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Siddharth Banka Rebecca Sayer Catherine Breen Stephanie Barton Julija Pavaine Sarah E. Sheppard Emma Bedoukian Cara Skraban Vishnu A Cuddapah Jill Clayton‐Smith 《American journal of medical genetics. Part A》2019,179(6):1058-1062
CREBBP loss‐of function variants cause Rubinstein–Taybi syndrome (RTS). There have been two separate reports of patients with missense variants in exon 30 or 31 of CREBBP in individuals lacking the characteristic facial and limb dysmorphism associated with RTS. Frequent features in this condition include variable intellectual disability, short stature, autistic behavior, microcephaly, feeding problems, epilepsy, recurrent upper airway infections, and mild hearing impairment. We report three further patients with de novo exon 31 CREBBP missense variants. The first individual has a c.5357G>A p. (Arg1786His) variant affecting the same codon as one of the previously described patients. Both these patients could be recognized by clinicians as mild RTS. Our second patient has a c.5602C>T p.(Arg1868Trp) variant that has been described in five other individuals who all share a strikingly similar phenotype. The third individual has a novel c.5354G>A p.(Cys1785Try) variant. Our reports expand the clinical spectrum to include ventriculomegaly, absent corpus callosum, staphyloma, cochlear malformations, and exomphalos. These additional cases also help to establish genotype–phenotype correlations in this disorder. After the first and last authors of the previous two reports, we propose to call this disorder “Menke–Hennekam syndrome” to establish it as a clinical entity distinct from RTS and to provide a satisfactory name for adoption by parents and professionals, thus facilitating appropriate clinical management and research. 相似文献
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Complex chromosomal rearrangements causing Langer–Giedion syndrome atypical phenotype: Genotype–phenotype correlation and literature review 下载免费PDF全文
Gerarda Cappuccio Rita Genesio Valentina Ronga Alberto Casertano Antonella Izzo Maria Pia Riccio Carmela Bravaccio Maria Carolina Salerno Lucio Nitsch Generoso Andria Daniela Melis 《American journal of medical genetics. Part A》2014,164(3):753-759
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An elderly Jervell and Lange‐Nielsen patient heterozygous compound for two new KCNQ1 mutations 下载免费PDF全文
Eliecer Coto Francisco J. García‐Fernández David Calvo Ricardo Salgado‐Aranda Javier Martín‐González Belén Alonso Sara Iglesias Juan Gómez 《American journal of medical genetics. Part A》2017,173(3):749-752
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Genotype–phenotype correlations in Cornelia de Lange syndrome: Behavioral characteristics and changes with age 下载免费PDF全文
Joanna Moss Jessica Penhallow Morad Ansari Stephanie Barton David Bourn David R. FitzPatrick Judith Goodship Peter Hammond Catherine Roberts Alice Welham Chris Oliver 《American journal of medical genetics. Part A》2017,173(6):1566-1574
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Rabia Faridi Risa Tona Alessandra Brofferio Michael Hoa Rafal Olszewski Isabelle Schrauwen Muhammad Z.K. Assir Akhtar A. Bandesha Asma A. Khan Atteeq U. Rehman Carmen Brewer Wasim Ahmed Suzanne M. Leal Sheikh Riazuddin Steven E. Boyden Thomas B. Friedman 《Human mutation》2019,40(2):162-176
KCNE1 encodes a regulatory subunit of the KCNQ1 potassium channel‐complex. Both KCNE1 and KCNQ1 are necessary for normal hearing and cardiac ventricular repolarization. Recessive variants in these genes are associated with Jervell and Lange‐Nielson syndrome (JLNS1 and JLNS2), a cardio‐auditory syndrome characterized by congenital profound sensorineural deafness and a prolonged QT interval that can cause ventricular arrhythmias and sudden cardiac death. Some normal‐hearing carriers of heterozygous missense variants of KCNE1 and KCNQ1 have prolonged QT intervals, a dominantly inherited phenotype designated Romano‐Ward syndrome (RWS), which is also associated with arrhythmias and elevated risk of sudden death. Coassembly of certain mutant KCNE1 monomers with wild‐type KCNQ1 subunits results in RWS by a dominant negative mechanism. This paper reviews variants of KCNE1 and their associated phenotypes, including biallelic truncating null variants of KCNE1 that have not been previously reported. We describe three homozygous nonsense mutations of KCNE1 segregating in families ascertained ostensibly for nonsyndromic deafness: c.50G>A (p.Trp17*), c.51G>A (p.Trp17*), and c.138C>A (p.Tyr46*). Some individuals carrying missense variants of KCNE1 have RWS. However, heterozygotes for loss‐of‐function variants of KCNE1 may have normal QT intervals while biallelic null alleles are associated with JLNS2, indicating a complex genotype‐phenotype spectrum for KCNE1 variants. 相似文献
