GREB1L as a candidate gene of Mayer–Rokitansky–Küster–Hauser Syndrome

Kyei-Barffour, Isaac; Kwarkoh, Roselind Kyei Baah

doi:10.1016/j.ejmg.2021.104158

Cited by 12 publications

(11 citation statements)

References 60 publications

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“…Copy number variants (CNVs) in 1q21.1, 16p11.2, 17q12, and 22q11 with the corresponding genes LHX1 and HNF1B , WNT signaling pathway genes such as WNT4 , WNT9B , and the HOX family as well as some others have been pivotal candidates [ 8 ]. Recently, whole exome sequencing (WES) was used to identify GREB1L as a potential candidate for MRKH type 2 cases with kidney anomalies [ 9 ], but in general, the multifaceted and complex phenotype of the type 2 MRKH syndrome makes interpretation of genetic findings challenging. Until recently, previous work only focused on genome-wide CNV detection using array-CGH assays or WES and SNP arrays [ 10 , 11 ] limiting detection to exonic variants and therefore discarding potential mutations in regulatory factors.…”

Section: Introductionmentioning

confidence: 99%

Genome Sequencing and Transcriptome Profiling in Twins Discordant for Mayer-Rokitansky-Küster-Hauser Syndrome

Buchert

Schenk²,

Hentrich³

et al. 2022

JCM

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To identify potential genetic causes for Mayer-Rokitansky-Küster-Hauser syndrome (MRKH), we analyzed blood and rudimentary uterine tissue of 5 MRKH discordant monozygotic twin pairs. Assuming that a variant solely identified in the affected twin or affected tissue could cause the phenotype, we identified a mosaic variant in ACTR3B with high allele frequency in the affected tissue, low allele frequency in the blood of the affected twin, and almost absent in blood of the unaffected twin. Focusing on MRKH candidate genes, we detected a pathogenic variant in GREB1L in one twin pair and their unaffected mother showing a reduced phenotypic penetrance. Furthermore, two variants of unknown clinical significance in PAX8 and WNT9B were identified. In addition, we conducted transcriptome analysis of affected tissue and observed perturbations largely similar to those in sporadic cases. These shared transcriptional changes were enriched for terms associated with estrogen and its receptors pointing at a role of estrogen in MRKH pathology. Our genome sequencing approach of blood and uterine tissue of discordant twins is the most extensive study performed on twins discordant for MRKH so far. As no clear pathogenic differences were detected, research to evaluate other regulatory layers are required to better understand the complex etiology of MRKH.

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Section: Introductionmentioning

confidence: 99%

Genome Sequencing and Transcriptome Profiling in Twins Discordant for Mayer-Rokitansky-Küster-Hauser Syndrome

Buchert

Schenk²,

Hentrich³

et al. 2022

JCM

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“…Our analysis for rare conserved variants in candidate genes for MRKH identified a heterozygous loss of function variant c.4665T>A, p.Tyr1555* in GREB1L . GREB1L has been previously associated with a variety of genitourinary disorders (OMIM #617805) including MRKH [6, 31-33]. Many affected families present with a pedigree with autosomal dominant inheritance and reduced penetrance and variable expressivity.…”

Section: Discussionmentioning

confidence: 99%

“…Copy Number Variants (CNVs) in 1q21.1, 16p11.2, 17q12, and 22q11 with the corresponding genes LHX1 and HNF1B , WNT signaling pathway genes such as WNT4, WNT9B and the HOX family as well as some others have been pivotal candidates [5]. Recently, WES was used to identify GREB1L as a potential candidate for MRKH type 2 cases with kidney anomalies [6], but in general the multifaceted phenotype of the type 2 MRKH syndrome makes interpretation of genetic findings complex. Until recently, previous work only focused on genome wide CNV detection using array-CGH assays or WES and SNP arrays [7, 8] limiting detection to exonic variants and therefore discarding potential mutations in regulatory factors.…”

Section: Introductionmentioning

confidence: 99%

Genome sequencing and transcriptome profiling in twins discordant for Mayer-Rokitansky-Küster-Hauser syndrome

