A unique missense variant in the E1A-binding protein P400 gene is implicated in schizophrenia by whole-exome sequencing and mutant mouse models

AbstractGenetic and epidemiological evidence has suggested that genetic factors are important in schizophrenia, although its pathophysiology is poorly understood. This study used whole-exome sequencing to investigate potential novel schizophrenia-causing genes in a Japanese family containing several members affected by severe or treatment-resistant schizophrenia. A missense variant, chr12:132064747C>T (rs200626129, P2805L), in the E1A-binding protein P400 (EP400) gene completely segregated with schizophrenia in this family. Furthermore, numerous other EP400 mutations were identified in the targeted sequencing of a schizophrenia patient cohort. We also created two lines of Ep400 gene-edited mice, which had anxiety-like behaviours and reduced axon diameters. Our findings suggest that rs200626129 in EP400 is likely to cause schizophrenia in this Japanese family, and may lead to a better understanding and treatment of schizophrenia.

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

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab253 ◽

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.

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A homozygous mutation of GNRHR in a familial case diagnosed with polycystic ovary syndrome

Acta Endocrinologica ◽

10.1530/eje-16-0968 ◽

2017 ◽

Vol 176 (5) ◽

pp. K9-K14 ◽

Cited By ~ 5

Author(s):

Sandrine Caburet ◽

Ronit Beck Fruchter ◽

Bérangère Legois ◽

Marc Fellous ◽

Stavit Shalev ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Sanger Sequencing ◽

Polycystic Ovary ◽

Missense Variant ◽

Genetic Alterations ◽

Homozygous Mutation ◽

Gonadotropin Secretion ◽

Whole Exome ◽

A Genome

Context PCOS is a heterogeneous condition characterized by hyperandrogenism and chronic anovulation and affects about 10% of women. Its etiology is poorly known, but a dysregulation of gonadotropin secretion is one of its hallmarks. Objective As the etiology of PCOS is unclear, we have performed a genome-wide analysis of a consanguineous family with three sisters diagnosed with PCOS. Methods Whole-exome sequencing and Sanger sequencing confirmation. Results Whole-exome sequencing allowed the detection of the missense variant rs104893836 located in the first coding exon of the GNRHR gene and leading to the p.Gln106Arg (p.Q106R) substitution. Sanger sequencing of all available individuals of the family confirmed that the variant was homozygous in the three affected sisters and heterozygous in both parents. Conclusions This is the first description of a GNRHR gene mutation in patients diagnosed with PCOS. Although we do not exclude a possible interaction of the identified variant with the genetic background and/or the environment, our result suggests that genetic alterations in the hypothalamo–pituitary axis may play role in the pathogenesis of PCOS.

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Abstract MP08: Whole Exome Sequencing Study Identified A Novel Variant For Kidney Function And Progression Of Chronic Kidney Disease

Circulation ◽

10.1161/circ.143.suppl_1.mp08 ◽

2021 ◽

Vol 143 (Suppl_1) ◽

Author(s):

Changwei Li ◽

Michael Francis ◽

Adrianna Westbrook ◽

Ruiyuan Zhang ◽

Ye Shen ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Kidney Function ◽

Cystatin C ◽

Smoking Status ◽

Missense Variant ◽

Ckd Progression ◽

Whole Exome

Introduction: Most genetic variants for chronic kidney disease (CKD) have been identified in non-coding regions, with functional roles that are difficult to interpret. Hypothesis: A whole exome sequencing study focusing on coding variants will reveal novel mechanisms of kidney function and CKD. Methods: We performed whole exome sequencing analyses of cystatin C among 29,789 UK Biobank (UKB) participants with further confirmation among 4,297 white and 607 African American participants of the Health and Retirement Study (HRS). Conditional analyses for loci achieving exome-wide significance ( P <3.5х10 -7 ) were conducted in UKB using both the exome (n=29,789) and imputed GWAS data (n=295,122). Genomic findings were tested for relevance to baseline estimated glomerular filtration rate (eGFR) and stringently adjudicated CKD progression events among participants of the Chronic Renal Insufficiency Cohort (CRIC) by race and smoking status, using a base model and a full model ( Table ). Results: We identified a common missense variant, CST9 rs2983640, in a previously reported locus ( CST3 intron rs13038305), of which the minor G allele was associated with lower serum cystatin C level (UKB: beta=-0.03 mg/L, P =7.64х10 -92 ; HRS whites: beta=-0.05 mg/L, P =4.71х10 -6 ; HRS African Americans: beta=-0.03 mg/L, P =0.64; and multi-ethnic meta-analysis beta=-0.03 mg/L, P =2.46х10 -91 ). After controlling for the CST3 variant, the G allele was associated with higher cystatin C level (UKB exome: beta=0.003 mg/L, P =0.04; UKB GWAS: beta=0.003 mg/L, P =1.47х10 -10 ). Similar associations were identified in white CRIC participants (direct effect: beta=-0.05 mg/L, P =0.005; conditional effect: beta=0.004 mg/L, P =0.86). The CST9 rs2983640 G allele was associated with lower baseline eGFR (base model beta=-0.33 ml/min/1.73 m 2 , P =1.98х10 -6 ) and higher hazard of developing CKD progression independent of the reported CST3 variant ( Table ). Conclusions: We identified a novel missense variant influencing cystatin C level and CKD progression.

