Exome sequencing identifies variants in FKBP4 that are associated with recurrent fetal loss in humans

Abstract Recurrent pregnancy loss (RPL) is defined as two or more consecutive miscarriages and affects an estimated 1.5% of couples trying to conceive. RPL has been attributed to genetic, endocrine, immune and thrombophilic disorders, but many cases remain unexplained. We investigated a Bangladeshi family where the proband experienced 29 consecutive pregnancy losses with no successful pregnancies from three different marriages. Whole exome sequencing identified rare genetic variants in several candidate genes. These were further investigated in Asian and white European RPL cohorts, and in Bangladeshi controls. FKBP4, encoding the immunophilin FK506-binding protein 4, was identified as a plausible candidate, with three further novel variants identified in Asian patients. None were found in European patients or controls. In silico structural studies predicted damaging effects of the variants in the structure-function properties of the FKBP52 protein. These were located within domains reported to be involved in Hsp90 binding and peptidyl-prolyl cis-trans isomerase (PPIase) activity. Profound effects on PPIase activity were demonstrated in transiently transfected HEK293 cells comparing wild-type and mutant FKBP4 constructs. Mice lacking FKBP4 have been previously reported as infertile through implantation failure. This study therefore strongly implicates FKBP4 as associated with fetal losses in humans, particularly in the Asian population.

Download Full-text

Whole-exome Sequencing Reveals Genetic Underpinnings of Tongue Carcinoma in Chinese Population

Asia-Pacific Journal of Oncology ◽

10.32948/ajo.2020.10.15 ◽

2020 ◽

pp. 1-9

Author(s):

Shuhang Wang ◽

Ning Jiang ◽

Zicheng Yu ◽

Yuan Fang ◽

Shujun Xing ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Asian Population ◽

Genetic Alterations ◽

Chinese Patients ◽

Driver Mutations ◽

Copy Number Loss ◽

Asian Patients ◽

Whole Exome ◽

Distinct Features

Oral tongue squamous cell carcinoma (OTSCC) is a common malignancy, of which the incidence has increased in China in the last decade. Surprisingly, while multiple studies have revealed the mutational features of OTSCC in Western populations, limited data was shown in Asian patients. Herein, we utilized whole-exome sequencing to profile the genetic alterations in 13 Chinese OTSCC and compared them to those from 40 Western patients published in Cancer Discovery. In result, some key driver mutations were observed in both Chinese and Western cohorts, such as TP53 (Chinese 60.0% vs Western 60.0%), FAT1 (Chinese 7.7% vs Western 30.0%), CASP8 (Chinese 7.7% vs Western 10.0%) and NOTCH1 (Chinese 15.4% vs Western 10.0%), while mutations in CDKN2A (23.1%) and NTRK3 (23.1%) were only observed in Chinese patients, indicating these two novel mutations might play vital roles in OTSCC tumorigenesis specifically in Asian population. Mutational signatures depicted both common and distinct features across cohorts. In addition, significant copy number loss was found in 7q22.1, 9q13.1, and focal regions spanning CDKN2A and CDKN2B. FOXP1-TEX261 (2p13.3:3p13) fusion, reported in various cancer types, was firstly observed in OTSCC. Also, we identified numerous actionable mutations with FDA approved targeted. Taken together, our study revealed the mutational features of Chinese OTSCC patients, either similar or distinct to those of Caucasian patients. CDKN2A and NTRK3 were observed as two novel drivers that might play essential roles in tumorigenesis in Chinese patients, and were found as two potential therapeutic targets, rendering it promising to develop novel therapies.

Download Full-text

Identification of rare genetic variants in Juvenile Idiopathic Arthritis using whole exome sequencing

Pediatric Rheumatology ◽

10.1186/1546-0096-13-s1-p144 ◽

2015 ◽

Vol 13 (S1) ◽

Author(s):

E Sanchez ◽

S Grandemange ◽

F Tran Mau-Them ◽

P Louis-Plence ◽

A Carbasse ◽

...

