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 reveals a de novo missense variant in EEF1A2 in a Rett syndrome‐like patient

2019 ◽  
Vol 7 (12) ◽  
pp. 2476-2482 ◽  
Author(s):  
Simranpreet Kaur ◽  
Nicole J. Van Bergen ◽  
Wendy Anne Gold ◽  
Stefanie Eggers ◽  
Sebastian Lunke ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Rett Syndrome ◽  
De Novo ◽  
Missense Variant ◽  
Whole Exome

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

scholarly journals Severe neurodevelopmental disease caused by a homozygous TLK2 variant

2019 ◽  
Vol 28 (3) ◽  
pp. 383-387 ◽  
Author(s):  
Ana Töpf ◽  
Yavuz Oktay ◽  
Sunitha Balaraju ◽  
Elmasnur Yilmaz ◽  
Ece Sonmezler ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Missense Variant ◽  
Cerebellar Vermis ◽  
Language Delay ◽  
Facial Dysmorphism ◽  
Neurodevelopmental Disease ◽  
Whole Exome ◽  
Neurodevelopmental Phenotype

Abstract A distinct neurodevelopmental phenotype characterised mainly by mild motor and language delay and facial dysmorphism, caused by heterozygous de novo or dominant variants in the TLK2 gene has recently been described. All cases reported carried either truncating variants located throughout the gene, or missense changes principally located at the C-terminal end of the protein mostly resulting in haploinsufficiency of TLK2. Through whole exome sequencing, we identified a homozygous missense variant in TLK2 in a patient showing more severe symptoms than those previously described, including cerebellar vermis hypoplasia and West syndrome. Both parents are heterozygous for the variant and clinically unaffected highlighting that recessive variants in TLK2 can also be disease causing and may act through a different pathomechanism.

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 Deleterious genetic variants in NOTCH1 are a major contributor to the incidence of non-syndromic Tetralogy of Fallot

2018 ◽  
Author(s):  
Donna J. Page ◽  
Matthieu J. Miossec ◽  
Simon G. Williams ◽  
Elisavet Fotiou ◽  
Richard M. Monaghan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Candidate Genes ◽  
Tetralogy Of Fallot ◽  
Whole Exome Sequencing ◽  
Genetic Variants ◽  
De Novo ◽  
Functional Domain ◽  
Functional Evaluation ◽  
Missense Variants ◽  
Whole Exome

AbstractAimsFamilial recurrence studies provide strong evidence for a genetic component to the predisposition to sporadic, non-syndromic Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease (CHD) phenotype. Rare genetic variants have been identified as important contributors to the risk of CHD, but relatively small numbers of TOF cases have been studied to date. Here, we use whole exome sequencing to assess the prevalence of rare, potentially deleterious variants in candidate genes previously associated with both syndromic and non-syndromic TOF, in the largest cohort of non-syndromic TOF patients reported to date.Methods & Results829 non-syndromic TOF patients underwent whole exome sequencing. A systematic review of the literature was conducted which revealed 77 genes in which mutations had been reported in patients with TOF. The presence of rare, deleterious variants in the 77 candidate genes was determined, defined by a minor allele frequency of ≤ 0.001 and scaled combined annotation-dependent depletion (CADD) score of ≥ 20. We found a clustering of heterozygous rare, deleterious variants in NOTCH1 (P=1.89E-15), DOCK6 (P=2.93E-07), MYOM2 (P= 7.35E-05), TTC37 (P=0.016), MESP1 (P=0.024) and TBX1 (P=0.039), after correcting for multiple testing. NOTCH1 was most frequently found to harbour deleterious variants. Changes were observed in 49 patients (6%; 95% confidence interval [CI]: 4.5% - 7.8%) and included six truncating/frameshift variants and forty missense variants. Sanger sequencing of the unaffected parents of thirteen cases identified five de novo variants. Variants were not confined to a single functional domain of the NOTCH1 protein but significant clustering of variants was evident in the EGF-like repeats (P=0.018). Three NOTCH1 missense variants (p.G200R, p.C607Y and de novo p.N1875S) were subjected to functional evaluation and showed a reduction in Jagged1 ligand-induced NOTCH signalling. p.C607Y, which exhibited the most significant reduction in signalling, also perturbed S1 cleavage of the NOTCH1 receptor in the Golgi.ConclusionThe NOTCH1 locus is a frequent site of genetic variants predisposing to non-syndromic TOF with 6% of patients exhibiting rare, deleterious variants. Our data supports the polygenic origin of TOF and suggests larger studies may identify additional loci.

scholarly journals Identification of De Novo JAK2 and MAPK7 Mutations Related to Autism Spectrum Disorder Using Whole-Exome Sequencing in a Chinese Child and Adolescent Trio-Based Sample

2019 ◽  
Vol 70 (2) ◽  
pp. 219-229 ◽  
Author(s):  
Jian Jiao ◽  
Manxue Zhang ◽  
Pingyuan Yang ◽  
Yan Huang ◽  
Xiao Hu ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Exome Sequencing ◽  
Candidate Genes ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Mapk Signaling ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Analysis Tool ◽  
Whole Exome

AbstractAutism spectrum disorder (ASD) is a neurodevelopmental disorder with high phenotypic and genetic heterogeneity. Whole-exome sequencing studies have shown that de novo single-nucleotide variations (SNVs) play an important role in sporadic ASD. The present study aimed to search for de novo SNVs using whole-exome sequencing in 59 unrelated Chinese ASD sporadic trios, and found 24 genes (including five reported ASD candidate genes CACNA1D, ACHE, YY1, TTN, and FBXO11) with de novo harmful SNVs. Five genes (CACNA1D, JAK2, ACHE, MAPK7, and PRKAG2) classified as “medium-confidence” genes were found to be related to ASD using the Phenolyzer gene analysis tool, which predicts the correlation between the candidate genes and the ASD phenotype. De novo SNVs in JAK2, MAPK7, and PRKAG2 were first found in ASD. Both JAK2 and MAPK7 were involved in the regulation of the MAPK signaling pathway. Gene co-expression and inter-gene interaction networks were constructed and gene expression data in different brain regions were further extracted, revealing that JAK2 and MAPK7 genes were associated with certain previously reported ASD genes and played an important role in early brain development. The findings of this study suggest that the aforementioned five reported ASD genes and JAK2 and MAPK7 may be related to ASD susceptibility. Further investigations of expression studies in cellular and animal models are needed to explore the mechanism underlying the involvement of JAK2 and MAPK7 in ASD.

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