Heterogeneous spectrum of CFTR gene mutations in Chinese patients with CAVD and the dilemma of genetic blocking strategy

in Reproduction
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  • 1 Department of Infertility and Sexual Medicine, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China

Correspondence should be addressed to Y Zhang; Email: zhxml@sina.com
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In brief

The genetic heterogeneity of CFTR gene mutations in Chinese patients with congenital absence of the vas deferens (CAVD) differs from the hotspot mutation pattern in Caucasians. This paper reviews and suggests a more suitable screening strategy for the Chinese considering the dilemma of CFTR genetic blocking.

Abstract

Congenital absence of the vas deferens (CAVD) is a major cause of obstructive azoospermia and male infertility, with CFTR gene mutation as the main pathogenesis. Other genes such as ADGRG2, SLC9A3, and PANK2 have been discovered and proven to be associated with CAVD in recent studies. Multiple CFTR hotspot mutations have been found in Caucasians in several foreign countries, and relevant genetic counseling and preimplantation genetic diagnosis (PGD) have been conducted for decades. However, when we examined research on Chinese CAVD, we discovered that CFTR mutations show heterogeneity in the Chinese Han population, and there is currently no well-established screening strategy. Therefore, we have reviewed the literature, combining domestic and international research as well as our own, aiming to review research progress on the CFTR gene in China and discuss the appropriate scope for CFTR gene detection, the detection efficiency of other CAVD-related genes, and the screening strategy applicable to the Chinese Han population. This study provides more valuable information for genetic counseling and a theoretical basis for PGD and treatment for couples with CAVD when seeking reproductive assistance.

Abstract

In brief

The genetic heterogeneity of CFTR gene mutations in Chinese patients with congenital absence of the vas deferens (CAVD) differs from the hotspot mutation pattern in Caucasians. This paper reviews and suggests a more suitable screening strategy for the Chinese considering the dilemma of CFTR genetic blocking.

Abstract

Congenital absence of the vas deferens (CAVD) is a major cause of obstructive azoospermia and male infertility, with CFTR gene mutation as the main pathogenesis. Other genes such as ADGRG2, SLC9A3, and PANK2 have been discovered and proven to be associated with CAVD in recent studies. Multiple CFTR hotspot mutations have been found in Caucasians in several foreign countries, and relevant genetic counseling and preimplantation genetic diagnosis (PGD) have been conducted for decades. However, when we examined research on Chinese CAVD, we discovered that CFTR mutations show heterogeneity in the Chinese Han population, and there is currently no well-established screening strategy. Therefore, we have reviewed the literature, combining domestic and international research as well as our own, aiming to review research progress on the CFTR gene in China and discuss the appropriate scope for CFTR gene detection, the detection efficiency of other CAVD-related genes, and the screening strategy applicable to the Chinese Han population. This study provides more valuable information for genetic counseling and a theoretical basis for PGD and treatment for couples with CAVD when seeking reproductive assistance.

Introduction

Definition, history, and classification of CAVD

The absence of the vas deferens was first discovered during an autopsy by Hunter, a Scottish urologist and anatomist. Then in the middle of the 20th century, urologists discovered that congenital absence of the vas deferens (CAVD) was one of the causes of male infertility (Nelson 1950). Over the years, with a large number of clinical observations and summaries, CAVD has been classified into three clinical subtypes: congenital bilateral absence of the vas deferens (CBAVD), congenital unilateral absence of the vas deferens (CUAVD), and a special subtype called congenital bilateral partial aplasia of the vas deferens (Wagenknecht et al. 1983). This phenotypic diversity makes the elucidation of the pathogenesis difficult, and in particular morphological abnormalities of the epididymis, seminal vesicles, and kidneys may also be associated with CAVD (Tizzano et al. 1994). Due to different clinical examination methods, there are differences in the size of seminal vesicles (including hypogoblet, atrophy, and dilation) or the lack of seminal vesicles reported in previous studies (Goldstein & Schlossberg 1988, Schlegel et al. 1996, Casals et al. 2000). In general, bilateral seminal vesicle abnormalities occurred twice as frequently in CBAVD than in other subtypes (50% vs 25%), while unilateral seminal vesicle abnormalities occurred predominantly in CUAVD (80%) and are usually ipsilateral. However, these data on CUAVD, mainly involving azoospermic patients, may be biased. The seminal vesicles and vas deferens are histologically homologous, and tissue studies suggest that their absence shares the same pathogenic mechanism (Trezise et al. 1993). In contrast, the relationship between the development of the kidney and the vas deferens is not very close; however, kidney abnormality combined with CAVD is not uncommon. Studies have shown that the incidence of unilateral renal absence (URA) combined with CAVD is as high as approximately 25%, while that of URA at birth is much lower (0.04%) (Laurichesse Delmas et al. 2017, Mieusset et al. 2017, Mieusset et al. 2020). Notably, the prevalence of URA in patients with CUAVD (20–40%) is two to four times that in patients with CBAVD (5–10%).

