Publications by authors named "Ernie M H F Bongers"

60 Publications

MCM complex members MCM3 and MCM7 are associated with a phenotypic spectrum from Meier-Gorlin syndrome to lipodystrophy and adrenal insufficiency.

Eur J Hum Genet 2021 Mar 2. Epub 2021 Mar 2.

Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.

The MCM2-7 helicase is a heterohexameric complex with essential roles as part of both the pre-replication and pre-initiation complexes in the early stages of DNA replication. Meier-Gorlin syndrome, a rare primordial dwarfism, is strongly associated with disruption to the pre-replication complex, including a single case described with variants in MCM5. Conversely, a biallelic pathogenic variant in MCM4 underlies immune deficiency with growth retardation, features also seen in individuals with pathogenic variants in other pre-initiation complex encoding genes such as GINS1, MCM10, and POLE. Through exome and chromium genome sequencing, supported by functional studies, we identify biallelic pathogenic variants in MCM7 and a strong candidate biallelic pathogenic variant in MCM3. We confirm variants in MCM7 are deleterious and through interfering with MCM complex formation, impact efficiency of S phase progression. The associated phenotypes are striking; one patient has typical Meier-Gorlin syndrome, whereas the second case has a multi-system disorder with neonatal progeroid appearance, lipodystrophy and adrenal insufficiency. We provide further insight into the developmental complexity of disrupted MCM function, highlighted by two patients with a similar variant profile in MCM7 but disparate clinical features. Our results build on other genetic findings linked to disruption of the pre-replication and pre-initiation complexes, and the replisome, and expand the complex clinical genetics landscape emerging due to disruption of DNA replication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41431-021-00839-4DOI Listing
March 2021

Polycystic liver disease genes: Practical considerations for genetic testing.

Eur J Med Genet 2021 Feb 6;64(3):104160. Epub 2021 Feb 6.

Department of Gastroenterology and Hepatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands. Electronic address:

The development of a polycystic liver is a characteristic of the monogenic disorders: autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), and autosomal dominant polycystic liver disease (ADPLD). Respectively two and one genes mainly cause ADPKD and ARPKD. In contrast, ADPLD is caused by at least six different genes which combined do not even explain the disease development in over half of the ADPLD population. Genetic testing is mainly performed to confirm the likelihood of developing PKD and if renal therapy is essential. However, pure ADPLD patients are frequently not genetically screened as knowledge about the genotype-phenotype correlation is currently limited. This paper will clarify the essence of genetic testing in ADPLD patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmg.2021.104160DOI Listing
February 2021

Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability.

Authors:
Benjamin Cogné Sophie Ehresmann Eliane Beauregard-Lacroix Justine Rousseau Thomas Besnard Thomas Garcia Slavé Petrovski Shiri Avni Kirsty McWalter Patrick R Blackburn Stephan J Sanders Kévin Uguen Jacqueline Harris Julie S Cohen Moira Blyth Anna Lehman Jonathan Berg Mindy H Li Usha Kini Shelagh Joss Charlotte von der Lippe Christopher T Gordon Jennifer B Humberson Laurie Robak Daryl A Scott Vernon R Sutton Cara M Skraban Jennifer J Johnston Annapurna Poduri Magnus Nordenskjöld Vandana Shashi Erica H Gerkes Ernie M H F Bongers Christian Gilissen Yuri A Zarate Malin Kvarnung Kevin P Lally Peggy A Kulch Brina Daniels Andres Hernandez-Garcia Nicholas Stong Julie McGaughran Kyle Retterer Kristian Tveten Jennifer Sullivan Madeleine R Geisheker Asbjorg Stray-Pedersen Jennifer M Tarpinian Eric W Klee Julie C Sapp Jacob Zyskind Øystein L Holla Emma Bedoukian Francesca Filippini Anne Guimier Arnaud Picard Øyvind L Busk Jaya Punetha Rolph Pfundt Anna Lindstrand Ann Nordgren Fayth Kalb Megha Desai Ashley Harmon Ebanks Shalini N Jhangiani Tammie Dewan Zeynep H Coban Akdemir Aida Telegrafi Elaine H Zackai Amber Begtrup Xiaofei Song Annick Toutain Ingrid M Wentzensen Sylvie Odent Dominique Bonneau Xénia Latypova Wallid Deb Sylvia Redon Frédéric Bilan Marine Legendre Caitlin Troyer Kerri Whitlock Oana Caluseriu Marine I Murphree Pavel N Pichurin Katherine Agre Ralitza Gavrilova Tuula Rinne Meredith Park Catherine Shain Erin L Heinzen Rui Xiao Jeanne Amiel Stanislas Lyonnet Bertrand Isidor Leslie G Biesecker Dan Lowenstein Jennifer E Posey Anne-Sophie Denommé-Pichon Claude Férec Xiang-Jiao Yang Jill A Rosenfeld Brigitte Gilbert-Dussardier Séverine Audebert-Bellanger Richard Redon Holly A F Stessman Christoffer Nellaker Yaping Yang James R Lupski David B Goldstein Evan E Eichler Francois Bolduc Stéphane Bézieau Sébastien Küry Philippe M Campeau

Am J Hum Genet 2019 03 28;104(3):530-541. Epub 2019 Feb 28.

Centre Hospitalier Universitaire Sainte-Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada; Department of Pediatrics, University of Montreal, Montreal, QC H3T1J4, Canada. Electronic address:

Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2019.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407527PMC
March 2019

De Novo Mutations Affecting the Catalytic Cα Subunit of PP2A, PPP2CA, Cause Syndromic Intellectual Disability Resembling Other PP2A-Related Neurodevelopmental Disorders.

Am J Hum Genet 2019 01 27;104(1):139-156. Epub 2018 Dec 27.

Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboudumc, PO Box 9101, 6500 HB Nijmegen, the Netherlands. Electronic address:

Type 2A protein phosphatases (PP2As) are highly expressed in the brain and regulate neuronal signaling by catalyzing phospho-Ser/Thr dephosphorylations in diverse substrates. PP2A holoenzymes comprise catalytic C-, scaffolding A-, and regulatory B-type subunits, which determine substrate specificity and physiological function. Interestingly, de novo mutations in genes encoding A- and B-type subunits have recently been implicated in intellectual disability (ID) and developmental delay (DD). We now report 16 individuals with mild to profound ID and DD and a de novo mutation in PPP2CA, encoding the catalytic Cα subunit. Other frequently observed features were severe language delay (71%), hypotonia (69%), epilepsy (63%), and brain abnormalities such as ventriculomegaly and a small corpus callosum (67%). Behavioral problems, including autism spectrum disorders, were reported in 47% of individuals, and three individuals had a congenital heart defect. PPP2CA de novo mutations included a partial gene deletion, a frameshift, three nonsense mutations, a single amino acid duplication, a recurrent mutation, and eight non-recurrent missense mutations. Functional studies showed complete PP2A dysfunction in four individuals with seemingly milder ID, hinting at haploinsufficiency. Ten other individuals showed mutation-specific biochemical distortions, including poor expression, altered binding to the A subunit and specific B-type subunits, and impaired phosphatase activity and C-terminal methylation. Four were suspected to have a dominant-negative mechanism, which correlated with severe ID. Two missense variants affecting the same residue largely behaved as wild-type in our functional assays. Overall, we found that pathogenic PPP2CA variants impair PP2A-B56(δ) functionality, suggesting that PP2A-related neurodevelopmental disorders constitute functionally converging ID syndromes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2018.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323609PMC
January 2019

Cellular ciliary phenotyping indicates pathogenicity of novel variants in and confirms a Mainzer-Saldino syndrome diagnosis.

Cilia 2018 23;7. Epub 2018 Feb 23.

1Department of Human Genetics (855), Radboud University Medical Centre, PO-Box 9101, 6500 HB Nijmegen, The Netherlands.

Background: Mainzer-Saldino syndrome (MZSDS) is a skeletal ciliopathy and part of the short-rib thoracic dysplasia (SRTD) group of ciliary disorders. The main characteristics of MZSDS are short limbs, mild narrow thorax, blindness, and renal failure. Thus far, variants in two genes are associated with MZSDS: and . In this study, we describe a 1-year-old girl presenting with mild skeletal abnormalities, Leber congenital amaurosis, and bilateral hearing difficulties. For establishing an accurate diagnosis, we combined clinical, molecular, and functional analyses.

Methods: We performed diagnostic whole-exome sequencing (WES) analysis to determine the genetic cause of the disease and analyzed two gene panels, containing all currently known genes in vision disorders, and in hearing impairment. Upon detection of the likely causative variants, ciliary phenotyping was performed in patient urine-derived renal epithelial cells (URECs) and rescue experiments were performed in CRISPR/Cas9-derived knock out cells to determine the pathogenicity of the detected variants in vitro. Cilium morphology, cilium length, and intraflagellar transport (IFT) were evaluated by immunocytochemistry.

Results: Diagnostic WES revealed two novel compound heterozygous variants in , encoding IFT140. Thorough investigation of WES data did not reveal any variants in candidate genes associated with hearing impairment. Patient-derived URECs revealed an accumulation of IFT-B protein IFT88 at the ciliary tip in 41% of the cells indicative of impaired retrograde IFT, while this was absent in cilia from control URECs. Furthermore, transfection of CRISPR/Cas9-derived knock out cells with an IFT140 construct containing the patient mutation p.Tyr923Asp resulted in a significantly higher percentage of IFT88 tip accumulation than transfection with the wild-type IFT140 construct.

Conclusions: By combining the clinical, genetic, and functional data from this study, we could conclude that the patient has SRTD9, also called Mainzer-Saldino syndrome, caused by variants in . We suggest the possibility that variants in may underlie hearing impairment. Moreover, we show that urine provides an excellent source to obtain patient-derived cells in a non-invasive manner to study the pathogenicity of variants detected by genetic testing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13630-018-0055-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247778PMC
February 2018

Nephrotic Syndrome With Mutations in NPHS2: The Role of R229Q and Implications for Genetic Counseling.

Am J Kidney Dis 2019 03 18;73(3):400-403. Epub 2018 Sep 18.

Department of Nephrology, Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, the Netherlands.

Mutations in the NPHS2 gene, which encodes the podocyte slit diaphragm protein podocin, cause autosomal recessive steroid-resistant nephrotic syndrome (Online Mendelian Inheritance in Man [OMIM] #600995). Basic research and clinical studies have provided important insights about genotype-phenotype correlations. This knowledge allows personalized genetic (risk) counseling and should lead to changes in the advice given to patients. A patient who carries the R229Q variant (which has a high allele frequency of 3.7% in the European population) in combination with a pathogenic variant in exon 7 or 8 is at high risk for developing nephrotic syndrome that may not manifest before adulthood, whereas a patient with 2 pathogenic variants will develop congenital or childhood-onset nephrotic syndrome. In contrast, a patient who carries the R229Q variant in combination with a pathogenic variant in exons 1 to 6 is unlikely to develop nephrotic syndrome. In this article, we review the emerging knowledge about the NPHS2 gene and translate these findings from the bench to practical advice for the clinical bedside.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.ajkd.2018.06.034DOI Listing
March 2019

Changes in the urinary extracellular vesicle proteome are associated with nephronophthisis-related ciliopathies.

J Proteomics 2019 02 30;192:27-36. Epub 2018 Jul 30.

Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address:

Nephronophthisis is one of the leading genetic causes of end-stage renal disease in childhood. Early diagnostics and prognostics for nephronophthisis are currently limited. We aimed to identify non-invasive protein biomarkers for nephronophthisis in urinary extracellular vesicles. Extracellular vesicles were isolated from urine of 12 patients with a nephronophthisis-related ciliopathy and 12 age- and gender-matched controls, followed by in-depth label-free LC-MS/MS proteomics analysis of gel fractionated extracellular vesicle proteins. Supervised cluster analysis of proteomic profiles separated patients from controls. We identified 156 differentially expressed proteins with fold change ≥4 in patients compared to controls (P < .05). Importantly, expression levels of discriminating proteins were correlated with chronic kidney disease stage, suggesting possible applications for urinary extracellular vesicle biomarkers in prognostics for nephronophthisis. Enrichment analysis of gene ontology terms revealed GO terms including signaling, actin cytoskeleton and endocytosis among the downregulated proteins in patients, whereas terms related to response to wounding and extracellular matrix organization were enriched among upregulated proteins. Our findings represent the first step towards a non-invasive diagnostic test for nephronophthisis. Further research is needed to determine specificity of the candidate biomarkers. In conclusion, proteomic profiles of urinary extracellular vesicles differentiate nephronophthisis-related ciliopathy patients from healthy controls. SIGNIFICANCE: Nephronophthisis is an important cause of end-stage renal disease in children and is associated with an average diagnostic delay of 3.5 years. This is the first study investigating candidate biomarkers for nephronophthisis using global proteomics analysis of urinary extracellular vesicles in patients with nephronophthisis compared to control individuals. We show that measuring protein markers in urinary extracellular vesicles is a promising approach for non-invasive early diagnostics of nephronophthisis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jprot.2018.07.008DOI Listing
February 2019

