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Aravinda Chakravarti - One of the best experts on this subject based on the ideXlab platform.
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gene and tissue level interactions in normal gastrointestinal development and Hirschsprung Disease
Proceedings of the National Academy of Sciences of the United States of America, 2019Co-Authors: Aravinda Chakravarti, Sumantra Chatterjee, Dallas R Auer, Stacey Gabriel, Priyanka NandakumarAbstract:The development of the gut from endodermal tissue to an organ with multiple distinct structures and functions occurs over a prolonged time during embryonic days E10.5–E14.5 in the mouse. During this process, one major event is innervation of the gut by enteric neural crest cells (ENCCs) to establish the enteric nervous system (ENS). To understand the molecular processes underpinning gut and ENS development, we generated RNA-sequencing profiles from wild-type mouse guts at E10.5, E12.5, and E14.5 from both sexes. We also generated these profiles from homozygous Ret null embryos, a model for Hirschsprung Disease (HSCR), in which the ENS is absent. These data reveal 4 major features: 1) between E10.5 and E14.5 the developmental genetic programs change from expression of major transcription factors and its modifiers to genes controlling tissue (epithelium, muscle, endothelium) specialization; 2) the major effect of Ret is not only on ENCC differentiation to enteric neurons but also on the enteric mesenchyme and epithelium; 3) a muscle genetic program exerts significant effects on ENS development; and 4) sex differences in gut development profiles are minor. The genetic programs identified, and their changes across development, suggest that both cell autonomous and nonautonomous factors, and interactions between the different developing gut tissues, are important for normal ENS development and its disorders.
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ret somatic mutations are underrecognized in Hirschsprung Disease
Genetics in Medicine, 2018Co-Authors: Qian Jiang, Fang Liu, Chunyue Miao, Zhen Zhang, Ping Xiao, Xiaoli Chen, Feng Zhang, Aravinda ChakravartiAbstract:We aimed to determine the frequency of RET mosaicism in Hirschsprung Disease (HSCR), test whether it has been underestimated, and to assess its contribution to HSCR risk. Targeted exome sequencing (n = 83) and RET single-gene screening (n = 69) were performed. Amplicon-based deep sequencing was applied on multiple tissue samples. TA cloning and sequencing were conducted for validation. We identified eight de novo mutations in 152 patients (5.2%), of which six were pathogenic mosaic mutations. Two of these patients were somatic mosaics, with mutations detected in blood, colon, and saliva (mutant allele frequency: 35–44%). In addition, germ-line mosaicism was identified in four clinically unaffected subjects, each with an affected child, in multiple tissues (mutant allele frequency: 1–28%). Somatic mutations of the RET gene are underrecognized in HSCR. Molecular investigation of the parents of patients with seemingly sporadic mutations is essential to determine recurrence risk in these families.
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enhancer variants synergistically drive dysfunction of a gene regulatory network in Hirschsprung Disease
Cell, 2016Co-Authors: Sumantra Chatterjee, Ashish Kapoor, Jennifer A Akiyama, Dallas R Auer, Dongwon Lee, Stacey Gabriel, Courtney Berrios, Len A Pennacchio, Aravinda ChakravartiAbstract:Common sequence variants in cis-regulatory elements (CREs) are suspected etiological causes of complex disorders. We previously identified an intronic enhancer variant in the RET gene disrupting SOX10 binding and increasing Hirschsprung Disease (HSCR) risk 4-fold. We now show that two other functionally independent CRE variants, one binding Gata2 and the other binding Rarb, also reduce Ret expression and increase risk 2- and 1.7-fold. By studying human and mouse fetal gut tissues and cell lines, we demonstrate that reduced RET expression propagates throughout its gene regulatory network, exerting effects on both its positive and negative feedback components. We also provide evidence that the presence of a combination of CRE variants synergistically reduces RET expression and its effects throughout the GRN. These studies show how the effects of functionally independent non-coding variants in a coordinated gene regulatory network amplify their individually small effects, providing a model for complex disorders.