Biological mechanisms and clinical diagnosis of CAVD

There are currently two explanations for the pathogenesis of CAVD, namely, abnormal expression or function of cystic fibrosis transmembrane conductance regulator (CFTR) protein caused by gene mutation and abnormal development of the mesonephric duct in the embryo. The CFTR gene is located on human chromosome 7q31.2, with a total length of 188,704 bp (Riordan et al. 1989). CFTR contains 27 regions encoding exons and encodes a peptide chain consisting of 1480 amino acids, which is mainly expressed in glandular epithelial cells of the respiratory tract, digestive tract, and reproductive tract. CFTR is composed of five domains, and a selective chloride channel is formed between two repetitive transmembrane domains (MSDs). A regulatory domain (RD) undergoes phosphorylation and dephosphorylation, and it promotes the binding and dissociation of two nucleotide-binding domains (NBDs) with ATP, causing conformational changes in the MSD and controlling the opening and closing of ion channels to maintain and regulate the transmembrane transport of ions across epithelial cells (Jentsch et al. 2002). CFTR controls channels that transport chloride and bicarbonate, which affects the concentration of liquid ions, pH levels, and liquid flow in glandular ducts (Choi et al. 2001). The epididymal duct and vas deferens are tortuous ducts with a small lumen, long duct, and long stroke, and the liquid in them is rich in various glycoproteins with viscosity (Zondek & Zondek 1980), which leads to a slow flow rate of liquid and easy stagnation and accumulation to cause obstruction. Tizzano et al. tested the reproductive tract tissues of neonates, infants and adults for CFTR expression. They found that from caput to cauda epididymis and then through the vas deferens to the seminal vesicles, CFTR expression gradually ceased. Interestingly, CFTR expression in the bilateral genital tracts was not consistent, suggesting that the morphological defects of the male reproductive ducts resulted from abnormal secretion processes rather than abnormal development (Tizzano et al. 1994). In summary, this mechanistic hypothesis is that abnormal expression or structure of CFTR leads to an insufficient transport function of its ion channels, resulting in an increased concentration and a decreased flow rate of liquid in the reproductive tract. Finally, the blockage of the lumen gradually develops into atrophy, degeneration, and disappearance of the vas deferens duct, which explains the existence of multiple subtypes of CAVD. Another potential or probable mechanism is that developmental defects of the mesonephric duct in the embryonic stage lead to undifferentiated or incomplete differentiation of the vas deferens. This hypothesis is supported by the fact that the development of the reproductive tract is homologous to that of the urinary tract and by the significantly lower detection rate of CFTR mutations in cases of CAVD with renal malformations. However, to date, no study has been conducted to clearly confirm and clarify the process and mechanism of vas deferens absence, and therefore, there is no treatment or prevention for this disease.

CAVD is diagnosed by impalpable scrotal vas deferens by physical examination and invisible pelvic or scrotal vas deferens by ultrasound, and the differential diagnosis mainly included nonobstructive azoospermia and oligozoospermia. Auxiliary diagnoses included normal testicular volume, decreased sperm volume, normal sex hormone levels, and testicular biopsy. There are three major circumstances in which CAVD is diagnosed: in men with cystic fibrosis (CF) or other genetically related conditions called CFTR-related disorders (CFTR-RDs), for which they have symptoms; in apparently healthy men who are referred for infertility due to azoospermia; or in asymptomatic fertile men with CAVD discovered by chance, such as during vasectomy or physical examination (Bieth et al. 2021). Upon diagnosis of CAVD, color Doppler ultrasound and MRI should be performed to assess whether there is any combination of epididymis or seminal vesicle defects, kidney and urinary system deformities, etc., and the volume and pH of semen and the level of seminal fructose may also contribute to the diagnosis.