Buchert

Schenk

Hentrich

et al. 2022

Preprint

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ObjectiveMayer-Rokitansky-Küster-Hauser syndrome (MRKH) is a rare congenital disease manifesting with aplasia or severe hypoplasia of uterine structures. Even though extensive studies have been performed, for the majority of cases the etiology remains unclear. In this study, we sought to identify genetic causes in discordant monozygotic (MZ) twins using genome sequencing of blood of both twins as well as uterine tissue of the affected twin. In addition, we profiled the endometrial transcriptome of affected twins to compare perturbations with those of sporadic MRKH cases.ResultsFirst, analyzing the data under the assumption that a variant solely identified in the affected twin or affected tissue could cause the phenotype, we identified a mosaic variant in ACTR3B with a high allele frequency in affected tissue, a low allele frequency in blood of the affected twin and almost absent in the blood of the unaffected twin. Since ACTR3B has not been reported for genitourinary anomalies before, clinical relevance of the variant needs to be clarified.Second, examining the data for candidate genes previously implied in MRKH, we detected a pathogenic variant in GREB1L in one twin pair and their unaffected mother showing a reduced phenotypic penetrance. Furthermore, two variants of unknown clinical significance in PAX8 and WNT9B were identified. Analysis for copy number and structural variants revealed no discordant variants in the twins or variants in candidate genes or regions.Third, we conducted transcriptome analysis of affected tissue and observed widespread perturbations largely similar to those in sporadic MRKH cases. These shared transcriptional changes were enriched for terms associated with estrogen and its receptors pointing at a key role of estrogen in MRKH pathology.ConclusionOur study on genome sequencing of blood and uterine tissue of discordant twins is the most extensive study performed on twins discordant for MRKH so far. Nevertheless, no clear pathogenic differences in the twins or between blood and tissue samples were detected. This points towards a more complex etiology of MRKH less dependent on genetic differences and more determined by epigenetic changes or environmental factors. Our transcriptome data showed a clear overlap with gene expression data of sporadic MRKH cases, indicating that the etiology for MRKH in discordant twins and sporadic cases is largely similar.

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“…For instance, factors that predispose COVID-19 patients to different degrees of morbidity are fairly understood [7] and the molecular basis of the disease identified [25] , [26] . The role of genomics in disease diagnoses and treatment [27] has contributed to the discovery of various therapeutic vulnerabilities of COVID-19 [7] , [28] , [29] .…”

Section: Introductionmentioning

confidence: 99%

Sterilizing Immunity against COVID-19: Developing Helper T cells I and II activating vaccines is imperative

Kyei-Barffour¹,

Addo²,

Aninagyei³

et al. 2021

Biomedicine & Pharmacotherapy

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Six months after the publication of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) sequence, a record number of vaccine candidates were listed, and quite a number of them have since been approved for emergency use against the novel coronavirus disease 2019 (COVID-19). This unprecedented pharmaceutical feat did not only show commitment, creativity and collaboration of the scientific community, but also provided a swift solution that prevented global healthcare system breakdown. Notwithstanding, the available data show that most of the approved COVID-19 vaccines protect only a proportion of recipients against severe disease but do not prevent clinical manifestation of COVID-19. There is therefore the need to probe further to establish whether these vaccines can induce sterilizing immunity, otherwise, COVID-19 vaccination would have to become a regular phenomenon. The emergence of SARS-CoV-2 variants could further affect the capability of the available COVID-19 vaccines to prevent infection and protect recipients from a severe form of the disease. These notwithstanding, data about which vaccine(s), if any, can confer sterilizing immunity are unavailable. Here, we discuss the immune responses to viral infection with emphasis on COVID-19, and the specific adaptive immune response to SARS-CoV-2 and how it can be harnessed to develop COVID-19 vaccines capable of conferring sterilizing immunity. We further propose factors that could be considered in the development of COVID-19 vaccines capable of stimulating sterilizing immunity. Also, an old, but effective vaccine development technology that can be applied in the development of COVID-19 vaccines with sterilizing immunity potential is reviewed.

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GREB1L as a candidate gene of Mayer–Rokitansky–Küster–Hauser Syndrome

Cited by 12 publications

References 60 publications

Genome Sequencing and Transcriptome Profiling in Twins Discordant for Mayer-Rokitansky-Küster-Hauser Syndrome

Genome Sequencing and Transcriptome Profiling in Twins Discordant for Mayer-Rokitansky-Küster-Hauser Syndrome

Genome sequencing and transcriptome profiling in twins discordant for Mayer-Rokitansky-Küster-Hauser syndrome

Sterilizing Immunity against COVID-19: Developing Helper T cells I and II activating vaccines is imperative

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