Clinical and genetic analyses of a Dutch cohort of 40 patients with a nephronophthisis-related ciliopathy.

Pediatr Nephrol 2018 10 5;33(10):1701-1712. Epub 2018 Jul 5.

Department of Pediatric Nephrology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: Nephronophthisis is an autosomal recessive ciliopathy and important cause of end-stage renal disease (ESRD) in children and young adults. Diagnostic delay is frequent. This study investigates clinical characteristics, initial symptoms, and genetic defects in a cohort with nephronophthisis-related ciliopathy, to improve early detection and genetic counseling.

Methods: Forty patients from 36 families with nephronophthisis-related ciliopathy were recruited at university medical centers and online. Comprehensive clinical and genotypic data were recorded. Patients without molecular diagnosis were offered genetic analysis.

Results: Of 40 patients, 45% had isolated nephronophthisis, 48% syndromic diagnosis, and 7% nephronophthisis with extrarenal features not constituting a recognizable syndrome. Patients developed ESRD at median 13 years (range 5-47). Median age of symptom onset was 9 years in both isolated and syndromic forms (range 5-26 vs. 5-33). Common presenting symptoms were fatigue (42%), polydipsia/polyuria (33%), and hypertension (21%). Renal ultrasound showed small-to-normal-sized kidneys, increased echogenicity (65%), cysts (43%), and abnormal corticomedullary differentiation (32%). Renal biopsies in eight patients showed nonspecific signs of chronic kidney disease (CKD). Twenty-three patients (58%) had genetic diagnosis upon inclusion. Thirteen of those without a genetic diagnosis gave consent for genetic testing, and a cause was identified in five (38%).

Conclusions: Nephronophthisis is genetically and phenotypically heterogeneous and should be considered in children and young adults presenting with persistent fatigue and polyuria, and in all patients with unexplained CKD. As symptom onset can occur into adulthood, presymptomatic monitoring of kidney function in syndromic ciliopathy patients should continue until at least age 30.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00467-018-3958-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132874PMC
October 2018

Sox11 gene disruption causes congenital anomalies of the kidney and urinary tract (CAKUT).

Kidney Int 2018 05 17;93(5):1142-1153. Epub 2018 Feb 17.

Université Nice Sophia Antipolis, Inserm, CNRS, iBV, Nice, France. Electronic address:

Congenital abnormalities of the kidney and the urinary tract (CAKUT) belong to the most common birth defects in human, but the molecular basis for the majority of CAKUT patients remains unknown. Here we show that the transcription factor SOX11 is a crucial regulator of kidney development. SOX11 is expressed in both mesenchymal and epithelial components of the early kidney anlagen. Deletion of Sox11 in mice causes an extension of the domain expressing Gdnf within rostral regions of the nephrogenic cord and results in duplex kidney formation. On the molecular level SOX11 directly binds and regulates a locus control region of the protocadherin B cluster. At later stages of kidney development, SOX11 becomes restricted to the intermediate segment of the developing nephron where it is required for the elongation of Henle's loop. Finally, mutation analysis in a cohort of patients suffering from CAKUT identified a series of rare SOX11 variants, one of which interferes with the transactivation capacity of the SOX11 protein. Taken together these data demonstrate a key role for SOX11 in normal kidney development and may suggest that variants in this gene predispose to CAKUT in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.kint.2017.11.026DOI Listing
May 2018

A Novel Hypokalemic-Alkalotic Salt-Losing Tubulopathy in Patients with Mutations.

J Am Soc Nephrol 2017 Oct 3;28(10):3118-3128. Epub 2017 Jul 3.

Nephrology, and

Mice lacking distal tubular expression of , the gene encoding the tight junction protein Claudin-10, show enhanced paracellular magnesium and calcium permeability and reduced sodium permeability in the thick ascending limb (TAL), leading to a urine concentrating defect. However, the function of renal Claudin-10 in humans remains undetermined. We identified and characterized mutations in two patients with a hypokalemic-alkalotic salt-losing nephropathy. The first patient was diagnosed with Bartter syndrome (BS) >30 years ago. At re-evaluation, we observed hypocalciuria and hypercalcemia, suggesting Gitelman syndrome (GS). However, serum magnesium was in the upper normal to hypermagnesemic range, thiazide responsiveness was not blunted, and genetic analyses did not show mutations in genes associated with GS or BS. Whole-exome sequencing revealed compound heterozygous sequence variants [c.446C>G (p.Pro149Arg) and c.465-1G>A (p.Glu157_Tyr192del)]. The patient had reduced urinary concentrating ability, with a preserved aquaporin-2 response to desmopressin and an intact response to furosemide. These findings were not in line with any other known salt-losing nephropathy. Subsequently, we identified a second unrelated patient showing a similar phenotype, in whom we detected compound heterozygous sequence variants [c.446C>G (p.(Pro149Arg) and c.217G>A (p.Asp73Asn)]. Cell surface biotinylation and immunofluorescence experiments in cells expressing the encoded mutants showed that only one mutation caused significant differences in Claudin-10 membrane localization and tight junction strand formation, indicating that these alterations do not fully explain the phenotype. These data suggest that pathogenic mutations affect TAL paracellular ion transport and cause a novel tight junction disease characterized by a non-BS, non-GS autosomal recessive hypokalemic-alkalotic salt-losing phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1681/ASN.2016080881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5619954PMC
October 2017

Whole-Exome Sequencing Identifies Biallelic IDH3A Variants as a Cause of Retinitis Pigmentosa Accompanied by Pseudocoloboma.