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Valerie K. Jordan Brieana Fregeau Xiaoyan Ge Jessica Giordano Ronald J. Wapner Tugce B. Balci Melissa T. Carter John A. Bernat Amanda N. Moccia Anshika Srivastava Donna M. Martin Stephanie L. Bielas John Pappas Melissa D. Svoboda Marlène Rio Nathalie Boddaert Vincent Cantagrel Andrea M. Lewis Fernando Scaglia Undiagnosed Diseases Network Jennefer N. Kohler Jonathan A. Bernstein Annika M. Dries Jill A. Rosenfeld Colette DeFilippo Willa Thorson Yaping Yang Elliott H. Sherr Weimin Bi Daryl A. Scott 《Human mutation》2018,39(5):666-675
Heterozygous variants in the arginine‐glutamic acid dipeptide repeats gene (RERE) have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Here, we report nine individuals with NEDBEH who carry partial deletions or deleterious sequence variants in RERE. These variants were found to be de novo in all cases in which parental samples were available. An analysis of data from individuals with NEDBEH suggests that point mutations affecting the Atrophin‐1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, renal anomalies, and sensorineural hearing loss when compared with loss‐of‐function variants that are likely to lead to haploinsufficiency. A high percentage of RERE pathogenic variants affect a histidine‐rich region in the Atrophin‐1 domain. We have also identified a recurrent two‐amino‐acid duplication in this region that is associated with the development of a CHARGE syndrome‐like phenotype. We conclude that mutations affecting RERE result in a spectrum of clinical phenotypes. Genotype–phenotype correlations exist and can be used to guide medical decision making. Consideration should also be given to screening for RERE variants in individuals who fulfill diagnostic criteria for CHARGE syndrome but do not carry pathogenic variants in CHD7. 相似文献
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More than 1,000 mutations have been identified in the cystic fibrosis (CF) transmembrane regulator (CFTR) disease gene. The impact of these mutations on the protein and the wide spectrum of CF phenotypes prompted a series of Genotype–Phenotype correlation studies. The CFTR genotype is invariably correlated with pancreatic status—in about 85% of cases with pancreatic insufficiency and in about 15% of cases with pancreatic sufficiency. The correlations between the CFTR genotype and pulmonary, liver, and gastrointestinal expression are debatable. The heterogeneous phenotype in CF patients bearing the same genotype or homozygotes for nonsense mutations implicated environmental and/or genetic factors in the disease. However, the discordant phenotype observed in CF siblings argued against a major role of environmental factors and suggested that genes other than CFTR modulate the CF phenotype. A locus that modulates gastrointestinal expression was identified in mice and subsequently in humans. By analyzing nine CF patients discordant for meconium ileus we were able to show that this locus had a dominant effect. Moreover, in a collaborative study we found a higher rate of polymorphisms in β‐defensin genes 1 and 2 in CF patients and in controls. In another multicenter study mutations in α‐1 antitrypsin (A1AT) and mannose binding lectin genes were found to be independent risk factors for liver disease in CF patients. The body of evidence available suggests that the variegated CF phenotype results from complex interactions between numerous gene products. © 2002 Wiley‐Liss, Inc. 相似文献
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Catherine Gallou Dominique Chauveau Stéphane Richard Dominique Joly Sophie Giraud Sylviane Olschwang Natacha Martin Céline Saquet Yves Chrétien Arnaud Méjean Jean‐Michel Correas Gérard Benoît Pierre Colombeau Jean‐Pierre Grünfeld Claudine Junien Christophe Béroud 《Human mutation》2004,24(5):435-436
The original article to which this Erratum refers was published in Human Mutation 24:215–224 Human Mutation(2004) 24(3) 215–224 In the published version of this article, the key to Figure 2 was omitted. Please find Figure 2 printed here in its entirety. 相似文献
