Whole-exome sequencing identifies mutations of TBC1D1 encoding a Rab-GTPase-activating protein in patients with congenital anomalies of the kidneys and urinary tract (CAKUT)

2015 ◽  
Vol 135 (1) ◽  
pp. 69-87 ◽  
Author(s):  
Anne Kosfeld ◽  
Martin Kreuzer ◽  
Christoph Daniel ◽  
Frank Brand ◽  
Anne-Kathrin Schäfer ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Congenital Anomalies ◽  
Rab Gtpase ◽  
Gtpase Activating Protein ◽  
Whole Exome

Whole exome sequencing identifies FOXL2, FOXA2 and FOXA3 as candidate genes for monogenic congenital anomalies of the kidneys and urinary tract

2021 ◽  
Author(s):  
Bixia Zheng ◽  
Steve Seltzsam ◽  
Chunyan Wang ◽  
Luca Schierbaum ◽  
Sophia Schneider ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Exome Sequencing ◽  
Candidate Genes ◽  
Whole Exome Sequencing ◽  
Congenital Anomalies ◽  
De Novo ◽  
Horseshoe Kidney ◽  
Missense Variant ◽  
Whole Exome ◽  
Fox Genes

Abstract Background Congenital anomalies of the kidneys and urinary tract (CAKUT) constitute the most common cause of chronic kidney disease in the first three decades of life. Variants in four Forkhead box (FOX) transcription factors have been associated with CAKUT. We hypothesized that other FOX genes, if highly expressed in developing kidney, may also represent monogenic causes of CAKUT. Methods We here performed whole exome sequencing (WES) in 541 families with CAKUT and generated 4 lists of CAKUT candidate genes: A) 36 FOX genes showing high expression during renal development, B) 4 FOX genes known to cause CAKUT to validate list A; C) 80 genes that we identified as unique potential novel CAKUT candidate genes when performing WES in 541 CAKUT families, and D) 175 genes identified from WES as multiple potential novel CAKUT candidate genes. Results To prioritize potential novel CAKUT candidates in FOX gene family, we overlapped 36 FOX genes (list A) with list C and D of WES-derived CAKUT candidates. Intersection with list C, identified a de novo FOXL2 in-frame deletion in a patient with eyelid abnormalities and ureteropelvic junction obstruction, and a homozygous FOXA2 missense variant in a patient with horseshoe kidney. Intersection with list D, identified a heterozygous FOXA3 missense variant in a CAKUT family with multiple affected individuals. Conclusion We hereby identified FOXL2, FOXA2 and FOXA3 as novel monogenic candidate genes of CAKUT, supporting the utility of a paralog-based approach to discover mutated genes associated with human disease.

scholarly journals Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract

2018 ◽  
Vol 29 (9) ◽  
pp. 2348-2361 ◽  
Author(s):  
Amelie T. van der Ven ◽  
Dervla M. Connaughton ◽  
Hadas Ityel ◽  
Nina Mann ◽  
Makiko Nakayama ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Congenital Anomalies ◽  
Causative Mutation ◽  
Deleterious Mutations ◽  
Whole Exome ◽  
Multiplex Families ◽  
High Fraction ◽  
Etiologic Diagnosis

BackgroundCongenital anomalies of the kidney and urinary tract (CAKUT) are the most prevalent cause of kidney disease in the first three decades of life. Previous gene panel studies showed monogenic causation in up to 12% of patients with CAKUT.MethodsWe applied whole-exome sequencing to analyze the genotypes of individuals from 232 families with CAKUT, evaluating for mutations in single genes known to cause human CAKUT and genes known to cause CAKUT in mice. In consanguineous or multiplex families, we additionally performed a search for novel monogenic causes of CAKUT.ResultsIn 29 families (13%), we detected a causative mutation in a known gene for isolated or syndromic CAKUT that sufficiently explained the patient’s CAKUT phenotype. In three families (1%), we detected a mutation in a gene reported to cause a phenocopy of CAKUT. In 15 of 155 families with isolated CAKUT, we detected deleterious mutations in syndromic CAKUT genes. Our additional search for novel monogenic causes of CAKUT in consanguineous and multiplex families revealed a potential single, novel monogenic CAKUT gene in 19 of 232 families (8%).ConclusionsWe identified monogenic mutations in a known human CAKUT gene or CAKUT phenocopy gene as the cause of disease in 14% of the CAKUT families in this study. Whole-exome sequencing provides an etiologic diagnosis in a high fraction of patients with CAKUT and will provide a new basis for the mechanistic understanding of CAKUT.

scholarly journals Whole-exome sequencing for prenatal diagnosis of fetuses with congenital anomalies of the kidney and urinary tract

2017 ◽  
Vol 32 (10) ◽  
pp. 1665-1675 ◽  
Author(s):  
Ting-ying Lei ◽  
Fang Fu ◽  
Ru Li ◽  
Dan Wang ◽  
Rong-yue Wang ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
Urinary Tract ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Congenital Anomalies ◽  
Whole Exome

scholarly journals Whole-exome sequencing in the molecular diagnosis of individuals with congenital anomalies of the kidney and urinary tract and identification of a new causative gene

