Publications by authors named "Gabriel C Dworschak"

21 Publications

  • Page 1 of 1

Currarino syndrome: a comprehensive genetic review of a rare congenital disorder.

Orphanet J Rare Dis 2021 Apr 9;16(1):167. Epub 2021 Apr 9.

Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, 53127, Bonn, Germany.

Background: The triad of a presacral mass, sacral agenesis and an anorectal anomaly constitutes the rare Currarino syndrome (CS), which is caused by dorsal-ventral patterning defects during embryonic development. The major causative CS gene is MNX1, encoding a homeobox protein.

Main Body: In the majority of patients, CS occurs as an autosomal dominant trait; however, a female predominance observed, implies that CS may underlie an additional mode(s) of inheritance. Often, the diagnosis of CS is established solely by clinical findings, impacting a detailed analysis of the disease. Our combined data, evaluating more than 60 studies reporting patients with CS-associated mutations, revealed a slightly higher incidence rate in females with a female-to-male ratio of 1.39:1. Overall, MNX1 mutation analysis was successful in only 57.4% of all CS patients investigated, with no mutation detected in 7.7% of the familial and 68% of the sporadic patients. Our studies failed to detect the presence of an expressed MNX1 isoform that might explain at least some of these mutation-negative cases.

Conclusion: Aside from MNX1, other genes or regulatory regions may contribute to CS and we discuss several cytogenetic studies and whole-exome sequencing data that have implicated further loci/genes in its etiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-021-01799-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034116PMC
April 2021

Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations.

Authors:
Dervla M Connaughton Rufeng Dai Danielle J Owen Jonathan Marquez Nina Mann Adda L Graham-Paquin Makiko Nakayama Etienne Coyaud Estelle M N Laurent Jonathan R St-Germain Lot Snijders Blok Arianna Vino Verena Klämbt Konstantin Deutsch Chen-Han Wilfred Wu Caroline M Kolvenbach Franziska Kause Isabel Ottlewski Ronen Schneider Thomas M Kitzler Amar J Majmundar Florian Buerger Ana C Onuchic-Whitford Mao Youying Amy Kolb Daanya Salmanullah Evan Chen Amelie T van der Ven Jia Rao Hadas Ityel Steve Seltzsam Johanna M Rieke Jing Chen Asaf Vivante Daw-Yang Hwang Stefan Kohl Gabriel C Dworschak Tobias Hermle Mariëlle Alders Tobias Bartolomaeus Stuart B Bauer Michelle A Baum Eva H Brilstra Thomas D Challman Jacob Zyskind Carrie E Costin Katrina M Dipple Floor A Duijkers Marcia Ferguson David R Fitzpatrick Roger Fick Ian A Glass Peter J Hulick Antonie D Kline Ilona Krey Selvin Kumar Weining Lu Elysa J Marco Ingrid M Wentzensen Heather C Mefford Konrad Platzer Inna S Povolotskaya Juliann M Savatt Natalia V Shcherbakova Prabha Senguttuvan Audrey E Squire Deborah R Stein Isabelle Thiffault Victoria Y Voinova Michael J G Somers Michael A Ferguson Avram Z Traum Ghaleb H Daouk Ankana Daga Nancy M Rodig Paulien A Terhal Ellen van Binsbergen Loai A Eid Velibor Tasic Hila Milo Rasouly Tze Y Lim Dina F Ahram Ali G Gharavi Heiko M Reutter Heidi L Rehm Daniel G MacArthur Monkol Lek Kristen M Laricchia Richard P Lifton Hong Xu Shrikant M Mane Simone Sanna-Cherchi Andrew D Sharrocks Brian Raught Simon E Fisher Maxime Bouchard Mustafa K Khokha Shirlee Shril Friedhelm Hildebrandt

Am J Hum Genet 2020 10 4;107(4):727-742. Epub 2020 Sep 4.

Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CAKUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a heterozygous de novo stop-gain variant in ZMYM2 in two different families with CAKUT. Through collaboration, we identified in total 14 different heterozygous loss-of-function mutations in ZMYM2 in 15 unrelated families. Most mutations occurred de novo, indicating possible interference with reproductive function. Human disease features are replicated in X. tropicalis larvae with morpholino knockdowns, in which expression of truncated ZMYM2 proteins, based on individual mutations, failed to rescue renal and craniofacial defects. Moreover, heterozygous Zmym2-deficient mice recapitulated features of CAKUT with high penetrance. The ZMYM2 protein is a component of a transcriptional corepressor complex recently linked to the silencing of developmentally regulated endogenous retrovirus elements. Using protein-protein interaction assays, we show that ZMYM2 interacts with additional epigenetic silencing complexes, as well as confirming that it binds to FOXP1, a transcription factor that has also been linked to CAKUT. In summary, our findings establish that loss-of-function mutations of ZMYM2, and potentially that of other proteins in its interactome, as causes of human CAKUT, offering new routes for studying the pathogenesis of the disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2020.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536580PMC
October 2020

A Genetics-First Approach Revealed Monogenic Disorders in Patients With ARM and VACTERL Anomalies.

Front Pediatr 2020 23;8:310. Epub 2020 Jun 23.

Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands.

The VATER/VACTERL association (VACTERL) is defined as the non-random occurrence of the following congenital anomalies: Vertebral, Anal, Cardiac, Tracheal-Esophageal, Renal, and Limb anomalies. As no unequivocal candidate gene has been identified yet, patients are diagnosed phenotypically. The aims of this study were to identify patients with monogenic disorders using a genetics-first approach, and to study whether variants in candidate genes are involved in the etiology of VACTERL or the individual features of VACTERL: Anorectal malformation (ARM) or esophageal atresia with or without trachea-esophageal fistula (EA/TEF). Using molecular inversion probes, a candidate gene panel of 56 genes was sequenced in three patient groups: VACTERL ( = 211), ARM ( = 204), and EA/TEF ( = 95). Loss-of-function (LoF) and additional likely pathogenic missense variants, were prioritized and validated using Sanger sequencing. Validated variants were tested for segregation and patients were clinically re-evaluated. In 7 out of the 510 patients (1.4%), pathogenic or likely pathogenic variants were identified in , and , genes that are associated with Townes-Brocks, Duane-radial-ray, and Opitz-G/BBB syndrome. These syndromes always include ARM or EA/TEF, in combination with at least two other VACTERL features. We did not identify LoF variants in the remaining candidate genes. None of the other candidate genes were identified as novel unequivocal disease genes for VACTERL. However, a genetics-first approach allowed refinement of the clinical diagnosis in seven patients, in whom an alternative molecular-based diagnosis was found with important implications for the counseling of the families.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fped.2020.00310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324789PMC
June 2020

Expanding the knowledge on development of CAKUT: molecular genetics and beyond.

Ann Transl Med 2019 Oct;7(20):596

Department of Pediatrics, Children's Hospital, Children's Hospital, University of Bonn, Bonn, Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/atm.2019.09.157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861812PMC
October 2019

Rare Variants in BNC2 Are Implicated in Autosomal-Dominant Congenital Lower Urinary-Tract Obstruction.

Am J Hum Genet 2019 05;104(5):994-1006

Department of Pediatrics, Children's Hospital, University Hospital Bonn, 53113 Bonn, Germany; Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany. Electronic address:

Congenital lower urinary-tract obstruction (LUTO) is caused by anatomical blockage of the bladder outflow tract or by functional impairment of urinary voiding. About three out of 10,000 pregnancies are affected. Although several monogenic causes of functional obstruction have been defined, it is unknown whether congenital LUTO caused by anatomical blockage has a monogenic cause. Exome sequencing in a family with four affected individuals with anatomical blockage of the urethra identified a rare nonsense variant (c.2557C>T [p.Arg853]) in BNC2, encoding basonuclin 2, tracking with LUTO over three generations. Re-sequencing BNC2 in 697 individuals with LUTO revealed three further independent missense variants in three unrelated families. In human and mouse embryogenesis, basonuclin 2 was detected in lower urinary-tract rudiments. In zebrafish embryos, bnc2 was expressed in the pronephric duct and cloaca, analogs of the mammalian lower urinary tract. Experimental knockdown of Bnc2 in zebrafish caused pronephric-outlet obstruction and cloacal dilatation, phenocopying human congenital LUTO. Collectively, these results support the conclusion that variants in BNC2 are strongly implicated in LUTO etiology as a result of anatomical blockage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2019.03.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506863PMC
May 2019

Duplication of 11p15 Associated With Congenital Diaphragmatic Hernia.

