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

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.

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Exome sequencing in paediatric patients with movement disorders

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01688-6 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Anna Ka-Yee Kwong ◽

Mandy Ho-Yin Tsang ◽

Jasmine Lee-Fong Fung ◽

Christopher Chun-Yu Mak ◽

Kate Lok-San Chan ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Movement Disorders ◽

Rare Variants ◽

Diagnostic Yield ◽

Neurological Diseases ◽

Genetic Diagnosis ◽

Potential Treatment ◽

Paediatric Patients ◽

Whole Exome

Abstract Background Movement disorders are a group of heterogeneous neurological diseases including hyperkinetic disorders with unwanted excess movements and hypokinetic disorders with reduction in the degree of movements. The objective of our study is to investigate the genetic etiology of a cohort of paediatric patients with movement disorders by whole exome sequencing and to review the potential treatment implications after a genetic diagnosis. Results We studied a cohort of 31 patients who have paediatric-onset movement disorders with unrevealing etiologies. Whole exome sequencing was performed and rare variants were interrogated for pathogenicity. Genetic diagnoses have been confirmed in 10 patients with disease-causing variants in CTNNB1, SPAST, ATP1A3, PURA, SLC2A1, KMT2B, ACTB, GNAO1 and SPG11. 80% (8/10) of patients with genetic diagnosis have potential treatment implications and treatments have been offered to them. One patient with KMT2B dystonia showed clinical improvement with decrease in dystonia after receiving globus pallidus interna deep brain stimulation. Conclusions A diagnostic yield of 32% (10/31) was reported in our cohort and this allows a better prediction of prognosis and contributes to a more effective clinical management. The study highlights the potential of implementing precision medicine in the patients.

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Whole Exome Sequencing of HIV-1 long-term non-progressors identifies rare variants in genes encoding innate immune sensors and signaling molecules

Scientific Reports ◽

10.1038/s41598-018-33481-0 ◽

2018 ◽

Vol 8 (1) ◽

Cited By ~ 3

Author(s):

Sara Konstantin Nissen ◽

Mette Christiansen ◽

Marie Helleberg ◽

Kathrine Kjær ◽

Sofie Eg Jørgensen ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Rare Variants ◽

Signaling Molecules ◽

Innate Immune ◽

Whole Exome ◽

Genes Encoding ◽

Hiv 1

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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.

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P2-131: WHOLE-EXOME SEQUENCING OF HISPANIC EARLY-ONSET ALZHEIMER DISEASE FAMILIES IDENTIFIES RARE VARIANTS IN MULTIPLE ALZHEIMER'S-RELATED GENES

Alzheimer s & Dementia ◽

10.1016/j.jalz.2014.05.806 ◽

2014 ◽

Vol 10 ◽

pp. P518-P519

Author(s):

Margaret Pericak-Vance ◽

Christiane Reitz ◽

Brian W. Kunkle ◽

Badri N. Vardarajan ◽

Martin A. Kohli ◽

...

Keyword(s):

Alzheimer Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Early Onset ◽

Rare Variants ◽

Whole Exome

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Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer's disease

Annals of Clinical and Translational Neurology ◽

10.1002/acn3.582 ◽

2018 ◽

Vol 5 (7) ◽

pp. 832-842 ◽

Cited By ~ 33

Author(s):

Neha S. Raghavan ◽

Adam M. Brickman ◽

Howard Andrews ◽

Jennifer J. Manly ◽

Nicole Schupf ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Rare Variants ◽

Whole Exome

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Whole exome sequencing and trio analysis to broaden the variant spectrum of genes in idiopathic hypogonadotropic hypogonadism

Asian Journal of Andrology ◽

10.4103/aja.aja_65_20 ◽

2020 ◽

Vol 0 (0) ◽

pp. 0

Author(s):

Shu-Yan Tang ◽

Zheng Li ◽

Jian Zhang ◽

Xiao-Bin Zhu ◽

Peng Li ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Hypogonadotropic Hypogonadism ◽

Idiopathic Hypogonadotropic Hypogonadism ◽

Whole Exome

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A Novel DES L115F Mutation Identified by Whole Exome Sequencing is Associated with Inherited Cardiac Conduction Disease

International Journal of Molecular Sciences ◽

10.3390/ijms20246227 ◽

2019 ◽

Vol 20 (24) ◽

pp. 6227 ◽

Cited By ~ 1

Author(s):

Lung-An Hsu ◽

Yu-Shien Ko ◽

Yung-Hsin Yeh ◽

Chi-Jen Chang ◽

Yi-Hsin Chan ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Structural Model ◽

Coiled Coil ◽

Cytoskeletal Proteins ◽

Cardiac Conduction ◽

Chinese Family ◽

Cardiac Ion Channels ◽

Whole Exome ◽

Genes Encoding

Inherited cardiac conduction disease (CCD) is rare; it is caused by a large number of mutations in genes encoding cardiac ion channels and cytoskeletal proteins. Recently, whole-exome sequencing has been successfully used to identify causal mutations for rare monogenic Mendelian diseases. We used trio-based whole-exome sequencing to study a Chinese family with multiple family members affected by CCD, and identified a heterozygous missense mutation (c.343C>T, p.Leu115Phe) in the desmin (DES) gene as the most likely candidate causal mutation for the development of CCD in this family. The mutation is novel and is predicted to affect the conformation of the coiled-coil rod domain of DES according to structural model prediction. Its pathogenicity in desmin protein aggregation was further confirmed by expressing the mutation, both in a cellular model and a CRISPR/CAS9 knock-in mouse model. In conclusion, our results suggest that whole-exome sequencing is a feasible approach to identify candidate genes underlying inherited conduction diseases.

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