Ophthalmology 2017 07 13;124(7):992-1003. Epub 2017 Apr 13.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands. Electronic address:

Purpose: To identify the genetic cause of and describe the phenotype in 4 families with autosomal recessive retinitis pigmentosa (arRP) that can be associated with pseudocoloboma.

Design: Case series.

Participants: Seven patients from 4 unrelated families with arRP, among whom 3 patients had bilateral early-onset macular pseudocoloboma.

Methods: We performed homozygosity mapping and whole-exome sequencing in 5 probands and 2 unaffected family members from 4 unrelated families. Subsequently, Sanger sequencing and segregation analysis were performed in additional family members. We reviewed the medical history of individuals carrying IDH3A variants and performed additional ophthalmic examinations, including full-field electroretinography, fundus photography, fundus autofluorescence imaging, and optical coherence tomography.

Main Outcome Measures: IDH3A variants, age at diagnosis, visual acuity, fundus appearance, visual field, and full-field electroretinography, fundus autofluorescence, and optical coherence tomography findings.

Results: We identified 7 different variants in IDH3A in 4 unrelated families, that is, 5 missense, 1 nonsense, and 1 frameshift variant. All participants showed symptoms early in life, ranging from night blindness to decreased visual acuity, and were diagnosed between the ages of 1 and 11 years. Four participants with biallelic IDH3A variants displayed a typical arRP phenotype and 3 participants were diagnosed with arRP and pseudocoloboma of the macula.

Conclusions: IDH3A variants were identified as a novel cause of typical arRP in some individuals associated with macular pseudocoloboma. We observed both phenotypes in 2 siblings carrying the same compound heterozygous variants, which could be explained by variable disease expression and warrants caution when making assertions about genotype-phenotype correlations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ophtha.2017.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868413PMC
July 2017

The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.

Authors:
Claire Redin Harrison Brand Ryan L Collins Tammy Kammin Elyse Mitchell Jennelle C Hodge Carrie Hanscom Vamsee Pillalamarri Catarina M Seabra Mary-Alice Abbott Omar A Abdul-Rahman Erika Aberg Rhett Adley Sofia L Alcaraz-Estrada Fowzan S Alkuraya Yu An Mary-Anne Anderson Caroline Antolik Kwame Anyane-Yeboa Joan F Atkin Tina Bartell Jonathan A Bernstein Elizabeth Beyer Ian Blumenthal Ernie M H F Bongers Eva H Brilstra Chester W Brown Hennie T Brüggenwirth Bert Callewaert Colby Chiang Ken Corning Helen Cox Edwin Cuppen Benjamin B Currall Tom Cushing Dezso David Matthew A Deardorff Annelies Dheedene Marc D'Hooghe Bert B A de Vries Dawn L Earl Heather L Ferguson Heather Fisher David R FitzPatrick Pamela Gerrol Daniela Giachino Joseph T Glessner Troy Gliem Margo Grady Brett H Graham Cristin Griffis Karen W Gripp Andrea L Gropman Andrea Hanson-Kahn David J Harris Mark A Hayden Rosamund Hill Ron Hochstenbach Jodi D Hoffman Robert J Hopkin Monika W Hubshman A Micheil Innes Mira Irons Melita Irving Jessie C Jacobsen Sandra Janssens Tamison Jewett John P Johnson Marjolijn C Jongmans Stephen G Kahler David A Koolen Jerome Korzelius Peter M Kroisel Yves Lacassie William Lawless Emmanuelle Lemyre Kathleen Leppig Alex V Levin Haibo Li Hong Li Eric C Liao Cynthia Lim Edward J Lose Diane Lucente Michael J Macera Poornima Manavalan Giorgia Mandrile Carlo L Marcelis Lauren Margolin Tamara Mason Diane Masser-Frye Michael W McClellan Cinthya J Zepeda Mendoza Björn Menten Sjors Middelkamp Liya R Mikami Emily Moe Shehla Mohammed Tarja Mononen Megan E Mortenson Graciela Moya Aggie W Nieuwint Zehra Ordulu Sandhya Parkash Susan P Pauker Shahrin Pereira Danielle Perrin Katy Phelan Raul E Piña Aguilar Pino J Poddighe Giulia Pregno Salmo Raskin Linda Reis William Rhead Debra Rita Ivo Renkens Filip Roelens Jayla Ruliera Patrick Rump Samantha L P Schilit Ranad Shaheen Rebecca Sparkes Erica Spiegel Blair Stevens Matthew R Stone Julia Tagoe Joseph V Thakuria Bregje W van Bon Jiddeke van de Kamp Ineke van Der Burgt Ton van Essen Conny M van Ravenswaaij-Arts Markus J van Roosmalen Sarah Vergult Catharina M L Volker-Touw Dorothy P Warburton Matthew J Waterman Susan Wiley Anna Wilson Maria de la Concepcion A Yerena-de Vega Roberto T Zori Brynn Levy Han G Brunner Nicole de Leeuw Wigard P Kloosterman Erik C Thorland Cynthia C Morton James F Gusella Michael E Talkowski

Nat Genet 2017 01 14;49(1):36-45. Epub 2016 Nov 14.

Molecular Neurogenetics Unit, Center for Human Genetic Research, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.3720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5307971PMC
January 2017

Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability.

Nat Neurosci 2016 09 1;19(9):1194-6. Epub 2016 Aug 1.

Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.

To identify candidate genes for intellectual disability, we performed a meta-analysis on 2,637 de novo mutations, identified from the exomes of 2,104 patient-parent trios. Statistical analyses identified 10 new candidate ID genes: DLG4, PPM1D, RAC1, SMAD6, SON, SOX5, SYNCRIP, TCF20, TLK2 and TRIP12. In addition, we show that these genes are intolerant to nonsynonymous variation and that mutations in these genes are associated with specific clinical ID phenotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nn.4352DOI Listing
September 2016

AGORA, a data- and biobank for birth defects and childhood cancer.

Birth Defects Res A Clin Mol Teratol 2016 Aug 6;106(8):675-84. Epub 2016 May 6.