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population variation in total genetic risk of Hirschsprung Disease from common ret sema3 and nrg1 susceptibility polymorphisms
Human Molecular Genetics, 2015Co-Authors: Ashish Kapoor, Maria X Sosa, Sumantra Chatterjee, Qian Jiang, Courtney Berrios, Prakash Chakraborty, Aravinda ChakravartiAbstract:The risk of Hirschsprung Disease (HSCR) is ∼15/100 000 live births per newborn but has been reported to show significant inter-individual variation from the effects of seven common susceptibility alleles at the RET, SEMA3 and NRG1 loci. We show, by analyses of these variants in 997 samples from 376 HSCR families of European ancestry, that significant genetic risk can only be detected at RET (rs2435357 and rs2506030) and at SEMA3 (rs11766001), but not at NRG1. RET rs2435357 also showed significant frequency differences by gender, segment length of aganglionosis and familiality. Further, in combination, Disease risk varied >30-fold between individuals with none and up to 6 susceptibility alleles. Thus, these polymorphisms can be used to stratify the newborn population into distinct phenotypic classes with defined risks to understand HSCR etiology.
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effects of ret and nrg1 polymorphisms in indonesian patients with Hirschsprung Disease
Journal of Pediatric Surgery, 2014Co-Authors: Ashish Kapoor, Albee Y Ling, Akhmad Makhmudi, Elisabeth Siti Herini, Maria X Sosa, Sumantra Chatterjee, Aravinda ChakravartiAbstract:Background Hirschsprung Disease (HSCR) is a neurocristopathy characterized by absence of intramural ganglion cells along variable lengths of the gastrointestinal tract in neonates. Three polymorphisms, rs2435357, within a conserved transcriptional enhancer of RET, and, rs7835688 and rs16879552, within intron 1 of NRG1, have been shown to be associated with isolated forms of HSCR. We wished to replicate these findings, and study the interactions between these variants, in Indonesian HSCR patients.
Anna Pelet - One of the best experts on this subject based on the ideXlab platform.
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trans ethnic meta analysis of genome wide association studies for Hirschsprung Disease
Human Molecular Genetics, 2016Co-Authors: Clara S Tang, Anna Pelet, Ashish Kapoor, Berta Luzontoro, Hongsheng Gui, Jeong Hyun Kim, Grzegorz M Burzynski, Francesca Lantieri, Courtney BerriosAbstract:Hirschsprung Disease (HSCR) is the most common cause of neonatal intestinal obstruction. It is characterized by the absence of ganglia in the nerve plexuses of the lower gastrointestinal tract. So far, three common Disease-susceptibility variants at the RET, SEMA3 and NRG1 loci have been detected through genome-wide association studies (GWAS) in Europeans and Asians to understand its genetic etiologies. Here we present a trans-ethnic meta-analysis of 507 HSCR cases and 1191 controls, combining all published GWAS results on HSCR to fine-map these loci and narrow down the putatively causal variants to 99% credible sets. We also demonstrate that the effects of RET and NRG1 are universal across European and Asian ancestries. In contrast, we detected a European-specific association of a low-frequency variant, rs80227144, in SEMA3 [odds ratio (OR) = 5.2, P = 4.7 × 10-10]. Conditional analyses on the lead SNPs revealed a secondary association signal, corresponding to an Asian-specific, low-frequency missense variant encoding RET p.Asp489Asn (rs9282834, conditional OR = 20.3, conditional P = 4.1 × 10-14). When in trans with the RET intron 1 enhancer risk allele, rs9282834 increases the risk of HSCR from 1.1 to 26.7. Overall, our study provides further insights into the genetic architecture of HSCR and has profound implications for future study designs.
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Epistasis between RET and BBS mutations modulates enteric innervation and causes syndromic Hirschsprung Disease.
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Loïc De Pontual, Norann A Zaghloul, Sophie Thomas, Erica E Davis, David M Mcgaughey, Hélène Dollfus, Clarisse Baumann, Seneca L Bessling, Candice Babarit, Anna PeletAbstract:Hirschsprung Disease (HSCR) is a common, multigenic neurocristopathy characterized by incomplete innervation along a variable length of the gut. The pivotal gene in isolated HSCR cases, either sporadic or familial, is RET. HSCR also presents in various syndromes, including Shah-Waardenburg syndrome (WS), Down (DS), and Bardet-Biedl (BBS). Here, we report 3 families with BBS and HSCR with concomitant mutations in BBS genes and regulatory RET elements, whose functionality is tested in physiologically relevant assays. Our data suggest that BBS mutations can potentiate HSCR predisposing RET alleles, which by themselves are insufficient to cause Disease. We also demonstrate that these genes interact genetically in vivo to modulate gut innervation, and that this interaction likely occurs through complementary, yet independent, pathways that converge on the same biological process.
