Truncating Mutations in the Adhesion G Protein-Coupled Receptor G2 Gene ADGRG2 Cause an X-Linked Congenital Bilateral Absence of Vas Deferens

Patat, Olivier; Pagin, A.; Siegfried, Aurore; Mitchell, Valérie; Chassaing, Nicolas; Faguer, Stanislas; Monteil, L.; Gaston, Véronique; Bujan, Louis; Courtade-Saïdi, Monique; Marcelli, F.; Lochard, Guy; Rigot, Jean-Marc; Mieusset, R.; Bieth, Éric

doi:10.1016/j.ajhg.2016.06.012

Cited by 129 publications

(92 citation statements)

References 34 publications

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“…We performed exome sequencing on the three members of family 1 (father, mother, and affected boy) and on all four members of family 2 (father, mother, affected boy, and unaffected sister). The summary of exome sequencing data for the probands and their parents is reported in (Imsland et al, 2012), ADGRD2was an adhesion G-protein-coupled recently involved in absence of the vas deferens (Patat et al, 2016), BMP15 is involved in ovarian function (de Castro, Cruz, & Leal 2016), and HEPH is involved in iron metabolism (Jiang et al, 2015). As patient 2 had myoclonic seizures, we searched for any second variant in the 33 known genes involved in epileptic encephalopathy (Epi4K Consortium et al, 2013) but we did not identified de novo or inherited variant in this list of genes suggesting either the occurrence of another variant in an unknown epilepsy genes or the non-specific epileptic status of patient 2.…”

Section: Exome Analysis Revealed Two Different Splice Variants In Thementioning

confidence: 99%

CSNK2B splice site mutations in patients cause intellectual disability with or without myoclonic epilepsy

et al. 2017

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De novo mutations are a frequent cause of disorders related to brain development. We report the results from the screening of two patients diagnosed with intellectual disability (ID) using exome sequencing to identify new causative de novo mutations. Exome sequencing was conducted in two patient-parent trios to identify de novo variants. In silico and expression studies were also performed to evaluate the functional consequences of these variants. The two patients presented developmental delay with minor facial dysmorphy. One of them presented pharmacoresistant myoclonic epilepsy. We identified two de novo splice variants (c.175+2T>G; c.367+2T>C) in the CSNK2B gene encoding the β subunit of the Caseine kinase 2 (CK2). CK2 is a ubiquitously expressed kinase that is present in high levels in brain and it appears to be constitutively active. The mRNA transcripts were abnormal and significantly reduced in affected fibroblasts and most likely produced truncated proteins. Taking into account that mutations in CSNK2A1, encoding the α subunit of CK2, were previously identified in patients with neurodevelopmental disorders and dysmorphic features, our study confirmed that the protein kinase CK2 plays a major role in brain, and showed that CSNK2, encoding the β subunit, is a novel ID gene. This study adds knowledge to the increasingly growing list of causative and candidate genes in ID and epilepsy, and highlights CSNK2B as a new gene for neurodevelopmental disorders.

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Section: Exome Analysis Revealed Two Different Splice Variants In Thementioning

confidence: 99%

CSNK2B splice site mutations in patients cause intellectual disability with or without myoclonic epilepsy

et al. 2017

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“…Congenital bilateral absence of vas deferens (CBAVD, MIM: 277180) is an important cause of male infertility and obstructive azoospermia, accounting for 1–2% of the infertile population (Yu et al ., ). CBAVD involves a complete or partial defect of the Wolffian duct derivatives and may occur either as an isolated reproductive disorder or as an atypical symptom of (CF, MIM: 219700)(Patat et al ., ). Appropriately, isolated CBAVD is suggested to share a common genetic mechanism with CF, because nearly all men with CF also exhibit CBAVD and are infertile owing to obstructive azoospermia (Chillon et al ., ; Wilschanski et al ., ).…”