Department for Health Evidence, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, The Netherlands.

Background: Research regarding the etiology of birth defects and childhood cancer is essential to develop preventive measures, but often requires large study populations. Therefore, we established the AGORA data- and biobank in the Netherlands. In this study, we describe its rationale, design, and ongoing data collection.

Methods: Children diagnosed with and/or treated for a structural birth defect or childhood cancer and their parents are invited to participate in the AGORA data- and biobank. Controls are recruited through random sampling from municipal registries. The parents receive questionnaires about demographics, family and pregnancy history, health status, prescribed medication, lifestyle, and occupational exposures before and during the index pregnancy. In addition, blood or saliva is collected from children and parents, while medical records are reviewed for diagnostic information.

Results: So far, we have collected data from over 6,860 families (3,747 birth defects, 905 childhood cancers, and 2,208 controls). The types of birth defects vary widely and comprise malformations of the digestive, respiratory, and urogenital tracts as well as facial, cardiovascular, kidney, skeletal, and central nervous system anomalies. The most frequently occurring childhood cancer types are acute lymphatic leukemia, Hodgkin and non-Hodgkin lymphoma, Wilms' tumor, and brain and spinal cord tumors. Our genetic and/or epidemiologic studies have been focused on hypospadias, anorectal malformations, congenital anomalies of the kidney and urinary tract (CAKUT), and orofacial clefts.

Conclusion: The large AGORA data- and biobank offers great opportunities for investigating genetic and nongenetic risk factors for disorders in children and is open to collaborative initiatives. Birth Defects Research (Part A) 106:675-684, 2016. © 2016 Wiley Periodicals, Inc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/bdra.23512DOI Listing
August 2016

Maternal risk factors involved in specific congenital anomalies of the kidney and urinary tract: A case-control study.

Birth Defects Res A Clin Mol Teratol 2016 Jul 4;106(7):596-603. Epub 2016 Apr 4.

Department for Health Evidence, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, The Netherlands.

Background: Congenital anomalies of the kidney and urinary tract (CAKUT) comprise a heterogeneous group of birth defects with a variety of genetic and nongenetic factors suspected of involvement in the etiology. However, little is known about risk factors in specific CAKUT phenotypes. Therefore, we studied potential maternal risk factors in individual phenotypes within the CAKUT spectrum.

Methods: Questionnaire data were collected from parents of 562 children with CAKUT and 2139 healthy controls within the AGORA data- and biobank. Potential maternal risk factors investigated included folic acid use, overweight and obesity, smoking, alcohol consumption, subfertility, and diabetes mellitus. We performed logistic regression analyses to assess associations between these potential risk factors and CAKUT phenotypes.

Results: Increased risks of CAKUT were observed for folic acid use and maternal obesity, while fertility treatment by in vitro fertilization or intrauterine insemination and diabetes diagnosed during pregnancy also seem to be associated with CAKUT. Use of multivitamins reduced the risk (odds ratio [OR], 0.5; 95% confidence interval [CI], 0.2-1.0) as opposed to use of folic acid supplements only (OR, 1.3; 95% CI, 1.0-1.8). Folic acid use was associated with duplex collecting systems (OR, 1.8; 95% CI, 1.0-3.4) and vesicoureteral reflux (OR, 1.8; 95% CI, 1.1-2.9) in particular. A relatively strong association was observed between diabetes during pregnancy and posterior urethral valves (OR, 2.6; 95% CI, 1.1-5.9).

Conclusion: Use of folic acid only seems to be counterproductive for prevention of CAKUT, in contrast to multivitamin use. Furthermore, we observed differences in risk factor patterns among CAKUT phenotypes, which stress the importance of separate analyses for each phenotype. Birth Defects Research (Part A) 106:596-603, 2016. © 2016 Wiley Periodicals, Inc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/bdra.23500DOI Listing
July 2016

Thiazide Responsiveness Testing in Patients With Renal Magnesium Wasting and Correlation With Genetic Analysis: A Diagnostic Test Study.

Am J Kidney Dis 2016 07 29;68(1):168-70. Epub 2016 Jan 29.

Radboud University Medical Center, Nijmegen, the Netherlands.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.ajkd.2015.12.023DOI Listing
July 2016

Wnt5a Deficiency Leads to Anomalies in Ureteric Tree Development, Tubular Epithelial Cell Organization and Basement Membrane Integrity Pointing to a Role in Kidney Collecting Duct Patterning.

PLoS One 2016 21;11(1):e0147171. Epub 2016 Jan 21.

Laboratory of Developmental Biology, Oulu Centre for Cell-Matrix Research, Biocenter Oulu and Infotech Oulu, and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.

The Wnts can be considered as candidates for the Congenital Anomaly of Kidney and Urinary Tract, CAKUT diseases since they take part in the control of kidney organogenesis. Of them Wnt5a is expressed in ureteric bud (UB) and its deficiency leads to duplex collecting system (13/90) uni- or bilateral kidney agenesis (10/90), hypoplasia with altered pattern of ureteric tree organization (42/90) and lobularization defects with partly fused ureter trunks (25/90) unlike in controls. The UB had also notably less tips due to Wnt5a deficiency being at E15.5 306 and at E16.5 765 corresponding to 428 and 1022 in control (p<0.02; p<0.03) respectively. These changes due to Wnt5a knock out associated with anomalies in the ultrastructure of the UB daughter epithelial cells. The basement membrane (BM) was malformed so that the BM thickness increased from 46.3 nm to 71.2 nm (p<0.01) at E16.5 in the Wnt5a knock out when compared to control. Expression of a panel of BM components such as laminin and of type IV collagen was also reduced due to the Wnt5a knock out. The P4ha1 gene that encodes a catalytic subunit of collagen prolyl 4-hydroxylase I (C-P4H-I) in collagen synthesis expression and the overall C-P4H enzyme activity were elevated by around 26% due to impairment in Wnt5a function from control. The compound Wnt5a+/-;P4ha1+/- embryos demonstrated Wnt5a-/- related defects, for example local hyperplasia in the UB tree. A R260H WNT5A variant was identified from renal human disease cohort. Functional studies of the consequence of the corresponding mouse variant in comparison to normal ligand reduced Wnt5a-signalling in vitro. Together Wnt5a has a novel function in kidney organogenesis by contributing to patterning of UB derived collecting duct development contributing putatively to congenital disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0147171PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721645PMC
August 2016

De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila.