Front Pediatr 2018 25;6:116. Epub 2018 Apr 25.

Institute of Human Genetics, University of Bonn, Bonn, Germany.

Congenital diaphragmatic hernia (CDH) is a rare defect of the diaphragm commonly associated with high morbidity and mortality due to lung hypoplasia and pulmonary hypertension. Although in 70% of patients the etiology of a CDH remains unknown, a multitude of causative chromosomal aberrations has been identified. We describe the first case of isolated 11p15 duplication with CDH. The 18.6 Mb large duplication affected 285 RefSeq genes and included the Beckwith-Wiedemann (BWS)-associated imprinting control region 2 (ICR2, TSS DMR), whereas the ICR1 ( TSS DMR) was not affected. We were able to demonstrate occurrence of the duplication. The paternal origin of the chromosomal material was detected by methylation testing the ICR2. Corresponding to other patients with duplications of the paternal ICR2 copy, a BWS phenotype is not present. The patient presented here together with the review of four other cases from the literature indicate an association between duplications of the chromosomal region 11p15 and developmental defects of the diaphragm. Thus, we suggest duplications of 11p15 as a rare cause of CDH. This association may or may not appear in the context of BWS depending on the extent of the duplication and the imprinting status. Hence, a genetic workup should be performed in patients with CDH, particularly when other abnormalities are noted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fped.2018.00116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5996915PMC
April 2018

Epidemiologic analysis of families with isolated anorectal malformations suggests high prevalence of autosomal dominant inheritance.

Orphanet J Rare Dis 2017 12 13;12(1):180. Epub 2017 Dec 13.

Institute of Human Genetics, University of Bonn, Bonn, Germany.

Background: Anorectal malformations (ARM) are rare abnormalities that occur in approximately 1 in 3000 live births with around 40% of patients presenting with isolated forms. Multiple familial cases reported, suggest underlying genetic factors that remain largely unknown. The recurrence in relatives is considered rare, however transmission rates of ARM by affected parents have never been determined before. The inheritance pattern of ARM was investigated in our database of patients with isolated ARM.

Results: Within our cohort of 327 patients with isolated ARM we identified eight adult patients from eight families who had in total 16 children with their healthy spouse. Of these ten had ARM, resulting in a recurrence risk of approximately one in two live births (10 of 16; 62%). From 226 families with 459 siblings we found two affected siblings in five families. Hence, the recurrence risk of ARM among siblings is approximately one in 92 live births (5 of 459; 1.0%).

Conclusions: Comparing the observed recurrence risk in our cohort with the prevalence in the general population, we see a 1500-fold increase in recurrence risk for offspring and a 32-fold increase if a sibling is affected. The recurrence risk of approximately 62% indicates an autosomal dominant mode of inheritance. Reliable figures on recurrence of ARM are becoming increasingly important since improved surgical techniques are able to maintain sexual function resulting in more offspring of patients with ARM. These data allow more precise counseling of families with ARM and support the need for genetic studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-017-0729-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729416PMC
December 2017

Targeted sequencing of 96 renal developmental microRNAs in 1213 individuals from 980 families with congenital anomalies of the kidney and urinary tract.

Nephrol Dial Transplant 2016 08 29;31(8):1280-3. Epub 2016 Jan 29.

Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA Howard Hughes Medical Institute, Chevy Chase, MD, USA.

Background: Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney diseases in children and young adults, accounting for ∼50% of cases. These anomalies represent maldevelopment of the genitourinary system and can be genetically explained in only 10-16% of cases by mutations or by copy number variations in protein coding sequences. Knock-out mouse models, lacking components of the microRNA (miRNA) processing machinery (i.e. Dicer, Drosha, Dgcr8), exhibit kidney malformations resembling human CAKUT.

Methods: Given the Dicer-null mouse phenotype, which implicates a central role for miRNAs gene regulation during kidney development, we hypothesized that miRNAs expressed during kidney development may cause CAKUT in humans if mutated. To evaluate this possibility we carried out Next-Generation sequencing of 96 stem-loop regions of 73 renal developmental miRNA genes in 1248 individuals with non-syndromic CAKUT from 980 families.