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Melissa J. Reeves Kerry E. Goetz Bin Guan Ehsan Ullah Delphine Blain Wadih M. Zein Santa J. Tumminia Robert B. Hufnagel 《Human mutation》2020,41(9):1528-1539
Molecular variant interpretation lacks disease gene‐specific cohorts for determining variant enrichment in disease versus healthy populations. To address the molecular etiology of retinal degeneration, specifically the PRPH2‐related retinopathies, we reviewed genotype and phenotype information obtained from 187 eyeGENE® participants from 161 families. Clinical details were provided by referring clinicians participating in the eyeGENE® Network. The cohort was sequenced for variants in PRPH2. Variant complementary DNA clusters and cohort frequency were compared to variants in public databases to help us to determine pathogenicity by current American College of Medical Genetics and Genomics/Association for Molecular Pathology interpretation criteria. The most frequent variant was c.828+3A>T, which affected 28 families (17.4%), and 25 of 79 (31.64%) variants were novel. The majority of missense variants clustered in the D2 intracellular loop of the peripherin‐2 protein, constituting a hotspot. Disease enrichment was noted for 23 (29.1%) of the variants. Hotspot and disease‐enrichment evidence modified variant classification for 16.5% of variants. The missense allele p.Arg172Trp was associated with a younger age of onset. To the best of our knowledge, this is the largest patient cohort review of PRPH2‐related retinopathy. Large disease gene‐specific cohorts permit gene modeling for hotspot and disease‐enrichment analysis, providing novel variant classification evidence, including for novel missense variants. 相似文献
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Rachel Rabin Alireza Radmanesh Ian A. Glass William B. Dobyns Kimberly A. Aldinger Joseph T. Shieh Shelby Romoser Hannah Bombei Leah Dowsett Pamela Trapane John A. Bernat Janice Baker Nancy J. Mendelsohn Bernt Popp Manuela Siekmeyer Ina Sorge Francis Hugh Sansbury Patrick Watts Nicola C. Foulds Jennifer Burton George Hoganson Jane A. Hurst Lara Menzies Deborah Osio Larissa Kerecuk Jan M. Cobben Khadijé Jizi Sebastien Jacquemont Stacey A. Bélanger Katharina Löhner Hermine E. Veenstra‐Knol Henny H. Lemmink Jennifer Keller‐Ramey Ingrid M. Wentzensen Sumit Punj Kirsty McWalter Jerica Lenberg Katarzyna A. Ellsworth Kelly Radtke Schahram Akbarian John Pappas 《American journal of medical genetics. Part A》2020,182(9):2037-2048
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Microarray and FISH‐based genotype–phenotype analysis of 22 Japanese patients with Wolf–Hirschhorn syndrome 下载免费PDF全文
Kenji Shimizu Keiko Wakui Tomoki Kosho Nobuhiko Okamoto Seiji Mizuno Kazuya Itomi Shigeto Hattori Kimio Nishio Osamu Samura Yoshiyuki Kobayashi Yuko Kako Takashi Arai Tsutomu Oh‐ishi Hiroshi Kawame Yoko Narumi Hirofumi Ohashi Yoshimitsu Fukushima 《American journal of medical genetics. Part A》2014,164(3):597-609
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Maryam Beheshtian Tara Akhtarkhavari Sepideh Mehvari Marzieh Mohseni Zohreh Fattahi Seyedeh Sedigheh Abedini Sanaz Arzhangi Mahsa Fadaee Payman Jamali Reza Najafipour Vera M. Kalscheuer Hao Hu Hans‐Hilger Ropers Hossein Najmabadi Kimia Kahrizi 《Clinical genetics》2021,99(1):187-192
Mutations in adaptor protein complex‐4 (AP‐4) genes have first been identified in 2009, causing a phenotype termed as AP‐4 deficiency syndrome. Since then several patients with overlapping phenotypes, comprised of intellectual disability (ID) and spastic tetraplegia have been reported. To delineate the genotype‐phenotype correlation of the AP‐4 deficiency syndrome, we add the data from 30 affected individuals from 12 out of 640 Iranian families with ID in whom we detected disease‐causing variants in AP‐4 complex subunits, using next‐generation sequencing. Furthermore, by comparing genotype‐phenotype findings of those affected individuals with previously reported patients, we further refine the genotype‐phenotype correlation in this syndrome. The most frequent reported clinical findings in the 101 cases consist of ID and/or global developmental delay (97%), speech disorders (92.1%), inability to walk (90.1%), spasticity (77.2%), and microcephaly (75.2%). Spastic tetraplegia has been reported in 72.3% of the investigated patients. The major brain imaging findings are abnormal corpus callosum morphology (63.4%) followed by ventriculomegaly (44.5%). Our result might suggest the AP‐4 deficiency syndrome as a major differential diagnostic for unknown hereditary neurodegenerative disorders. 相似文献