Eur J Hum Genet 2016 08 13;24(8):1145-53. Epub 2016 Jan 13.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

Recently WAC was reported as a candidate gene for intellectual disability (ID) based on the identification of a de novo mutation in an individual with severe ID. WAC regulates transcription-coupled histone H2B ubiquitination and has previously been implicated in the 10p12p11 contiguous gene deletion syndrome. In this study, we report on 10 individuals with de novo WAC mutations which we identified through routine (diagnostic) exome sequencing and targeted resequencing of WAC in 2326 individuals with unexplained ID. All but one mutation was expected to lead to a loss-of-function of WAC. Clinical evaluation of all individuals revealed phenotypic overlap for mild ID, hypotonia, behavioral problems and distinctive facial dysmorphisms, including a square-shaped face, deep set eyes, long palpebral fissures, and a broad mouth and chin. These clinical features were also previously reported in individuals with 10p12p11 microdeletion syndrome. To investigate the role of WAC in ID, we studied the importance of the Drosophila WAC orthologue (CG8949) in habituation, a non-associative learning paradigm. Neuronal knockdown of Drosophila CG8949 resulted in impaired learning, suggesting that WAC is required in neurons for normal cognitive performance. In conclusion, we defined a clinically recognizable ID syndrome, caused by de novo loss-of-function mutations in WAC. Independent functional evidence in Drosophila further supported the role of WAC in ID. On the basis of our data WAC can be added to the list of ID genes with a role in transcription regulation through histone modification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ejhg.2015.282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970694PMC
August 2016

TRIO loss of function is associated with mild intellectual disability and affects dendritic branching and synapse function.

Hum Mol Genet 2016 Mar 31;25(5):892-902. Epub 2015 Dec 31.

Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands,

Recently, we marked TRIO for the first time as a candidate gene for intellectual disability (ID). Across diverse vertebrate species, TRIO is a well-conserved Rho GTPase regulator that is highly expressed in the developing brain. However, little is known about the specific events regulated by TRIO during brain development and its clinical impact in humans when mutated. Routine clinical diagnostic testing identified an intragenic de novo deletion of TRIO in a boy with ID. Targeted sequencing of this gene in over 2300 individuals with ID, identified three additional truncating mutations. All index cases had mild to borderline ID combined with behavioral problems consisting of autistic, hyperactive and/or aggressive behavior. Studies in dissociated rat hippocampal neurons demonstrated the enhancement of dendritic formation by suppressing endogenous TRIO, and similarly decreasing endogenous TRIO in organotypic hippocampal brain slices significantly increased synaptic strength by increasing functional synapses. Together, our findings provide new mechanistic insight into how genetic deficits in TRIO can lead to early neuronal network formation by directly affecting both neurite outgrowth and synapse development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddv618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754042PMC
March 2016

De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome.

Am J Hum Genet 2015 Dec;97(6):904-13

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Exome Laboratory, Baylor Miraca Genetics Laboratories, Houston, TX 77030, USA. Electronic address:

Meier-Gorlin syndrome (MGS) is a genetically heterogeneous primordial dwarfism syndrome known to be caused by biallelic loss-of-function mutations in one of five genes encoding pre-replication complex proteins: ORC1, ORC4, ORC6, CDT1, and CDC6. Mutations in these genes cause disruption of the origin of DNA replication initiation. To date, only an autosomal-recessive inheritance pattern has been described in individuals with this disorder, with a molecular etiology established in about three-fourths of cases. Here, we report three subjects with MGS and de novo heterozygous mutations in the 5' end of GMNN, encoding the DNA replication inhibitor geminin. We identified two truncating mutations in exon 2 (the 1(st) coding exon), c.16A>T (p.Lys6(∗)) and c.35_38delTCAA (p.Ile12Lysfs(∗)4), and one missense mutation, c.50A>G (p.Lys17Arg), affecting the second-to-last nucleotide of exon 2 and possibly RNA splicing. Geminin is present during the S, G2, and M phases of the cell cycle and is degraded during the metaphase-anaphase transition by the anaphase-promoting complex (APC), which recognizes the destruction box sequence near the 5' end of the geminin protein. All three GMNN mutations identified alter sites 5' to residue Met28 of the protein, which is located within the destruction box. We present data supporting a gain-of-function mechanism, in which the GMNN mutations result in proteins lacking the destruction box and hence increased protein stability and prolonged inhibition of replication leading to autosomal-dominant MGS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2015.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678788PMC
December 2015

Prioritization and burden analysis of rare variants in 208 candidate genes suggest they do not play a major role in CAKUT.

Kidney Int 2016 Feb;89(2):476-86

The leading cause of end-stage renal disease in children is attributed to congenital anomalies of the kidney and urinary tract (CAKUT). Familial clustering and mouse models support the presence of monogenic causes. Genetic testing is insufficient as it mainly focuses on HNF1B and PAX2 mutations that are thought to explain CAKUT in 5–15% of patients. To identify novel, potentially pathogenic variants in additional genes, we designed a panel of genes identified from studies on familial forms of isolated or syndromic CAKUT and genes suggested by in vitro and in vivo CAKUT models. The coding exons of 208 genes were analyzed in 453 patients with CAKUT using next-generation sequencing. Rare truncating, splice-site variants, and non-synonymous variants, predicted to be deleterious and conserved, were prioritized as the most promising variants to have an effect on CAKUT. Previously reported disease-causing mutations were detected, but only five were fully penetrant causal mutations that improved diagnosis. We prioritized 148 candidate variants in 151 patients, found in 82 genes, for follow-up studies. Using a burden test, no significant excess of rare variants in any of the genes in our cohort compared with controls was found. Thus, in a study representing the largest set of genes analyzed in CAKUT patients to date, the contribution of previously implicated genes to CAKUT risk was significantly smaller than expected, and the disease may be more complex than previously assumed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ki.2015.319DOI Listing
February 2016

Meier-Gorlin syndrome.

Orphanet J Rare Dis 2015 Sep 17;10:114. Epub 2015 Sep 17.

