Pathogenic role of <i><scp>ADGRG</scp>2</i> in <scp>CBAVD</scp> patients replicated in Chinese population

Yang, Bin; Wang, J.; Zhang, W.; Pan, Hui; Li, T.; Liu, B.; Li, H.; Wang, B.

doi:10.1111/andr.12407

Cited by 45 publications

(32 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Patat et al identified three hemizygous ADGRG2 variants causing truncated proteins in four patients by whole exome sequencing after excluding CFTR variants. We replicated these findings in a cohort of Chinese CBAVD patients and also detected another two ADGRG2 deleterious missense variants in two CFTR ‐negative patients (Yang et al, ), supporting the fact that ADGRG2 variations may explain a proportion of CBAVD cases.…”

Section: Introductionsupporting

confidence: 81%

Compound heterozygous mutations in CFTR causing CBAVD in Chinese pedigrees

Yang

Wang²,

Zhang³

et al. 2018

Molec Gen & Gen Med

Self Cite

View full text Add to dashboard Cite

BackgroundCongenital bilateral absence of the vas deferens (CBAVD) is an important cause of obstructive azoospermia and male infertility. Mutations of CFTR caused the majority of CBAVD cases, and ADGRG2 was recently identified as a new pathogenic gene. Yet, most of the genetic evidence came from sporadic cases, and only one mutation in CFTR can be found in patients.MethodsIn present study, we collected two CBAVD pedigrees, each having two affected male siblings. We performed whole exome sequencing on all patients and validated all potential variants by Sanger sequencing.ResultsWe excluded ADGRG2 variants but identified compound heterozygous variants of CFTR in both families (NM_000492.3:c.1210‐33_1210‐6GT[13]T[5] and c.4056G>C;p.Gln1352Cys in pedigree 1, c.592G>C;p.Ala198Pro and c.3717G>A;p.Arg1239= in pedigree 2), which were subsequently validated by direct sequencing. c.1210‐33_1210‐6GT[13]T[5] (also known as IVS8‐T5‐TG13) was a known disease‐causing variant causing the skipping of exon 9 of CFTR and inherited from the proband's mother. p.Gln1352Cys and Ala198Pro were rare or novel in public databases and predicted to be deleterious. The p.Arg1239= was a synonymous variant but located at the end of an exon, which was predicted to alter the splicing pattern.ConclusionOur study, in which compound heterozygous variants were identified in two pedigrees, provides more familial evidence that only recessive variants (homozygous or compound heterozygous) in CFTR cause CBAVD. Furthermore, whole exome sequencing may be utilized as a useful tool for mutation screening of genes causing CBAVD.

show abstract

Section: Introductionsupporting

confidence: 81%

Compound heterozygous mutations in CFTR causing CBAVD in Chinese pedigrees

Yang

Wang²,

Zhang³

et al. 2018

Molec Gen & Gen Med

Self Cite

View full text Add to dashboard Cite

show abstract

“…The establishment of the causal role of these mutations in the iCBAVD phenotype was based on a set of arguments: (i) male ADGRG2 knockout (KO) mice develop OA without any other significant abnormality (Davies et al 2004), (ii) histological examination of an epididymal biopsy of one of the four individuals showed a lack of expression of ADGRG2 in the epithelium of efferent ductules that were abnormally dilated, (iii) one of the truncated mutations was identified in two infertile individuals related by a maternal link (a nephew and a maternal uncle). Since then, three publications (Yang et al 2017;Yuan et al 2019; Khan et al 2018) have reported the identification of five new rare variations of ADGRG2 in six iCBAVD patients of Asian origin with no pathogenic CFTR mutation: two nonsense mutations classified as pathogenic, including one in two infertile brothers of Pakistani origin (Khan et al 2018) and three missense mutations, including one affecting the GPS region which was classified as pathogenic (Yang et al 2017). These six patients had no renal abnormalities.…”