Results: We sequenced 96 stem-loop regions encoded by 73 miRNA genes that are expressed during kidney development in humans, mice and rats. Overall, we identified in 31/1213 individuals from 26 families with 17 different single nucleotide variants. Two variants did not segregate with the disease and hence were not causative. Thirteen variants were likely benign variants because they occurred in control populations and/or they affected nucleotides of weak evolutionary conservation. Two out of 1213 unrelated individuals had potentially pathogenic variants with unknown biologic relevance affecting miRNAs MIR19B1 and MIR99A.

Conclusions: Our results indicate that mutations affecting mature microRNAs in individuals with CAKUT are rare and thus most likely not a common cause of CAKUT in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ndt/gfv447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967727PMC
August 2016

Targeted Resequencing of 29 Candidate Genes and Mouse Expression Studies Implicate ZIC3 and FOXF1 in Human VATER/VACTERL Association.

Hum Mutat 2015 Dec 14;36(12):1150-4. Epub 2015 Sep 14.

Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

The VATER/VACTERL association describes the combination of congenital anomalies including vertebral defects, anorectal malformations, cardiac defects, tracheoesophageal fistula with or without esophageal atresia, renal malformations, and limb defects. As mutations in ciliary genes were observed in diseases related to VATER/VACTERL, we performed targeted resequencing of 25 ciliary candidate genes as well as disease-associated genes (FOXF1, HOXD13, PTEN, ZIC3) in 123 patients with VATER/VACTERL or VATER/VACTERL-like phenotype. We detected no biallelic mutation in any of the 25 ciliary candidate genes; however, identified an identical, probably disease-causing ZIC3 missense mutation (p.Gly17Cys) in four patients and a FOXF1 de novo mutation (p.Gly220Cys) in a further patient. In situ hybridization analyses in mouse embryos between E9.5 and E14.5 revealed Zic3 expression in limb and prevertebral structures, and Foxf1 expression in esophageal, tracheal, vertebral, anal, and genital tubercle tissues, hence VATER/VACTERL organ systems. These data provide strong evidence that mutations in ZIC3 or FOXF1 contribute to VATER/VACTERL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.22859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4643331PMC
December 2015

Increased psychosocial risk, depression and reduced quality of life living with autosomal dominant polycystic kidney disease.

Nephrol Dial Transplant 2016 07 12;31(7):1130-40. Epub 2015 Aug 12.

Kidney Genetics Group, Academic Unit of Nephrology, Department of Infection and Immunity, University of Sheffield Medical School, Sheffield, UK Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield Kidney Institute, Sheffield, UK.

Background: The psychosocial impact of living with autosomal dominant polycystic kidney disease (ADPKD) is poorly understood. In this study, we assessed the overall quality of life (QOL), mood, perceived social support and psychosocial risk of having a diagnosis of ADPKD in a patient cohort from a major UK nephrology centre serving a large catchment population.

Methods: A postal questionnaire was sent to 349 patients registered at the Sheffield Kidney Institute with chronic kidney disease but not on renal replacement therapy (RRT). The questionnaire incorporated three validated forms: kidney disease quality-of-life short form (KDQOL SF1.3) to assess QOL; nine-item patient health questionnaire (PHQ9) to screen for depression; multidimensional scale of perceived social support (MSPSS) to evaluate perceived social support; as well as a novel genetic psychosocial risk instrument (GPRI-ADPKD) designed to study the specific psychosocial impact of coping with a diagnosis of ADPKD.

Results: The overall response rate was 53%. Patients with a lower estimated glomerular filtration rate (<30 mL/min) or larger kidneys (mean length on ultrasound ≥17 cm) reported reduced QOL and increased psychosocial risk. Clinically significant depression was reported in 22% and 62% felt guilty about passing ADPKD on to their children. In multivariate analysis, female gender was associated with overall poorer psychosocial well-being, whereas increasing age, lower kidney function, larger kidneys and loss of a first degree relative from ADPKD were additional risk factors for QOL, depression or psychosocial risk, respectively.

Conclusions: Our results reveal a significantly poorer QOL and increasing psychosocial risk with markers of disease progression in patients, particularly women, with ADPKD prior to starting RRT. The future management strategy of ADPKD should address these issues and provide for better individual and family support throughout the patient journey.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ndt/gfv299DOI Listing
July 2016

Mutations of the SLIT2-ROBO2 pathway genes SLIT2 and SRGAP1 confer risk for congenital anomalies of the kidney and urinary tract.