Department of Human Genetics 836, Institute for Genetic and Metabolic Disease, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.

Meier-Gorlin syndrome (MGS) is a rare autosomal recessive primordial dwarfism disorder, characterized by microtia, patellar applasia/hypoplasia, and a proportionate short stature. Associated clinical features encompass feeding problems, congenital pulmonary emphysema, mammary hypoplasia in females and urogenital anomalies, such as cryptorchidism and hypoplastic labia minora and majora. Typical facial characteristics during childhood comprise a small mouth with full lips and micro-retrognathia. During ageing, a narrow, convex nose becomes more prominent. The diagnosis MGS should be considered in patients with at least two of the three features of the clinical triad of microtia, patellar anomalies, and pre- and postnatal growth retardation. In patients with short stature and/or microtia, the patellae should be assessed with care by ultrasonography before age 6 or radiography thereafter. Mutations in one of five genes (ORC1, ORC4, ORC6, CDT1, and CDC6) of the pre-replication complex, involved in DNA-replication, are detected in approximately 67-78% of patients with MGS. Patients with ORC1 and ORC4 mutations appear to have the most severe short stature and microcephaly. Management should be directed towards in-depth investigation, treatment and prevention of associated problems, such as growth retardation, feeding problems, hearing loss, luxating patellae, knee pain, gonarthrosis, and possible pulmonary complications due to congenital pulmonary emphysema with or without broncho- or laryngomalacia. Growth hormone treatment is ineffective in most patients with MGS, but may be effective in patients in whom growth continues to decrease after the first year of life (usually growth velocity normalizes after the first year) and with low levels of IGF1. At present, few data is available about reproduction of females with MGS, but the risk of premature labor might be increased. Here, we propose experience-based guidelines for the regular care and treatment of MGS patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-015-0322-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574002PMC
September 2015

Genetic, environmental, and epigenetic factors involved in CAKUT.

Nat Rev Nephrol 2015 Dec 18;11(12):720-31. Epub 2015 Aug 18.

Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, PO Box 85090, 3508 AB, Utrecht, Netherlands.

Congenital anomalies of the kidney and urinary tract (CAKUT) refer to a spectrum of structural renal malformations and are the leading cause of end-stage renal disease in children. The genetic diagnosis of CAKUT has proven to be challenging due to genetic and phenotypic heterogeneity and incomplete genetic penetrance. Monogenic causes of CAKUT have been identified using different approaches, including single gene screening, and gene panel and whole exome sequencing. The majority of the identified mutations, however, lack substantial evidence to support a pathogenic role in CAKUT. Copy number variants or single nucleotide variants that are associated with CAKUT have also been identified. Numerous studies support the influence of epigenetic and environmental factors on kidney development and the natural history of CAKUT, suggesting that the pathogenesis of this syndrome is multifactorial. In this Review we describe the current knowledge regarding the genetic susceptibility underlying CAKUT and the approaches used to investigate the genetic basis of CAKUT. We outline the associated environmental risk factors and epigenetic influences on CAKUT and discuss the challenges and strategies used to fully address the involvement and interplay of these factors in the pathogenesis of the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nrneph.2015.140DOI Listing
December 2015

A study of the clinical and radiological features in a cohort of 93 patients with a COL2A1 mutation causing spondyloepiphyseal dysplasia congenita or a related phenotype.

Am J Med Genet A 2015 Mar 21;167A(3):461-75. Epub 2015 Jan 21.

Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.

Type 2 collagen disorders encompass a diverse group of skeletal dysplasias that are commonly associated with orthopedic, ocular, and hearing problems. However, the frequency of many clinical features has never been determined. We retrospectively investigated the clinical, radiological, and genotypic data in a group of 93 patients with molecularly confirmed SEDC or a related disorder. The majority of the patients (80/93) had short stature, with radiological features of SEDC (n = 64), others having SEMD (n = 5), Kniest dysplasia (n = 7), spondyloperipheral dysplasia (n = 2), or Torrance-like dysplasia (n = 2). The remaining 13 patients had normal stature with mild SED, Stickler-like syndrome or multiple epiphyseal dysplasia. Over 50% of the patients had undergone orthopedic surgery, usually for scoliosis, femoral osteotomy or hip replacement. Odontoid hypoplasia was present in 56% (95% CI 38-74) and a correlation between odontoid hypoplasia and short stature was observed. Atlanto-axial instability, was observed in 5 of the 18 patients (28%, 95% CI 10-54) in whom flexion-extension films of the cervical spine were available; however, it was rarely accompanied by myelopathy. Myopia was found in 45% (95% CI 35-56), and retinal detachment had occurred in 12% (95% CI 6-21; median age 14 years; youngest age 3.5 years). Thirty-two patients complained of hearing loss (37%, 95% CI 27-48) of whom 17 required hearing aids. The ophthalmological features and possibly also hearing loss are often relatively frequent and severe in patients with splicing mutations. Based on clinical findings, age at onset and genotype-phenotype correlations in this cohort, we propose guidelines for the management and follow-up in this group of disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.36922DOI Listing
March 2015

Functional models for congenital anomalies of the kidney and urinary tract.

Nephron 2015 19;129(1):62-7. Epub 2014 Dec 19.

Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most common developmental diseases in humans; however, the cause for most patients remains unknown. Efforts to identify novel genetic causes for CAKUT through next-generation sequencing techniques have led to the discovery of new genes and risk factors. Concomitantly, these same efforts have generated large gene candidate lists requiring individual functional characterization. Appropriate model systems are needed to assess the functionality of genes and pathogenicity of genetic variants discovered in CAKUT patients. In this review, we discuss how cellular, animal, and personal (human) models are being used to study CAKUT candidate genes and what their major advantages and disadvantages are with respect to relevance and throughput.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000369313DOI Listing
September 2015

CHD7, the gene mutated in CHARGE syndrome, regulates genes involved in neural crest cell guidance.

Hum Genet 2014 Aug 13;133(8):997-1009. Epub 2014 Apr 13.

Institute of Human Genetics, University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37073, Göttingen, Germany.