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segregation at three loci explains familial and population risk in Hirschsprung Disease
Nature Genetics, 2002Co-Authors: Stacey Bolk Gabriel, Anna Pelet, Remi Salomon, Jeanne Amiel, Misha Angrist, Myriam Fornage, Tania Attiebitach, Jane M Olson, Robert M.w. HofstraAbstract:Hirschsprung Disease (HSCR), the most common hereditary cause of intestinal obstruction, shows considerable variation and complex inheritance. Coding sequence mutations in RET, GDNF, EDNRB, EDN3 and SOX10 lead to long-segment (L-HSCR) and syndromic HSCR but fail to explain the transmission of the much more common short-segment form (S-HSCR). We conducted a genome scan in families with S-HSCR and identified susceptibility loci at 3p21, 10q11 and 19q12 that seem to be necessary and sufficient to explain recurrence risk and population incidence. The gene at 10q11 is probably RET, supporting its crucial role in all forms of HSCR; however, coding sequence mutations are present in only 40% of linked families, suggesting the importance of noncoding variation. Here we show oligogenic inheritance of S-HSCR, the 3p21 and 19q12 loci as RET-dependent modifiers, and a parent-of-origin effect at RET. This study demonstrates by a complete genetic dissection why the inheritance pattern of S-HSCR is nonmendelian.
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large scale deletions and smadip1 truncating mutations in syndromic Hirschsprung Disease with involvement of midline structures
American Journal of Human Genetics, 2001Co-Authors: Jeanne Amiel, Anna Pelet, Yolanda Espinosaparrilla, Julie Steffann, Philippe Gosset, M Prieur, Odile Boute, Agnes Choiset, Didier Lacombe, Nicole PhilipAbstract:Hirschsprung Disease (HSCR) is a common malformation of neural-crest–derived enteric neurons that is frequently associated with other congenital abnormalities. The SMADIP1 gene recently has been recognized as Disease causing in some patients with 2q22 chromosomal rearrangement, resulting in syndromic HSCR with mental retardation, with microcephaly, and with facial dysmorphism. We screened 19 patients with HSCR and mental retardation and eventually identified large-scale SMADIP1 deletions or truncating mutations in 8 of 19 patients. These results allow further delineation of the spectrum of malformations ascribed to SMADIP1 haploinsufficiency, which includes frequent features such as hypospadias and agenesis of the corpus callosum. Thus, SMADIP1, which encodes a transcriptional corepressor of Smad target genes, may play a role not only in the patterning of neural-crest–derived cells and of CNS but also in the development of midline structures in humans.
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endothelin 3 gene mutations in isolated and syndromic Hirschsprung Disease
European Journal of Human Genetics, 1997Co-Authors: Christelle Bidaud, Tawab Attie, Anna Pelet, G. Van Camp, Patrick J. Willems, Maryse Bonduelle, Remi Salomon, Jeanne Amiel, C Nihoulfekete, Arnold MunnichAbstract:Abstract Hirschsprung Disease (HSCR, aganglionic megacolon) is a frequent congenital malformation regarded as a multigenic neurocristopathy. Four susceptibility genes have recently been identified in HSCR, namely the RET proto-oncogene, the glial cell line-derived neurotrophic factor (GDNF), the endothelin B receptor (EDNRB) and the endothelin-3 genes (EDN3). Homozygosity for EDN3 mutations has been previously shown to cause the Shah-Waardenburg syndrome, a combination of HSCR with features of the Waardenburg syndrome. Here, we report on heterozygous EDN3 missense mutations in isolatec HSCR. The present data give further support to the role of the endothelin signaling pathway in the development of neural crest-derived enteric neurons. They also suggest the possibility that either recessive or weakly penetrant dominant alleles could occur at the EDN3 locus, depending on the nature of the mutation.
Jeanne Amiel - One of the best experts on this subject based on the ideXlab platform.