2016 ◽  
Vol 19 (4) ◽  
pp. 412-420 ◽  
Author(s):  
Mir Reza Bekheirnia ◽  
Nasim Bekheirnia ◽  
Matthew N. Bainbridge ◽  
Shen Gu ◽  
Zeynep Hande Coban Akdemir ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Molecular Diagnosis ◽  
Congenital Anomalies ◽  
Causative Gene ◽  
Whole Exome

Whole‐exome sequencing in the evaluation of fetal congenital anomalies of the kidney and urinary tract detected by ultrasonography

2020 ◽  
Vol 40 (10) ◽  
pp. 1290-1299 ◽  
Author(s):  
Ting‐Ying Lei ◽  
Fang Fu ◽  
Ru Li ◽  
Qiu‐Xia Yu ◽  
Kun Du ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Congenital Anomalies ◽  
Whole Exome

scholarly journals Case Report: An Infant With Kabuki Syndrome, Alobar Holoprosencephaly and Truncus Arteriosus: A Case for Whole Exome Sequencing in Neonates With Congenital Anomalies

2021 ◽  
Vol 12 ◽  
Author(s):  
Rishika P. Sakaria ◽  
Parul G. Zaveri ◽  
Shannon Holtrop ◽  
Jie Zhang ◽  
Chester W. Brown ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Congenital Anomalies ◽  
Large Scale ◽  
Heart Diseases ◽  
Truncus Arteriosus ◽  
Kabuki Syndrome ◽  
Whole Exome ◽  
Anomalous Pulmonary Venous Return ◽  
Spectrum Of Patients

Kabuki syndrome is a rare multiple anomalies syndrome associated with mutations in KMT2D or KDM6A. It is characterized by infantile hypotonia, developmental delay and/or intellectual disability, long palpebral fissures with everted lateral third of the lower eyelids and typical facial features. Intracranial anomalies occur infrequently in patients with KS and holoprosencephaly has only been recently described. Additionally, though congenital heart diseases are common in patients with KS, to our knowledge truncus arteriosus has never been reported in a patient with KS. We present an unusual case of KS in an infant with holoprosencephaly and truncus arteriosus with partial anomalous pulmonary venous return. Duo whole exome sequencing in our patient identified a pathogenic nonsense variant in exon 10 of KMT2D (c.2782C > T; p. Gln928*) establishing the diagnosis. This report further expands the phenotypic spectrum of patients with Kabuki syndrome and emphasizes the utility of performing large scale sequencing in neonates with multiple congenital anomalies.

Diagnostic yield of chromosomal microarray and trio whole exome sequencing in cryptogenic cerebral palsy

2021 ◽  
pp. jmedgenet-2021-107884
Author(s):  
Michal Yechieli ◽  
Suleyman Gulsuner ◽  
Hilla Ben-Pazi ◽  
Aviva Fattal ◽  
Adi Aran ◽  
...  
Keyword(s):  
Cerebral Palsy ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Congenital Anomalies ◽  
Point Mutations ◽  
High Yield ◽  
Chromosomal Microarray ◽  
Dysmorphic Features ◽  
Whole Exome ◽  
Clinically Significant

ObjectiveTo determine the yield of genetic diagnoses using chromosomal microarray (CMA) and trio whole exome sequencing (WES), separately and combined, among patients with cryptogenic cerebral palsy (CP).MethodsTrio WES of patients with prior CMA analysis for cryptogenic CP, defined as disabling, non-progressive motor symptoms beginning before the age of 3 years without known cause.ResultsGiven both CMA analysis and trio WES, clinically significant genetic findings were identified for 58% of patients (26 of 45). Diagnoses were eight large CNVs detected by CMA and 18 point mutations detected by trio WES. None had more than one severe mutation. Approximately half of events (14 of 26) were de novo. Yield was significantly higher in patients with CP with comorbidities (69%, 22 of 32) than in those with pure motor CP (31%, 4 of 13; p=0.02). Among patients with genetic diagnoses, CNVs were more frequent than point mutations among patients with congenital anomalies (OR 7.8, 95% CI 1.2 to 52.4) or major dysmorphic features (OR 10.5, 95% CI 1.4 to 73.7). Clinically significant mutations were identified in 18 different genes: 14 with known involvement in CP-related disorders and 4 responsible for other neurodevelopmental conditions. Three possible new candidate genes for CP were ARGEF10, RTF1 and TAOK3.ConclusionsCryptogenic CP is genetically highly heterogeneous. Genomic analysis has a high yield and is warranted in all these patients. Trio WES has higher yield than CMA, except in patients with congenital anomalies or major dysmorphic features, but these methods are complementary. Patients with negative results with one approach should also be tested by the other.

scholarly journals Rapid whole exome sequencing in pregnancies to identify the underlying genetic cause in fetuses with congenital anomalies detected by ultrasound imaging

2020 ◽  
Vol 40 (8) ◽  
pp. 972-983 ◽  
Author(s):  
Chantal Deden ◽  
Kornelia Neveling ◽  
Dimitra Zafeiropopoulou ◽  
Christian Gilissen ◽  
Rolph Pfundt ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Ultrasound Imaging ◽  
Congenital Anomalies ◽  
Whole Exome
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