Hum Genet 2015 Aug 31;134(8):905-16. Epub 2015 May 31.

Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA.

Congenital anomalies of the kidney and urinary tract (CAKUT) account for 40-50% of chronic kidney disease that manifests in the first two decades of life. Thus far, 31 monogenic causes of isolated CAKUT have been described, explaining ~12% of cases. To identify additional CAKUT-causing genes, we performed whole-exome sequencing followed by a genetic burden analysis in 26 genetically unsolved families with CAKUT. We identified two heterozygous mutations in SRGAP1 in 2 unrelated families. SRGAP1 is a small GTPase-activating protein in the SLIT2-ROBO2 signaling pathway, which is essential for development of the metanephric kidney. We then examined the pathway-derived candidate gene SLIT2 for mutations in cohort of 749 individuals with CAKUT and we identified 3 unrelated individuals with heterozygous mutations. The clinical phenotypes of individuals with mutations in SLIT2 or SRGAP1 were cystic dysplastic kidneys, unilateral renal agenesis, and duplicated collecting system. We show that SRGAP1 is expressed in early mouse nephrogenic mesenchyme and that it is coexpressed with ROBO2 in SIX2-positive nephron progenitor cells of the cap mesenchyme in developing rat kidney. We demonstrate that the newly identified mutations in SRGAP1 lead to an augmented inhibition of RAC1 in cultured human embryonic kidney cells and that the SLIT2 mutations compromise the ability of the SLIT2 ligand to inhibit cell migration. Thus, we report on two novel candidate genes for causing monogenic isolated CAKUT in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00439-015-1570-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4497857PMC
August 2015

Genome-wide mapping of copy number variations in patients with both anorectal malformations and central nervous system abnormalities.

Birth Defects Res A Clin Mol Teratol 2015 Apr 24;103(4):235-42. Epub 2014 Sep 24.

Institute of Human Genetics, University of Bonn, Bonn, Germany.

Background: Anorectal malformations (ARM) have a prevalence of around 1 in 2500 live births. In around 50% of patients, the malformation is isolated, while in the remainder it arises within the context of complex genetic abnormalities or a defined genetic syndrome. Recent studies have implicated rare copy number variations (CNVs) in both isolated and nonisolated ARM, and identified plausible candidate genes.

Methods: In the present study, array-based molecular karyotyping was performed to identify causative CNVs in 32 sporadic ARM patients with comorbid abnormalities of the central nervous system (CNS). This phenotype was selected to enrich for rare CNVs, since previous research has implicated rare CNVs in both CNS abnormalities and ARM.

Results: In five patients, a probable disease-causing CNV was identified (del6q14.3q16.3, del14q32.2, del17q12q21.2, and two patients with del22q11.21). In three of these patients, the CNVs were de novo. For the remaining two patients, no parental DNA was available. Deletions at 22q11.21 and 6q14.3 have been associated with both CNS abnormalities and ARM. In contrast, deletions at 14q32.2 have only been described in patients with CNS abnormalities, and the del17q12q21.2 is a novel CNV. Expression studies in mice suggest that NEUROD2 and RARA, which reside within the newly identified del17q12q21.2 region, are candidate genes for the formation of microcephaly and ARM.

Conclusion: The present data suggest that CNVs are a frequent cause of the ARM with CNS abnormalities phenotype, and that array-analysis is indicated in such patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/bdra.23321DOI Listing
April 2015

Heterozygous FGF8 mutations in patients presenting cryptorchidism and multiple VATER/VACTERL features without limb anomalies.

Birth Defects Res A Clin Mol Teratol 2014 Oct 8;100(10):750-9. Epub 2014 Aug 8.

Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.

Background: The acronym VATER/VACTERL association describes the combination of at least three of the following cardinal features: vertebral defects, anorectal malformations, cardiac defects, tracheoesophageal fistula with or without esophageal atresia, renal malformations, and limb defects. Although fibroblast growth factor-8 (FGF8) mutations have mainly found in patients with Kallmann syndrome, mice with a hypomorphic Fgf8 allele or complete gene invalidation display, aside from gonadotropin-releasing hormone deficiency, parts or even the entire spectrum of human VATER/VACTERL association.