Genetics of CFTR and genetic spectrum of CAVD patients in China

The impact of CFTR mutations on its function and associated clinical phenotypes

According to the pathogenic mechanism of CFTR dysfunction, gene mutations can be divided into six classes (Zielenski & Tsui 1995, Rowe et al. 2005, Wang et al. 2014). Class I, involving defective protein production, is mainly caused by nonsense mutations, frameshift mutations, and splicing mutations, which prevent the biosynthesis of CFTR protein. For example, the second most common CF mutation, G542X, creates a premature stop codon, which leads to early termination of transcription, causing a severe reduction in CFTR mRNA and eventually little or no functional CFTR protein reaching the plasma membrane (Hamosh et al. 1992). Class II, characterized by defective protein maturation and premature degradation, is caused by damage to the synthesis and folding process of CFTR protein. The prime example is F508del, the most common CF mutation in Caucasians (70% detection rate) (Rosenstein & Cutting 1998), which generates a misfolded polypeptide with no ability to resist digestive enzymes that are then degraded by the proteasome shortly after synthesis before it reaches its crucial site of action at the cell surface (Cheng et al. 1990, Farinha et al. 2013). Class III involves defective channel regulation. Although normal CFTR protein is produced and transferred to the cell membrane, it loses certain regulatory functions, and its ion transport function is compromised. The third most common CF mutation, G551D, possesses little or no chloride channel function in vivo because of the abnormal function of an NBD, resulting in disordered regulation (Bompadre et al. 2007). Fortunately, it is also the first clinically applicable CFTR mutation that can be targeted for treatment with an ion transport enhancer (ivacaftor) at the cellular molecular level (Van Goor et al. 2009, Ramsey et al. 2011). Class IV, involving defective channel conduction, is characterized by a reduction in the single-channel conductance of CFTR to different degrees, thereby reducing transport conduction efficiency. The common CF mutation R117H was estimated to reduce the single-channel conductance efficiency by approximately 15% (Sheppard et al. 1993). Class V involves reduced protein synthesis. Mutations of this class may include promoter mutations that reduce transcription (e.g. c-34C>T (Lukowski et al. 2011)), nucleotide alterations that promote alternative splicing of the CFTR transcript (e.g. 5T variant (Rave-Harel et al. 1997)), and amino acid substitutions that cause inefficient protein maturation (e.g. P574H and A455E (Kristidis et al. 1992)). All these mutations are considered to generate CFTR protein of normal function but with reduced expression compared to WT levels of tissue expression (Zielenski & Tsui 1995). Class VI, which involves reduced protein stability, was discovered and proposed by Haardt et al. in a study on the mechanism of the Q1412X termination mutation at the end of the coding chain (Haardt et al. 1999). Their study showed that Q1412X mutation reduces CFTR stability at the plasma membrane (half-life in COS cells: WT CFTR, 14 h; Q1412X, 3.5 h) but has no effect on the protein synthesis process.

Classes I–III are categorized as severe mutations and are associated with CF disease or severe pancreatic insufficiency of CFTR-RDs. Classes IV–VI are classified as mild mutations, for which the expressed CFTR protein can still bear part of the normal protein function, and they are associated with milder CFTR-RDs such as CAVD (LaRusch et al. 2014). CF is one of the most common autosomal recessive genetic diseases in Caucasians. The main manifestations of the disease are recurrent pulmonary infection, pancreatic insufficiency, and infertility caused by CAVD. The life span of these patients is usually much shorter than that of healthy patients, and approximately 95% of patients with CF have CBAVD. Although the prevalence of CF is lower in the non-Caucasian population, the prevalence of CBAVD does not seem to differ between regions and populations, showing a consistent level of approximately 1 in 1000 (Bombieri et al. 2011). In the Chinese population, CAVD dominates, and CF disease or severe CFTR-RDs are relatively rare. Several studies supported the conclusion that CBAVD is caused by compound heterozygosity for either one severe and one mild mutation or two mild mutations (Cuppens & Cassiman 2004, Claustres 2005). Chillon et al. studied CBAVD patients without clinical manifestations of CF and found that the combination of the 5T allele with a severe mutation in the other CFTR gene was the most common cause of CBAVD, which is consistent with the former conclusion since the 5T allele is the most common mild CFTR mutation. However, patients with CAVD alone were found to have race-specific CFTR mutations (Yang et al. 2015). According to statistics from our previous research, the most common mutation type in Chinese CBAVD patients is the combination of two mild mutations; that is, homozygous 5T alleles are dominant (Feng et al. 2019, Luo et al. 2021). To our knowledge, studies indicating which CFTR mutation types are associated with each subtype of CAVD have not been published. For CUAVDs, less than half of the patients carry at least one CFTR mutation according to comprehensive gene scanning, which means that more than half of the CUAVDs are not closely related (Cai et al. 2019, Mieusset et al. 2020), and some of them are combined with renal abnormalities, which are usually CFTR mutation-free (McCallum et al. 2001, Kolettis & Sandlow 2002, Yang et al. 2015).