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contribution of rare and common variants determine complex Diseases Hirschsprung Disease as a model
Developmental Biology, 2013Co-Authors: Maria M Alves, Isabella Ceccherini, Jeanne Amiel, Guillermo Antiñolo, Salud Borrego, Aravindra Chakravarti, Raquel M Fernandez, Yunia Sribudiani, Rutger W W Brouwer, Maria Merce GarciabarceloAbstract:Finding genes for complex Diseases has been the goal of many genetic studies. Most of these studies have been successful by searching for genes and mutations in rare familial cases, by screening candidate genes and by performing genome wide association studies. However, only a small fraction of the total genetic risk for these complex genetic Diseases can be explained by the identified mutations and associated genetic loci. In this review we focus on Hirschsprung Disease (HSCR) as an example of a complex genetic disorder. We describe the genes identified in this congenital malformation and postulate that both common 'low penetrant' variants in combination with rare or private 'high penetrant' variants determine the risk on HSCR, and likely, on other complex Diseases. We also discuss how new technological advances can be used to gain further insights in the genetic background of complex Diseases. Finally, we outline a few steps to develop functional assays in order to determine the involvement of these variants in Disease development.
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segregation at three loci explains familial and population risk in Hirschsprung Disease
Nature Genetics, 2002Co-Authors: Stacey Bolk Gabriel, Anna Pelet, Remi Salomon, Jeanne Amiel, Misha Angrist, Myriam Fornage, Tania Attiebitach, Jane M Olson, Robert M.w. HofstraAbstract:Hirschsprung Disease (HSCR), the most common hereditary cause of intestinal obstruction, shows considerable variation and complex inheritance. Coding sequence mutations in RET, GDNF, EDNRB, EDN3 and SOX10 lead to long-segment (L-HSCR) and syndromic HSCR but fail to explain the transmission of the much more common short-segment form (S-HSCR). We conducted a genome scan in families with S-HSCR and identified susceptibility loci at 3p21, 10q11 and 19q12 that seem to be necessary and sufficient to explain recurrence risk and population incidence. The gene at 10q11 is probably RET, supporting its crucial role in all forms of HSCR; however, coding sequence mutations are present in only 40% of linked families, suggesting the importance of noncoding variation. Here we show oligogenic inheritance of S-HSCR, the 3p21 and 19q12 loci as RET-dependent modifiers, and a parent-of-origin effect at RET. This study demonstrates by a complete genetic dissection why the inheritance pattern of S-HSCR is nonmendelian.
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large scale deletions and smadip1 truncating mutations in syndromic Hirschsprung Disease with involvement of midline structures
American Journal of Human Genetics, 2001Co-Authors: Jeanne Amiel, Anna Pelet, Yolanda Espinosaparrilla, Julie Steffann, Philippe Gosset, M Prieur, Odile Boute, Agnes Choiset, Didier Lacombe, Nicole PhilipAbstract:Hirschsprung Disease (HSCR) is a common malformation of neural-crest–derived enteric neurons that is frequently associated with other congenital abnormalities. The SMADIP1 gene recently has been recognized as Disease causing in some patients with 2q22 chromosomal rearrangement, resulting in syndromic HSCR with mental retardation, with microcephaly, and with facial dysmorphism. We screened 19 patients with HSCR and mental retardation and eventually identified large-scale SMADIP1 deletions or truncating mutations in 8 of 19 patients. These results allow further delineation of the spectrum of malformations ascribed to SMADIP1 haploinsufficiency, which includes frequent features such as hypospadias and agenesis of the corpus callosum. Thus, SMADIP1, which encodes a transcriptional corepressor of Smad target genes, may play a role not only in the patterning of neural-crest–derived cells and of CNS but also in the development of midline structures in humans.
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Hirschsprung Disease associated syndromes and genetics a review
Journal of Medical Genetics, 2001Co-Authors: Jeanne Amiel, Stanislas LyonnetAbstract:Hirschsprung Disease (HSCR, aganglionic megacolon) represents the main genetic cause of functional intestinal obstruction with an incidence of 1/5000 live births. This developmental disorder is a neurocristopathy and is characterised by the absence of the enteric ganglia along a variable length of the intestine. In the last decades, the development of surgical approaches has importantly decreased mortality and morbidity which allowed the emergence of familial cases. Isolated HSCR appears to be a non-Mendelian malformation with low, sex-dependent penetrance, and variable expression according to the length of the aganglionic segment. While all Mendelian modes of inheritance have been described in syndromic HSCR, isolated HSCR stands as a model for genetic disorders with complex patterns of inheritance. The tyrosine kinase receptor RET is the major gene with both rare coding sequence mutations and/or a frequent variant located in an enhancer element predisposing to the Disease. Hitherto, 10 genes and five loci have been found to be involved in HSCR development.