Methods: We performed FGF8 gene analysis in 49 patients with VATER/VACTERL association and 27 patients presenting with a VATER/VACTERL-like phenotype (two cardinal features).

Results: We identified two heterozygous FGF8 mutations in patients displaying either VATER/VACTERL association (p.Gly29_Arg34dup) or a VATER/VACTERL-like phenotype (p.Pro26Leu) without limb anomalies. Whereas the duplication mutation has not been reported before, p.Pro26Leu was once observed in a Kallmann syndrome patient. Both our patients had additional bilateral cryptorchidism, a key phenotypic feature in males with FGF8 associated Kallmann syndrome. Each mutation was paternally inherited. Besides delayed puberty in both and additional unilateral cryptorchidism in one of the fathers, they were otherwise healthy. Serum hormone levels downstream the gonadotropin-releasing hormone in both patients and their fathers were within normal range.

Conclusion: Our results suggest FGF8 mutations to contribute to the formation of the VATER/VACTERL association. Further studies are needed to support this observation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/bdra.23278DOI Listing
October 2014

Mild recessive mutations in six Fraser syndrome-related genes cause isolated congenital anomalies of the kidney and urinary tract.

J Am Soc Nephrol 2014 Sep 3;25(9):1917-22. Epub 2014 Apr 3.

Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; Howard Hughes Medical Institute, Chevy Chase, Maryland

Congenital anomalies of the kidney and urinary tract (CAKUT) account for approximately 40% of children with ESRD in the United States. Hitherto, mutations in 23 genes have been described as causing autosomal dominant isolated CAKUT in humans. However, >90% of cases of isolated CAKUT still remain without a molecular diagnosis. Here, we hypothesized that genes mutated in recessive mouse models with the specific CAKUT phenotype of unilateral renal agenesis may also be mutated in humans with isolated CAKUT. We applied next-generation sequencing technology for targeted exon sequencing of 12 recessive murine candidate genes in 574 individuals with isolated CAKUT from 590 families. In 15 of 590 families, we identified recessive mutations in the genes FRAS1, FREM2, GRIP1, FREM1, ITGA8, and GREM1, all of which function in the interaction of the ureteric bud and the metanephric mesenchyme. We show that isolated CAKUT may be caused partially by mutations in recessive genes. Our results also indicate that biallelic missense mutations in the Fraser/MOTA/BNAR spectrum genes cause isolated CAKUT, whereas truncating mutations are found in the multiorgan form of Fraser syndrome. The newly identified recessive biallelic mutations in these six genes represent the molecular cause of isolated CAKUT in 2.5% of the 590 affected families in this study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1681/ASN.2013101103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4147986PMC
September 2014

Mutations in 12 known dominant disease-causing genes clarify many congenital anomalies of the kidney and urinary tract.

Kidney Int 2014 Jun 15;85(6):1429-33. Epub 2014 Jan 15.

1] Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Congenital anomalies of the kidney and urinary tract (CAKUT) account for approximately half of children with chronic kidney disease. CAKUT can be caused by monogenic mutations; however, data are lacking on their frequency. Genetic diagnosis has been hampered by genetic heterogeneity and lack of genotype-phenotype correlation. To determine the percentage of cases with CAKUT that can be explained by mutations in known CAKUT genes, we analyzed the coding exons of the 17 known dominant CAKUT-causing genes in a cohort of 749 individuals from 650 families with CAKUT. The most common phenotypes in this CAKUT cohort were vesicoureteral reflux in 288 patients, renal hypodysplasia in 120 patients, and unilateral renal agenesis in 90 patients. We identified 37 different heterozygous mutations (33 novel) in 12 of the 17 known genes in 47 patients from 41 of the 650 families (6.3%). These mutations include (number of families): BMP7 (1), CDC5L (1), CHD1L (5), EYA1 (3), GATA3 (2), HNF1B (6), PAX2 (5), RET (3), ROBO2 (4), SALL1 (9), SIX2 (1), and SIX5 (1). Furthermore, several mutations previously reported to be disease-causing are most likely benign variants. Thus, in a large cohort over 6% of families with isolated CAKUT are caused by a mutation in 12 of 17 dominant CAKUT genes. Our report represents one of the most in-depth diagnostic studies of monogenic causes of isolated CAKUT in children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ki.2013.508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4040148PMC
June 2014

Single-gene causes of congenital anomalies of the kidney and urinary tract (CAKUT) in humans.