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genetic Variants ◽

Whole Exome ◽

Rare Genetic Variants

Download Full-text

Whole‐Exome Sequencing of a Saudi Epilepsy Cohort Reveals Association Signals in Known and Potentially Novel Loci

10.21203/rs.3.rs-915593/v1 ◽

2021 ◽

Author(s):

Amein Kadhem AlAli ◽

Abdulrahman Al-Enazi ◽

Ahmed Ammar ◽

Mahmoud Hajj ◽

Cyril Cyrus ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Rare Variants ◽

High Rate ◽

Variants Of Unknown Significance ◽

Pathogenic Variants ◽

Whole Exome ◽

Novel Variants ◽

Unknown Significance ◽

Rare Genetic Variants

Abstract Background Epilepsy, a serious chronic neurological condition effecting up to 100 million people globally, has clear genetic underpinnings including common and rare variants. In Saudi Arabia the prevalence of epilepsy is high and caused mainly by perinatal and genetic factors. No whole-exome sequencing (WES) studies have been performed to date in Saudi Arabian Epilepsy cohorts. This offers a unique opportunity for the discovery of rare genetic variants impacting this disease as there is a high rate of consanguinity amongst large tribal pedigrees. Results We performed WES on 144 individuals diagnosed with epilepsy, to interrogate known Epilepsy related genes for known and functional novel variants. We also used an American College of Medical Genetics (ACMG) guideline based variant prioritization approach in an attempt to discover putative causative variants. We identified a 32 potentially causative pathogenic variants across 30 different genes in 44/144 (30%) of these Saudi Epilepsy individuals. We also identified 232 variants of unknown significance (VUS) across 101 different genes in 133/144 (92%) subjects. Strong enrichment of variants of likely pathogenicity were observed in previously described epilepsy-associated loci, and a number of putative pathogenic variants in novel loci are also observed. Conclusion Several putative pathogenic variants known to be epilepsy-related loci were identified for the first time in our population, in addition to several potential new loci have been identified which may be prioritized for further investigation.

Download Full-text

Whole-exome sequencing for the discovery of rare genetic variants that protect from coronary artery disease

Coronary Artery Disease ◽

10.1097/mca.0000000000000367 ◽

2016 ◽

Vol 27 (4) ◽

pp. 253-254

Author(s):

Jane A. Leopold

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genetic Variants ◽

Whole Exome ◽

Rare Genetic Variants ◽

Artery Disease

Download Full-text

Identification of Novel Genes Associated to Major Mental Disease by Whole Exome Sequencing in Families with High Prevalence

European Psychiatry ◽

10.1016/j.eurpsy.2017.01.305 ◽

2017 ◽

Vol 41 (S1) ◽

pp. S98-S99

Author(s):

J. Pol Fuster ◽

L. Ruiz Guerra ◽

B. Ortega Vila ◽

A. Medina Dols ◽

B. Bisbal Carrió ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genetic Variants ◽

Mental Disease ◽

Psychotic Symptoms ◽

Disease Etiology ◽

New Genes ◽

Whole Exome ◽

High Prevalence ◽

Rare Genetic Variants

IntroductionThe identification of new genetic variants underlying psychosis is crucial to improve its molecular diagnosis and to determine the disease etiology, which is necessary to develop new therapeutic targets.AimTo identify novel rare genetic variants associated to mental disorders, using whole exome sequencing (WES).MethodsTwo families with high prevalence of mental disease were genotyped using WES. The first family has 5 members affected, the mother with a bipolar disorder, three sons, two with schizophrenia and one with schizoaffective disorder, and a cousin with major depression and psychotic symptoms. The second family is constituted by 38 members affected by major mental diseases in three generations. Key affected members of each family were genotyped by WES. Shared rare variants, with allelic frequencies below 0.5% in general population, were identified among the affected members of the family. The segregation of those variants was confirmed by Sanger sequencing.ResultsIn family 1, thirty-seven genetic variants related to neurodevelopment were identified. Two of those variants in the genes TRIP12 and RNF25 segregated with psychosis. In family 2, seven rare genetic variants contained in genes related to neurodevelopment were identified. A mutation in the gene ARHGAP19 segregated with psychosis.ConclusionsThree new genes have been found to be associated with psychosis. TRIP12 and RNF25 encode two E3-ubiquitin ligases which modulate the Wnt pathway, mutations in which lead to neurodevelopmental defects. ARHGAP19 encodes a GTPase which regulates the RhoA protein, involved in the regulation of the cytoskeleton.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Download Full-text