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A brother and sister born to a Saudi couple showed aging appearance, wrinkled skin over the hands and feet, inelastic skin, prominent veins over the hands, and other musculoskeletal and connective tissue manifestations. Both children were small for their age and had congenital dislocation of the hips. The paper describes the main manifestations and compares them with the previously described two families. 相似文献
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Cristina Di Stefano Giuseppe Zampino Pierpaolo Mastroiacovo Tracy J. Wright Giovanni Sorge Angelo Selicorni Romano Tenconi Alessandro Zappalà Agatino Battaglia Maja Di Rocco Giandomenico Palka Rosanna Pallotta Michael R. Altherr Giovanni Neri 《American journal of medical genetics. Part A》2000,94(3):254-261
We report on a clinical‐genetic study of 16 Wolf‐Hirschhorn syndrome (WHS) patients. Hemizygosity of 4p16.3 was detected by conventional prometaphase chromosome analysis (11 patients) or by molecular probes on apparently normal chromosomes (4 patients). One patient had normal chromosomes without a detectable molecular deletion within the WHS “critical region.” In each deleted patient, the deletion was demonstrated to be terminal by fluorescence in situ hybridization (FISH). The proximal breakpoint of the rearrangement was established by prometaphase chromosome analysis in cases with a visible deletion. It was within the 4p16.1 band in six patients, apparently coincident with the distal half of this band in five patients. The extent of each of the four submicroscopic deletions was established by FISH analyses with a set of overlapping cosmid clones spanning the 4p16.3 region. We found ample variations in both the size of the deletions and the position of the respective breakpoints. The precise definition of the cytogenetic defect permitted an analysis of the genotype‐phenotype correlations in WHS, leading to the proposal of a set of minimal diagnostic criteria, which in turn may facilitate the selection of critical patients in the search for the gene(s) responsible for this disorder. We observed that genotype‐phenotype correlations in WHS mostly depend on the size of the deletion, a deletion of <3.5 Mb resulting in a mild phenotype, in which malformations are absent. The absence of a detectable molecular deletion is still consistent with a WHS diagnosis. Based on these observations a “minimal” WHS phenotype was inferred, the clinical manifestations of which are restricted to the typical facial appearance, mild mental and growth retardation, and congenital hypotonia. Am. J. Med. Genet. 94:254–261, 2000. © 2000 Wiley‐Liss, Inc. 相似文献
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Doris Hofer Karl Paul Katrin Fantur Michael Beck Friederike Bürger Catherine Caillaud Ksenija Fumic Jana Ledvinova Agnieszka Lugowska Helen Michelakakis Briguita Radeva Uma Ramaswami Barbara Plecko Eduard Paschke 《Human mutation》2009,30(8):1214-1221
Alterations in GLB1, the gene coding for acid β‐D‐galactosidase (β‐Gal), can result in GM1 gangliosidosis (GM1), a neurodegenerative disorder, or in Morquio B disease (MBD), a phenotype with dysostosis multiplex and normal central nervous system (CNS) function. While most MBD patients carry a common allele, c.817TG>CT (p.W273L), only few of the >100 mutations known in GM1 can be related to a certain phenotype. In 25 multiethnic patients with GM1 or MBD, 11 missense mutations were found as well as one novel insertion and a transversion causing aberrant gene products. Except c.602G>A (p.R201H) and two novel alleles, c.592G>T (p.D198Y) and c.1189C>G (p.P397A), all mutants resulted in significantly reduced β‐Gal activities (<10% of normal) upon expression in COS‐1 cells. Although c.997T>C (p.Y333H) expressed 3% of normal activity, the mutant protein was localized in the lysosomal‐endosomal compartment. A homozygous case presented with late infantile GM1, while a heterozygous, juvenile case carried p.Y333H together with p.R201H. This allele, recently found in homozygous MBD, gives rise to rough endoplasmic reticulum (RER)‐located β‐Gal precursors. Thus, unlike classical MBD, the phenotype of heterozygotes carrying p.R201H may rather be determined by poorly active, properly transported products of the counter allele than by the mislocalized p.R201H precursors. Hum Mutat 30, 1–8, 2009. © 2009 Wiley‐Liss, Inc. 相似文献