those with HSCR and DS 0.41 +/- 0.04), demonstrating an association and interaction between RET and chromosome 21 gene dosage. This is the first report of a genetic interaction between a common functional variant (rs2435357) and a not infrequent copy number error (chromosome 21 dosage) in two human developmental disorders. Hum Mutat 30:771-775, 2009. (C) 2009 Wiley-Liss, Inc

A human model for multigenic inheritance: Phenotypic expression in Hirschsprung disease requires both the RET gene and a new 9q31 locus

Reduced penetrance in genetic disorders may be either dependent or independent of the genetic background of gene carriers. Hirschsprung disease (HSCR) demonstrates a complex pattern of inheritance with ≈50% of familial cases being heterozygous for mutations in the receptor tyrosine kinase RET. Even when identified, the penetrance of RET mutations is only 50–70%, gender-dependent, and varies with the extent of aganglionosis. We searched for additional susceptibility genes which, in conjunction with RET, lead to phenotypic expression by studying 12 multiplex HSCR families. Haplotype analysis and extensive mutation screening demonstrated three types of families: six families harboring severe RET mutations (group I); and the six remaining families, five of which are RET-linked families with no sequence alterations and one RET-unlinked family (group II). Although the presence of RET mutations in group I families is sufficient to explain HSCR inheritance, a genome scan reveals a new susceptibility locus on 9q31 exclusively in group II families. As such, the gene at 9q31 is a modifier of HSCR penetrance. These observations imply that identification of new susceptibility factors in a complex disease may depend on classification of families by mutational type at known susceptibility genes

Que sont les solutions fondées sur la nature pour la gestion du risque inondation ? Appropriations d’un concept international en France et aux États-unis

International audienceNature-based Solutions (NbS) have been defined and promoted at the international level, and their implementation in different institutional contexts remains little studied. In this article, we propose to analyze the appropriation of the concept across multiple scales in France and the United States. Through social science research anchored in an international research project, we study the definition and implementation of NBS for flood management policies in both countries, at national/federal and local scales. Our preliminary results show that in France, the concept seems to be very much linked to the definition of the International Union for Conservation of Nature (IUCN) and is mainly supported by biodiversity stakeholders. However, the concept still seems to be little used by flood management stakeholders. On the other hand, in the United States, the concept is being developed by The Nature Conservancy (TNC). The concept seems to be more mobilized by public policies related to flood management. Its appropriation nevertheless distances it from the ambition of preserving biodiversity to embrace the preservation of the environment, a term understood differently by actors and organizations.Les « solutions fondées sur la nature » (SFN) ont été définies et promues à l’échelle internationale, et leur déploiement dans différents contextes institutionnels demeure encore peu étudié. Nous proposons dans cet article d’étudier la déclinaison de ce concept à différentes échelles, en France et aux États-Unis. Grâce à une recherche ancrée en sciences sociales dans le cadre d’un projet international, nous étudions la définition et la mise en oeuvre de SFN pour les politiques de gestion des inondations dans les deux pays, aux échelles nationale/fédérale, et locales. Nos résultats préliminaires montrent qu’en France, le concept semble très lié à la définition de l’Union internationale pour la conservation de la nature (UICN) et est surtout soutenu par les acteurs du monde de la conservation de la nature. Au contraire, le concept semble encore peu approprié par les acteurs de la gestion des inondations. En revanche, aux États-Unis, c’est l’organisation The Nature Conservancy (TNC) qui promeut le concept. Le concept semble davantage mobilisé par les politiques publiques liées à la gestion des inondations. Son appropriation semble néanmoins l’éloigner de l’ambition de préservation de la biodiversité

A gene for Holt–Oram syndrome maps to the distal long arm of chromosome 12

Holt–Oram syndrome (HOS) is an autosomal dominant condition of unknown origin characterized by congenital septal heart defects with associated malformations of the upper limbs (radial ray). Here, we report on the mapping of a gene causing HOS to the distal long arm of chromosome 12 (12q21–qter) by linkage analysis in nine informative families (Zmax=6.81 at θ=0 at the D12S354 locus). Also, multipoint linkage analysis places the HOS gene within the genetic interval between D12S84 and D12S79 (multipoint lod–score in log base 10=8.10). The mapping of a gene for HOS is, to our knowledge, the first chromosomal localization of a gene responsible for congenital septal heart defect in human. The characterization of the HOS gene will hopefully shed light on the molecular mechanisms that govern heart septation in the early stages of embryogenesis