Pediatr Nephrol 2014 Apr 8;29(4):695-704. Epub 2014 Jan 8.

Department of Medicine, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA.

Congenital anomalies of the kidney and urinary tract (CAKUT) cover a wide range of structural malformations that result from defects in the morphogenesis of the kidney and/or urinary tract. These anomalies account for about 40-50 % of children with chronic kidney disease worldwide. Knowledge from genetically modified mouse models suggests that single gene mutations in renal developmental genes may lead to CAKUT in humans. However, until recently, only a handful of CAKUT-causing genes were reported, most of them in familial syndromic cases. Recent findings suggest that CAKUT may arise from mutations in a multitude of different single gene causes. We focus here on single-gene causes of CAKUT and their developmental origin. Currently, more than 20 monogenic CAKUT-causing genes have been identified. High-throughput sequencing techniques make it likely that additional CAKUT-causing genes will be identified in the near future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00467-013-2684-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4676405PMC
April 2014

Whole-exome resequencing reveals recessive mutations in TRAP1 in individuals with CAKUT and VACTERL association.

Kidney Int 2014 Jun 23;85(6):1310-7. Epub 2013 Oct 23.

1] Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Congenital abnormalities of the kidney and urinary tract (CAKUT) account for approximately half of children with chronic kidney disease and they are the most frequent cause of end-stage renal disease in children in the US. However, its genetic etiology remains mostly elusive. VACTERL association is a rare disorder that involves congenital abnormalities in multiple organs including the kidney and urinary tract in up to 60% of the cases. By homozygosity mapping and whole-exome resequencing combined with high-throughput mutation analysis by array-based multiplex PCR and next-generation sequencing, we identified recessive mutations in the gene TNF receptor-associated protein 1 (TRAP1) in two families with isolated CAKUT and three families with VACTERL association. TRAP1 is a heat-shock protein 90-related mitochondrial chaperone possibly involved in antiapoptotic and endoplasmic reticulum stress signaling. Trap1 is expressed in renal epithelia of developing mouse kidney E13.5 and in the kidney of adult rats, most prominently in proximal tubules and in thick medullary ascending limbs of Henle's loop. Thus, we identified mutations in TRAP1 as highly likely causing CAKUT or VACTERL association with CAKUT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ki.2013.417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997628PMC
June 2014

De novo 13q deletions in two patients with mild anorectal malformations as part of VATER/VACTERL and VATER/VACTERL-like association and analysis of EFNB2 in patients with anorectal malformations.

Am J Med Genet A 2013 Dec 16;161A(12):3035-41. Epub 2013 Aug 16.

Institute of Human Genetics, University of Bonn, Bonn, Germany.

Anorectal malformations (ARMs) comprise a broad spectrum of conditions ranging from mild anal anomalies to complex cloacal malformations. In 40-50% of cases, ARM occurs within the context of defined genetic syndromes or complex multiple congenital anomalies, such as VATER/VACTERL (vertebral defects [V], ARMs [A], cardiac defects [C], tracheoesophageal fistula with or without esophageal atresia [TE], renal malformations [R], and limb defects [L]) association. Here, we report the identification of deletions at chromosome 13q using single nucleotide polymorphism-based array analysis in two patients with mild ARM as part of VATER/VACTERL and VATER/VACTERL-like associations. Both deletions overlap the previously defined critical region for ARM. Heterozygous Efnb2 murine knockout models presenting with mild ARM suggest EFNB2 as an excellent candidate gene in this region. Our patients showed a mild ARM phenotype, closely resembling that of the mouse. We performed a comprehensive mutation analysis of the EFNB2 gene in 331 patients with isolated ARM, or ARM as part of VATER/VACTERL or VATER/VACTERL-like associations. However, we did not identify any disease-causing mutations. Given the convincing argument for EFNB2 as a candidate gene for ARM, analyses of larger samples and screening of functionally relevant non-coding regions of EFNB2 are warranted. In conclusion, our report underlines the association of chromosome 13q deletions with ARM, suggesting that routine molecular diagnostic workup should include the search for these deletions. Despite the negative results of our mutation screening, we still consider EFNB2 an excellent candidate gene for contributing to the development of ARM in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.36153DOI Listing
December 2013

An incompletely penetrant novel MAFB (p.Ser56Phe) variant in autosomal dominant multicentric carpotarsal osteolysis syndrome.