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endothelin 3 gene mutations in isolated and syndromic Hirschsprung Disease
European Journal of Human Genetics, 1997Co-Authors: Christelle Bidaud, Tawab Attie, Anna Pelet, G. Van Camp, Patrick J. Willems, Maryse Bonduelle, Remi Salomon, Jeanne Amiel, C Nihoulfekete, Arnold MunnichAbstract:Abstract Hirschsprung Disease (HSCR, aganglionic megacolon) is a frequent congenital malformation regarded as a multigenic neurocristopathy. Four susceptibility genes have recently been identified in HSCR, namely the RET proto-oncogene, the glial cell line-derived neurotrophic factor (GDNF), the endothelin B receptor (EDNRB) and the endothelin-3 genes (EDN3). Homozygosity for EDN3 mutations has been previously shown to cause the Shah-Waardenburg syndrome, a combination of HSCR with features of the Waardenburg syndrome. Here, we report on heterozygous EDN3 missense mutations in isolatec HSCR. The present data give further support to the role of the endothelin signaling pathway in the development of neural crest-derived enteric neurons. They also suggest the possibility that either recessive or weakly penetrant dominant alleles could occur at the EDN3 locus, depending on the nature of the mutation.
Raj P Kapur - One of the best experts on this subject based on the ideXlab platform.
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Diagnosis of Hirschsprung Disease.
Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society, 2019Co-Authors: Lusine Ambartsumyan, Caitlin Smith, Raj P KapurAbstract:Diagnosis or exclusion of Hirschsprung Disease (HSCR) is a frequent exercise in any pediatric hospital. Although HSCR may present at different ages and with varied clinical findings, the most commo...
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remodeling of rectal innervation after pullthrough surgery for Hirschsprung Disease relevance to criteria for the determination of retained transition zone
Pediatric and Developmental Pathology, 2019Co-Authors: Raj P Kapur, Marc A. Levitt, Lusine Ambartsumyan, Michael A Arnold, Jeffrey R Avansino, Miriam R Conces, Richard J Wood, Kelley J MastAbstract:BackgroundAfter pullthrough surgery for Hirschsprung Disease (HSCR), Glut1-positive submucosal nerve hypertrophy is used to diagnose retained transition zone in the neorectum. We hypothesized that ...
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Supplemental material for Infra-anastomotic Innervation of Residual Aganglionic Distal Rectum After Pull-through Surgery for Hirschsprung Disease
2019Co-Authors: Raj P Kapur, Michael A Arnold, Miriam R ConcesAbstract:Supplemental Material for Infra-anastomotic Innervation of Residual Aganglionic Distal Rectum After Pull-through Surgery for Hirschsprung Disease by Raj P Kapur, Michael A Arnold and Miriam R Conces in Pediatric and Developmental Pathology
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histology of the transition zone in Hirschsprung Disease
The American Journal of Surgical Pathology, 2016Co-Authors: Raj P KapurAbstract:Surgical management of Hirschsprung Disease requires resection of the aganglionic bowel and transition zone, a length of ganglionic bowel, immediately proximal to the aganglionic segment, with neuropathologic features that seem to correlate with dysmotility. Pathologists must be able to recognize histopathologic features of the transition zone in hematoxylin and eosin-stained sections in order to interpret intraoperative frozen sections and ensure adequate resection. The proximal ganglionic portions of colonic resection specimens from 59 patients with distal aganglionosis were analyzed with closely spaced transverse sections to map the distribution of the 3 most commonly referenced features of transition zone (partial circumferential aganglionosis, myenteric hypoganglionosis, and submucosal nerve hypertrophy). Each of these "primary" findings was restricted to a region ≤5 cm proximal to the aganglionic segment in the overwhelming majority of patients. Exceptions were more common with longer aganglionic segments. Three other neuroanatomic phenotypes (gangliosclerosis, ectopic myenteric ganglia, and eosinophilic ganglionitis) of uncertain clinical significance were distributed more irregularly and often over much longer distances. Routine resection of at least 5 cm of ganglionic bowel proximal to the aganglionic segment may reduce the incidence of transition zone pull-through. However, routine intraoperative frozen section examination of the proximal resection margin to exclude the 3 primary forms of hematoxylin and eosin neuropathology described in this study is strongly advised.