Whole exome sequencing identifies deleterious rare variants in CCDC141 in familial self-limited delayed puberty

npj Genomic Medicine ◽

10.1038/s41525-021-00274-w ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Tansit Saengkaew ◽

Gerard Ruiz-Babot ◽

Alessia David ◽

Alessandra Mancini ◽

Katia Mariniello ◽

...

Keyword(s):

Cell Migration ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Rare Variants ◽

Hypogonadotropic Hypogonadism ◽

Coiled Coil ◽

Hek293 Cells ◽

Delayed Puberty ◽

Acetylated Tubulin ◽

Whole Exome

AbstractDevelopmental abnormalities of the gonadotropin-releasing hormone (GnRH) neuronal network result in a range of conditions from idiopathic hypogonadotropic hypogonadism to self-limited delayed puberty. We aimed to discover important underlying regulators of self-limited delayed puberty through interrogation of GnRH pathways. Whole exome sequencing (WES) data consisting of 193 individuals, from 100 families with self-limited delayed puberty, was analysed using a virtual panel of genes related to GnRH development and function (n = 12). Five rare predicted deleterious variants in Coiled-Coil Domain Containing 141 (CCDC141) were identified in 21 individuals from 6 families (6% of the tested cohort). Homology modeling predicted all five variants to be deleterious. CCDC141 mutant proteins showed atypical subcellular localization associated with abnormal distribution of acetylated tubulin, and expression of mutants resulted in a significantly delayed cell migration, demonstrated in transfected HEK293 cells. These data identify mutations in CCDC141 as a frequent finding in patients with self-limited delayed puberty. The mis-localization of acetylated tubulin and reduced cell migration seen with mutant CCDC141 suggests a role of the CCDC141-microtubule axis in GnRH neuronal migration, with heterozygous defects potentially impacting the timing of puberty.

Download Full-text

Identification of Possible Risk Variants of Familial Strabismus Using Exome Sequencing Analysis

Genes ◽

10.3390/genes12010075 ◽

2021 ◽

Vol 12 (1) ◽

pp. 75

Author(s):

Joon-Yong An ◽

Jae Ho Jung ◽

Leejee Choi ◽

Eric D. Wieben ◽

Brian G. Mohney

Keyword(s):

Exome Sequencing ◽

Genetic Variants ◽

Primary Outcome ◽

Family Members ◽

Great Promise ◽

Genetic Profile ◽

Sequencing Analysis ◽

Risk Variants ◽

Whole Exome ◽

Rare Genetic Variants

Purpose: To investigate candidate genes associated with familial strabismus and propose a theory of their interaction in familial strabismus associated with early neurodevelopment. Methods: Eighteen families, including 53 patients diagnosed with strabismus and 34 unaffected family members, were analyzed. All patients with strabismus and available unaffected family members were evaluated using whole exome sequencing. The primary outcome was to identify rare occurring variants among affected individuals and investigate the evidence of their genetic heterogeneity. These results were compared with exome sequencing analysis to build a comprehensive genetic profile of the study families. Results: We observed 60 variants from 58 genes in 53 patients diagnosed with strabismus. We prioritized the most credible risk variants, which showed clear segregation in family members affected by strabismus. As a result, we found risk variants in four genes (FAT3, KCNH2, CELSR1, and TTYH1) in five families, suggesting their role in development of familial strabismus. In other families, there were several rare genetic variants in affected cases, but we did not find clear segregation pattern across family members. Conclusion: Genomic sequencing holds great promise in elucidating the genetic causes of strabismus; further research with larger cohorts or other related approaches are warranted.

Download Full-text