Int J Mol Med 2013 Jul 10;32(1):174-8. Epub 2013 May 10.

Institute of Human Genetics, University Hospital of Bonn, D-53127 Bonn, Germany.

Multicentric carpotarsal osteolysis syndrome (MCTO) is a rare autosomal dominant skeletal dysplasia usually presenting in early childhood with variable phenotypic features and course. Clinical manifestations comprise aggressive osteolysis of the carpal and tarsal bones in particular, an often progressive nephropathy leading to end-stage renal disease, craniofacial anomalies and mental impairment. Recently, heterozygous missense mutations in the V-maf musculoaponeurotic fibrosarcoma oncogene homolog B (avian) (MAFB) gene have been causally related to MCTO patients in 13 unrelated families investigated. Contrary to these findings suggesting complete penetrance, in the present study, we identified a novel missense MAFB variant present not only in the patient, but also in his unaffected mother, sister and maternal grandmother. This observation demonstrates an incomplete penetrance for some MAFB mutations, thereby suggesting that modifier genes, epigenetic mechanisms or environmental factors may modulate the MCTO phenotype. This should be considered in diagnosis and genetic counseling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/ijmm.2013.1373DOI Listing
July 2013

De novo microduplications at 1q41, 2q37.3, and 8q24.3 in patients with VATER/VACTERL association.

Eur J Hum Genet 2013 Dec 3;21(12):1377-82. Epub 2013 Apr 3.

1] Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany [3] Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA.

The acronym VATER/VACTERL association describes the combination of at least three of the following congenital anomalies: vertebral defects (V), anorectal malformations (A), cardiac defects (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb defects (L). We aimed to identify highly penetrant de novo copy number variations (CNVs) that contribute to VATER/VACTERL association. Array-based molecular karyotyping was performed in a cohort of 41 patients with VATER/VACTERL association and 6 patients with VATER/VACTERL-like phenotype including all of the patients' parents. Three de novo CNVs were identified involving chromosomal regions 1q41, 2q37.3, and 8q24.3 comprising one (SPATA17), two (CAPN10, GPR35), and three (EPPK1, PLEC, PARP10) genes, respectively. Pre-existing data from the literature prompted us to choose GPR35 and EPPK1 for mouse expression studies. Based on these studies, we prioritized GPR35 for sequencing analysis in an extended cohort of 192 patients with VATER/VACTERL association and VATER/VACTERL-like phenotype. Although no disease-causing mutation was identified, our mouse expression studies suggest GPR35 to be involved in the development of the VATER/VACTERL phenotype. Follow-up of GPR35 and the other genes comprising the identified duplications is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ejhg.2013.58DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3831074PMC
December 2013

VATER/VACTERL association: identification of seven new twin pairs, a systematic review of the literature, and a classical twin analysis.

Clin Dysmorphol 2012 Oct;21(4):191-5

Institute of Human Genetics.

The VATER/VACTERL association is typically defined by the presence of at least three of the following congenital malformations: vertebral anomalies, anal atresia, cardiac malformations, tracheo-esophageal fistula, renal anomalies, and limb abnormalities. The identification of 14 twin pairs with an initial diagnosis of VATER/VACTERL association at our clinical centers led to the performance of a classical twin study. This involved a thorough evaluation of these 14 twin pairs and a further 55 twin pairs identified from a systematic review of the literature. The zygosity, concordance, and malformation status of all 69 twin pairs were evaluated. Twenty-four twin pairs fulfilled the criteria for inclusion in a comparison of the concordance rates between monozygous (MZ) and dizygous (DZ) twin pairs. The pairwise concordance rates were 15% [95% confidence interval (CI) 4-42%] for MZ and 18% (95% CI 5-48%) for DZ twin pairs (P=0.53). The probandwise concordance rates were 27% (95% CI 11-52%) for MZ and 31% (95% CI 13-58%) for DZ twin pairs (P=0.40). Although based on a limited number of twin pairs, the findings of the present study are consistent with the low number of familial cases reported to date, and suggest that the role of inherited genetic factors in the majority of VATER/VACTERL cases is limited.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MCD.0b013e328358243cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126840PMC
October 2012