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calretinin immunoreactive mucosal innervation in very short segment Hirschsprung Disease a potentially misleading observation
Pediatric and Developmental Pathology, 2014Co-Authors: Raj P KapurAbstract:Absent calretinin-immunoreactive (CRir) mucosal innervation in aganglionic rectal biopsies is considered a useful diagnostic finding for Hirschsprung Disease. Analysis of a series of rectosigmoid r...
Stanislas Lyonnet - One of the best experts on this subject based on the ideXlab platform.
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Hirschsprung Disease associated syndromes and genetics a review
Journal of Medical Genetics, 2001Co-Authors: Jeanne Amiel, Stanislas LyonnetAbstract:Hirschsprung Disease (HSCR, aganglionic megacolon) represents the main genetic cause of functional intestinal obstruction with an incidence of 1/5000 live births. This developmental disorder is a neurocristopathy and is characterised by the absence of the enteric ganglia along a variable length of the intestine. In the last decades, the development of surgical approaches has importantly decreased mortality and morbidity which allowed the emergence of familial cases. Isolated HSCR appears to be a non-Mendelian malformation with low, sex-dependent penetrance, and variable expression according to the length of the aganglionic segment. While all Mendelian modes of inheritance have been described in syndromic HSCR, isolated HSCR stands as a model for genetic disorders with complex patterns of inheritance. The tyrosine kinase receptor RET is the major gene with both rare coding sequence mutations and/or a frequent variant located in an enhancer element predisposing to the Disease. Hitherto, 10 genes and five loci have been found to be involved in HSCR development.
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mutation of the endothelin 3 gene in the waardenburg Hirschsprung Disease shah waardenburg syndrome
Nature Genetics, 1996Co-Authors: Patrick Edery, Christelle Bidaud, Helene Martelli, Tawab Attie, Anna Pelet, Robert M.w. Hofstra, Arnold Munnich, Jeanne Amiel, Stanislas LyonnetAbstract:Hirschsprung Disease (HSCR) and Waardenburg syndrome (WS) are congenital malformations regarded as neurocristopathies since both disorders involve neural crest-derived cells1–3. The WS-HSCR association (Shah-Waardenburg syndrome)4 is a rare autosomal recessive condition that occasionally has been ascribed to mutations of the endothelin-receptor B (EDNRB) gene5,6. WS-HSCR mimicks the megacolon and white coat-spotting observed in Ednrb mouse mutants7. Since mouse mutants for the EDNRB ligand, endothelin-3 (EDN3), displayed a similar phenotype8, the EDA/3 gene was regarded as an alternative candidate gene in WS-HSCR. Here, we report a homozygous substitution/deletion mutation of the EDA/3 gene in a WS-HSCR patient. EDA/3 thus becomes the third known gene (after RET and EDNRB) predisposing to HSCR, supporting the view that the endothelin-signaling pathways play a major role in the development of neural crests.
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a gene for Hirschsprung Disease maps to the proximal long arm of chromosome 10
Nature Genetics, 1993Co-Authors: Stanislas Lyonnet, Anna Pelet, C Nihoulfekete, Alessandra Bolino, Laurent Abel, M L Briard, V Moksiu, H Kaariainen, G Martucciello, Margherita LeroneAbstract:Hirschsprung Disease (HSCR) is a frequent congenital disorder (1 in 5,000 newborns) of unknown origin characterized by the absence of parasympathetic intrinsic ganglion cells of the hindgut. Taking advantage of a proximal deletion of chromosome 10q (del 10q11.2–q21.2) in a patient with total colonic aganglionosis, and of a high–density genetic map of microsatellite DNA markers, we performed genetic linkage analysis in 15 non–syndromic long–segment and short–segment HSCR families. Multipoint linkage analysis indicated that the most likely location for a HSCR locus is between loci D10S208 and D10S196, suggesting that a dominant gene for HSCR maps to 10q11.2, a region to which other neural crest defects have been mapped.