Section: Adgrg 2 Mutationsmentioning

confidence: 99%

Genetics of the congenital absence of the vas deferens

2020

View full text Add to dashboard Cite

Congenital absence of the vas deferens (CAVD) may have various clinical presentations depending on whether it is bilateral (CBAVD) or unilateral (CUAVD), complete or partial, and associated or not with other abnormalities of the male urogenital tract. CBAVD is usually discovered in adult men either during the systematic assessment of cystic fibrosis or other CFTR-related conditions, or during the exploration of isolated infertility with obstructive azoospermia. The prevalence of CAVDs in men is reported to be approximately 0.1%. However, this figure is probably underestimated, because unilateral forms of CAVD in asymptomatic fertile men are not usually diagnosed. The diagnosis of CAVDs is based on clinical, ultrasound, and sperm examinations. The majority of subjects with CAVD carry at least one cystic fibrosis-causing mutation that warrants CFTR testing and in case of a positive result, genetic counseling prior to conception. Approximately 2% of the cases of CAVD are hemizygous for a loss-of-function mutation in the ADGRG2 gene that may cause a familial form of X-linked infertility. However, despite this recent finding, 10-20% of CBAVDs and 60-70% of CUAVDs remain without a genetic diagnosis. An important proportion of these unexplained CAVDs coexist with a solitary kidney suggesting an early organogenesis disorder (Wolffian duct), unlike CAVDs related to CFTR or ADGRG2 mutations, which might be the result of progressive degeneration that begins later in fetal life and probably continues after birth. How the dysfunction of CFTR, ADGRG2, or other genes such as SLC29A3 leads to this involution is the subject of various pathophysiological hypotheses that are discussed in this review.

show abstract

“…A recent study of OA patients with CBAVD and CFTR -negative results reported loss-of-function mutations in ADGRG2 in 3/26 patients (~12%). Another study in a Chinese population identified missense mutations in a small fraction of OA patients, suggesting varied incidence of ADGRG2 mutations in different ethnic groups 17 . While truncating mutations were reported in the gene previously 16 , 17 , here we reported the first Pakistani family with an ADGRG2 mutation.…”

Section: Discussionmentioning

confidence: 99%

“…Another study in a Chinese population identified missense mutations in a small fraction of OA patients, suggesting varied incidence of ADGRG2 mutations in different ethnic groups 17 . While truncating mutations were reported in the gene previously 16 , 17 , here we reported the first Pakistani family with an ADGRG2 mutation. This study offers strong evidence with mutation co-segregating with phenotype in 5 affected males and 5 additional family members.…”

Section: Discussionmentioning

confidence: 99%

“…Yet, a significant fraction of OA patients has not been identified as having CFTR mutations. Recently, a new X-linked gene responsible for OA, ADGRG2 , was discovered 16 , 17 . Targeted deletion of Adgrg2 in the mouse was reported to cause progressive obstructive infertility due to impairment in the efferent duct fluid reabsorption process 18 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

X-linked ADGRG2 mutation and obstructive azoospermia in a large Pakistani family

Khan

Pollock

Jiang

et al. 2018

Sci Rep

View full text Add to dashboard Cite

We performed whole exome sequencing to identify an unknown genetic cause of azoospermia and male infertility in a large Pakistani family. Three infertile males were subjected to semen analysis, hormone testing, testicular histology, ultrasonography, karyotyping, Y-chromosome microdeletion and CFTR testing. The clinical testing suggested a diagnosis of obstructive azoospermia (OA). To identify the cause, we performed whole exome sequencing (WES) for 2 infertile brothers and 2 fertile family members. For segregation analysis and variant confirmation, we performed Sanger sequencing. WES data analysis of the family revealed segregated variants in 3 candidate genes. We considered novel nonsense variant c.2440C > T(p.Arg814*) in X-linked gene ADGRG2 as biologically most plausible. It is predicted to truncate the protein by 204 amino acids (aa) at a key transmembrane domain. Adgrg2-knockout male mice show sperm loss due to obstructive fluid stasis, while ADGRG2 mutations cause OA in the infertile male patients. Our analysis of testicular histology reveals secondary severe reduction of spermatogenesis, consistent with human and knockout mouse phenotypes. The ADGRG2 nonsense mutation is absent in the largest population databases, ExAC and gnomAD. Analysis of the novel nonsense mutation in extended family members confirmed co-segregation of the mutation with OA in all affected males. The likely pathogenic nature of the mutation is supported by its truncation effect on the transmembrane domain and distinctive ultrasound results. The study demonstrates effectiveness of WES in discovering a genetic cause of azoospermia.

show abstract

Pathogenic role of ADGRG2 in CBAVD patients replicated in Chinese population

Cited by 45 publications

References 15 publications

Compound heterozygous mutations in CFTR causing CBAVD in Chinese pedigrees

Compound heterozygous mutations in CFTR causing CBAVD in Chinese pedigrees

Genetics of the congenital absence of the vas deferens

X-linked ADGRG2 mutation and obstructive azoospermia in a large Pakistani family

Contact Info

Product

Resources

About