Section: Introductionmentioning

confidence: 97%

Pathogenic role of ADGRG2 in CBAVD patients replicated in Chinese population

et al. 2017

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Congenital bilateral absence of the vas deferens (CBAVD) is an important cause of obstructive azoospermia and male infertility worldwide. Cystic fibrosis transmembrane conductance regulator (CFTR) mutations are the main pathogenic cause, although a proportion of cases are still unexplained. Recently, adhesion G protein-coupled receptor G2 (ADGRG2) gene, a novel pathogenic gene for CBAVD was identified. We did a single population replication study in Chinese CBAVD patients to replicate its role in CBAVD developing. In this study, we performed whole-exome sequencing in 18 unrelated CBAVD patients and identified two missense variants in two patients (c.G1709A, p.C570Y; and c.A2968G, p.K990E). Both variants were predicted to be deleterious and highly conserved in silico. The p.C570Y variant is located in the G protein-coupled receptor (GPCR) proteolysis site domain, which is functionally necessary for autoproteolysis, while the p.K990E variant is in the N-terminal fragment that may regulate activity of the adhesion GPCR. We did not find any potential pathogenic CFTR variants, implying the ADGRG2 variants are the genetic cause in these patients. To the best of our knowledge, these are the first two ADGRG2 variants to be identified in Chinese CBAVD patients, which further validate the disease-causing role of ADGRG2 in this congenital defect.

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“…These obstructions can be caused by a congenital unilateral or bilateral absence of the vas deferens. The most common genetic cause of obstructive azoospermia (OA) are biallelic variants in the CFTR gene (Anguiano et al 1992; Culard et al 1994; Dumur et al 1990; Oates and Amos 1994; Patrizio et al 1993) and variants in the recently identified X-linked gene ADGRG2 (Patat et al 2016).…”

Section: Resultsmentioning

confidence: 99%

A systematic review and standardized clinical validity assessment of male infertility genes

Oud¹,

Voložonoka

Smits

et al. 2018

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Study question Which genes are confidently linked to human male infertility? Summary answer Our systematic literature search and clinical validity assessment reveals that a total of 67 genes are currently confidently linked to 81 human male infertility phenotypes. What is known already The discovery of novel male infertility genes is rapidly accelerating with the availability of Next-Generation Sequencing methods, but the quality of evidence for gene-disease relationships varies greatly. In order to improve genetic research, diagnostics and counseling, there is a need for an evidence-based overview of the currently known genes. Study design, size, duration We performed a systematic literature search and evidence assessment for all publications in Pubmed until June 2018 covering genetic causes of male infertility and/or defective male genitourinary development. Participants/materials, setting, methods Two independent reviewers conducted the literature search and included papers on the monogenic causes of human male infertility and excluded papers on genetic association or risk factors, karyotype anomalies and/or copy number variations affecting multiple genes. Next, the quality and the extent of all evidence supporting selected genes was weighed by a standardized scoring method and used to determine the clinical validity of each gene-disease relationship as expressed by the following six categories: no evidence, limited, moderate, strong, definitive or unable to classify. Main results and the role of chance From a total of 23,031 records, we included 1,286 publications about monogenic causes of male infertility leading to a list of 471 gene-disease relationships. The clinical validity of these gene-disease relationships varied widely and ranged from definitive (n=36) to strong (n=12), moderate (n=33), limited (n=86) or no evidence (n=154). A total of 150 gene-disease relationships could not be classified. Limitations, reasons for caution Our literature search was limited to Pubmed. Wider implications of the findings The comprehensive overview will aid researchers and clinicians in the field to establish gene lists for diagnostic screening using validated gene-disease criteria and identify gaps in our knowledge of male infertility. For future studies, the authors discuss the relevant and important international guidelines regarding research related to gene discovery and provide specific recommendations to the field of male infertility. Study funding/competing interest(s) This work was supported by a VICI grant from The Netherlands Organisation for Scientific Research (918-15-667 to JAV).

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Truncating Mutations in the Adhesion G Protein-Coupled Receptor G2 Gene ADGRG2 Cause an X-Linked Congenital Bilateral Absence of Vas Deferens

Cited by 129 publications

References 34 publications

CSNK2B splice site mutations in patients cause intellectual disability with or without myoclonic epilepsy

CSNK2B splice site mutations in patients cause intellectual disability with or without myoclonic epilepsy

Pathogenic role of ADGRG2 in CBAVD patients replicated in Chinese population

A systematic review and standardized clinical validity assessment of male infertility genes

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