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Whole exome sequencing analysis identifies a missense variant in COL1A2 gene which causes osteogenesis imperfecta Type IV in a family from Saudi Arabia

Journal of Musculoskeletal Surgery and Research ◽

10.4103/jmsr.jmsr_26_17 ◽

2017 ◽

Vol 1 (2) ◽

pp. 33 ◽

Cited By ~ 1

Author(s):

Musharraf Jelani ◽

YaserM Alkhiary ◽

Anum Ramzan ◽

Muhammad Ilyas ◽

Ubaidullah Khan ◽

...

Keyword(s):

Saudi Arabia ◽

Osteogenesis Imperfecta ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Missense Variant ◽

Osteogenesis Imperfecta Type ◽

Sequencing Analysis ◽

Type Iv ◽

Whole Exome ◽

Col1a2 Gene

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A polygenic predictor of treatment-resistant depression using whole exome sequencing and genome-wide genotyping

Translational Psychiatry ◽

10.1038/s41398-020-0738-5 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 8

Author(s):

Chiara Fabbri ◽

Siegfried Kasper ◽

Alexander Kautzky ◽

Joseph Zohar ◽

Daniel Souery ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Genome Wide ◽

Whole Exome ◽

Resistant Depression

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

Clinical Case Reports ◽

10.1002/ccr3.2511 ◽

2019 ◽

Vol 7 (12) ◽

pp. 2476-2482 ◽

Cited By ~ 1

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

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Homozygous missense variant in the TTN gene causing autosomal recessive limb-girdle muscular dystrophy type 10

BMC Medical Genetics ◽

10.1186/s12881-019-0895-7 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 5

Author(s):

Amjad Khan ◽

Rongrong Wang ◽

Shirui Han ◽

Muhammad Umair ◽

Safdar Abbas ◽

...

Keyword(s):

Muscular Dystrophy ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Autosomal Recessive ◽

Missense Variant ◽

Pathogenic Variant ◽

Limb Girdle Muscular Dystrophy ◽

Molecular Diagnostic ◽

Sequencing Analysis ◽

Whole Exome

Abstract Background Limb-girdle muscular dystrophies (LGMDs) are large group of heterogeneous genetic diseases, having a hallmark feature of muscle weakness. Pathogenic mutations in the gene encoding the giant skeletal muscle protein titin (TTN) are associated with several muscle disorders, including cardiomyopathy, recessive congenital myopathies and limb-girdle muscular dystrophy (LGMD) type10. The phenotypic spectrum of titinopathies is expanding, as next generation sequencing (NGS) technology makes screening of this large gene possible. Aim This study aimed to identify the pathogenic variant in a consanguineous Pakistani family with autosomal recessive LGMD type 10. Methods DNA from peripheral blood samples were obtained, whole exome sequencing (WES) was performed and several molecular and bioinformatics analysis were conducted to identify the pathogenic variant. TTN coding and near coding regions were further amplified using PCR and sequenced via Sanger sequencing. Results Whole exome sequencing analysis revealed a novel homozygous missense variant (c.98807G > A; p.Arg32936His) in the TTN gene in the index patients. No heterozygous individuals in the family presented LGMD features. The variant p.Arg32936His leads to a substitution of the arginine amino acid at position 32,936 into histidine possibly causing LGMD type 10. Conclusion We identified a homozygous missense variant in TTN, which likely explains LGMD type 10 in this family in line with similar previously reported data. Our study concludes that WES is a successful molecular diagnostic tool to identify pathogenic variants in large genes such as TTN in highly inbred population.

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A Novel Missense Variant of TP63 Heterozygously Present in Split-Hand/Foot Malformation

BioMed Research International ◽

10.1155/2020/4215632 ◽

2020 ◽

Vol 2020 ◽

pp. 1-5

Author(s):

Hao Geng ◽

Dongdong Tang ◽

Chuan Xu ◽

Xiaojin He ◽

Zhiguo Zhang

Keyword(s):

Blood Sample ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Peripheral Blood ◽

Sanger Sequencing ◽

Missense Variant ◽

Chinese Family ◽

Peripheral Blood Sample ◽

Whole Exome ◽

Novel Variant

Background. Split-hand/foot malformation (SHFM) is a severe congenital disability mainly characterized by the absence or hypoplasia of the central ray of the hand/foot. To date, several candidate genes associated with SHFM have been identified, including TP63, DLX5, DLX6, FGFR1, and WNT10B. Herein, we report a novel variant of TP63 heterozygously present in affected members of a family with SHFM. Methods. This study investigated a Chinese family, in which the proband and his son suffered from SHFM. The peripheral blood sample of the proband was used to perform whole-exome sequencing (WES) to explore the possible genetic causes of this disease. Postsequencing bioinformatic analyses and Sanger sequencing were conducted to verify the identified variants and parental origins on all family members in the pedigree. Results. By postsequencing bioinformatic analyses and Sanger sequencing, we identified a novel missense variant (NM_003722.4:c.948G>A; p.Met316Ile) of TP63 in this family that results in a substitution of methionine with isoleucine, which is probably associated with the occurrence of SHFM. Conclusion. A novel missense variant (NM_003722.4:c.948G>A; p.Met316Ile) of TP63 in SHFM was thus identified, which may enlarge the spectrum of known TP63 variants and also provide new approaches for genetic counselling of families with SHFM.

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