Heterozygous loss of function mutations in CHD7 (chromodomain helicase DNA-binding protein 7) lead to CHARGE syndrome, a complex developmental disorder affecting craniofacial structures, cranial nerves and several organ systems. Recently, it was demonstrated that CHD7 is essential for the formation of multipotent migratory neural crest cells, which migrate from the neural tube to many regions of the embryo, where they differentiate into various tissues including craniofacial and heart structures. So far, only few CHD7 target genes involved in neural crest cell development have been identified and the role of CHD7 in neural crest cell guidance and the regulation of mesenchymal-epithelial transition are unknown. Therefore, we undertook a genome-wide microarray expression analysis on wild-type and CHD7 deficient (Chd7 (Whi/+) and Chd7 (Whi/Whi)) mouse embryos at day 9.5, a time point of neural crest cell migration. We identified 98 differentially expressed genes between wild-type and Chd7 (Whi/Whi) embryos. Interestingly, many misregulated genes are involved in neural crest cell and axon guidance such as semaphorins and ephrin receptors. By performing knockdown experiments for Chd7 in Xenopus laevis embryos, we found abnormalities in the expression pattern of Sema3a, a protein involved in the pathogenesis of Kallmann syndrome, in vivo. In addition, we detected non-synonymous SEMA3A variations in 3 out of 45 CHD7-negative CHARGE patients. In summary, we discovered for the first time that Chd7 regulates genes involved in neural crest cell guidance, demonstrating a new aspect in the pathogenesis of CHARGE syndrome. Furthermore, we showed for Sema3a a conserved regulatory mechanism across different species, highlighting its significance during development. Although we postulated that the non-synonymous SEMA3A variants which we found in CHD7-negative CHARGE patients alone are not sufficient to produce the phenotype, we suggest an important modifier role for SEMA3A in the pathogenesis of this multiple malformation syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00439-014-1444-2DOI Listing
August 2014

Early presentation of cystic kidneys in a family with a homozygous INVS mutation.

Am J Med Genet A 2014 Jul 26;164A(7):1627-34. Epub 2014 Mar 26.

Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands; Radboud Institute for Health Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.

Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease that is the most frequent monogenic cause of end-stage renal disease in children. Infantile NPHP, often in combination with other features like situs inversus, are commonly caused by mutations in the INVS gene. INVS encodes the ciliary protein inversin, and mutations induce dysfunction of the primary cilia. In this article, we present a family with two severely affected fetuses that were aborted after discovery of grossly enlarged cystic kidneys by ultrasonography before 22 weeks gestation. Exome sequencing showed that the fetuses were homozygous for a previously unreported nonsense mutation, resulting in a truncation in the IQ1 domain of inversin. This mutation induces nonsense-mediated RNA decay, as suggested by a reduced RNA level in fibroblasts derived from the fetus. However, a significant amount of mutant INVS RNA was present in these fibroblasts, yielding mutant inversin protein that was mislocalized. In control fibroblasts, inversin was present in the ciliary axoneme as well as at the basal body, whereas in the fibroblasts from the fetus, inversin could only be detected at the basal body. The phenotype of both fetuses is partly characteristic of infantile NPHP and Potter sequence. We also identified that the fetuses had mild skeletal abnormalities, including shortening and bowing of long bones, which may expand the phenotypic spectrum associated with INVS mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.36501DOI Listing
July 2014

A de novo non-sense mutation in ZBTB18 in a patient with features of the 1q43q44 microdeletion syndrome.

Eur J Hum Genet 2014 Jun 6;22(6):844-6. Epub 2013 Nov 6.

Department of Human Genetics, Institute for Genetic and Metabolic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands.

The phenotype of patients with a chromosome 1q43q44 microdeletion (OMIM; 612337) is characterized by intellectual disability with no or very limited speech, microcephaly, growth retardation, a recognizable facial phenotype, seizures, and agenesis of the corpus callosum. Comparison of patients with different microdeletions has previously identified ZBTB18 (ZNF238) as a candidate gene for the 1q43q44 microdeletion syndrome. Mutations in this gene have not yet been described. We performed exome sequencing in a patient with features of the 1q43q44 microdeletion syndrome that included short stature, microcephaly, global developmental delay, pronounced speech delay, and dysmorphic facial features. A single de novo non-sense mutation was detected, which was located in ZBTB18. This finding is consistent with an important role for haploinsufficiency of ZBTB18 in the phenotype of chromosome 1q43q44 microdeletions. The corpus callosum is abnormal in mice with a brain-specific knock-out of ZBTB18. Similarly, most (but not all) patients with the 1q43q44 microdeletion syndrome have agenesis or hypoplasia of the corpus callosum. In contrast, the patient with a ZBTB18 point mutation reported here had a structurally normal corpus callosum on brain MRI. Incomplete penetrance or haploinsufficiency of other genes from the critical region may explain the absence of corpus callosum agenesis in this patient with a ZBTB18 point mutation. The findings in this patient with a mutation in ZBTB18 will contribute to our understanding of the 1q43q44 microdeletion syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ejhg.2013.249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023223PMC
June 2014

Identification of pathogenic gene variants in small families with intellectually disabled siblings by exome sequencing.

J Med Genet 2013 Dec 11;50(12):802-11. Epub 2013 Oct 11.

Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

Background: Intellectual disability (ID) is a common neurodevelopmental disorder affecting 1-3% of the general population. Mutations in more than 10% of all human genes are considered to be involved in this disorder, although the majority of these genes are still unknown.

Objectives: We investigated 19 small non-consanguineous families with two to five affected siblings in order to identify pathogenic gene variants in known, novel and potential ID candidate genes. Non-consanguineous families have been largely ignored in gene identification studies as small family size precludes prior mapping of the genetic defect.

Methods And Results: Using exome sequencing, we identified pathogenic mutations in three genes, DDHD2, SLC6A8, and SLC9A6, of which the latter two have previously been implicated in X-linked ID phenotypes. In addition, we identified potentially pathogenic mutations in BCORL1 on the X-chromosome and in MCM3AP, PTPRT, SYNE1, and ZNF528 on autosomes.

Conclusions: We show that potentially pathogenic gene variants can be identified in small, non-consanguineous families with as few as two affected siblings, thus emphasising their value in the identification of syndromic and non-syndromic ID genes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmedgenet-2013-101644DOI Listing
December 2013