CFTR genetic spectrum of Chinese CAVD patients

The genetic heterogeneity of Chinese patients differs from the hotspot mutation pattern in Caucasians

In China, screening studies for the CFTR gene are lacking. In our previous mutation analysis of the CFTR gene in CAVD patients, we estimated that between 63 and 72.5% of Chinese patients presented at least one mutated CFTR allele (Yang et al. 2015, Luo et al. 2021). The reason may be that infertility caused by CAVD is the main disease related to CFTR in China, and the need for further studies seems less urgent compared with that for the fatal CF disease in other countries. However, in recent years, with the increase in reproductive health examinations and the improvement of medical examination technology, the number of confirmed cases of CAVD has greatly increased, and screening research related to the CFTR gene has gradually increased. Although more than 2000 CFTR mutations have been reported worldwide (https://www.genet.sickkids.on.ca/), new mutations continue to be identified, yet few studies have been conducted to prove their pathogenicity (https://www.cftr2.org/). Through a literature review and database searches, we summarized the types of pathogenic mutations found in the CAVD population in China. Li et al. detected 30 different exonic mutations in 73 Chinese patients with CBAVD, including nine novel mutations (Li et al. 2012). Yang et al. detected eight different exonic mutations, including four novel mutations, in 19 Chinese patients with CAVD (Yang et al. 2015). Bai et al. detected seven mutations in the promoter regions in 66 Chinese patients with CBAVD (Bai et al. 2018). Yuan et al. detected 28 different exonic mutations in 72 Chinese patients with CAVD, including 5 novel mutations (Yuan et al. 2019). Wang et al. detected 15 different exonic mutations in 38 Chinese patients with CBAVD, including 4 novel mutations (Wang et al. 2020). In our previous study, we screened 276 Chinese patients with CAVD and detected 63 different mutations, among which 13 novel mutations were found. The most common pathogenic allele frequency was observed for 5T (c.1210–12T[5], 27.54%), p.Q1352H (c.4056G > C, 5.98%), and p.I556V (c.1666A > G, 3.08%) (Luo et al. 2021). In summary, the CFTR mutations in the Chinese CAVD population are very scattered and heterogeneous, similar to those in local studies in India (Sharma et al. 2009, Sharma et al. 2014), with no mutations occurring more than 10% of the time, except for 5T (38% on average in major Chinese studies, 31% in non-Caucasian studies (Lu et al. 2014, Bieth et al. 2021), which should be classified as a hotspot mutation. This pattern is significantly different from that in Caucasians, in that Caucasian patients with CAVD have multiple hotspot mutations. Specifically, the highest mutant gene frequency is observed for the well-known F508del, and statistics and calculations from large series show that the average mutant frequency of F508del in isolated CBAVD (iCBAVD) patients is approximately 28%, while that in CF patients is as high as 70%. A global oversight of the prevalence of CFTR gene mutations detected in CAVD patients and the characteristics of CFTR hotspot mutations in CAVD patients are summarized in Fig. 1 and Tables 1, 2. Therefore, for many years, multiple reproduction centers in Europe and America have been routinely screened for high-frequency mutation sites in Caucasians, such as F508del, for preimplantation genetic diagnosis (PGD) in CAVD patients (Field & Martin 2011, Girardet et al. 2015). In contrast, unfortunately, an efficient screening method and authoritative genetic counseling guidelines in China have not been developed.

Figure 1
Figure 1

Distribution of mutations in the CFTR gene detected in patients with CAVD on transcripts. This graph summarizes the CFTR gene mutations in the transcript (and 5T allele). The size of a pie on a lollipop indicates the gene frequency of the mutation, and the hotspot mutations has been labeled accordingly.

Citation: Reproduction 164, 3; 10.1530/REP-21-0315

Table 1

Description of CFTR mutations in CAVD patients (details of Fig. 1).

MutationAmino acid changeDeteced in
S50PSer→ProBoth races
E56KGlu→LysCaucasian
E56GGlu→GlyCaucasian
D58NAsp→AsnCaucasian
R75QArg→GlnCaucasian
F78Sfs*13Phe→Ser fs*13Chinese
F87IPhe→IleCaucasian
L88XLeu→TerminationChinese
Q98PGln→ProCaucasian
L101SLeu→SerCaucasian
D110YAsp→TyrCaucasian
P111LPro→LeuCaucasian
N113IAsn→IleCaucasian
R117GArg→GlyCaucasian
R117HArg→HisCaucasian
S118PSer→ProCaucasian
Y122HTyr→HisCaucasian
I125TIle→ThrBoth races
G126SGly→SerCaucasian
G126CGly→CysCaucasian
R134GArg→GlyChinese
P140SPro→SerBoth races
H146RHis→ArgCaucasian
Q151KGln→LysCaucasian
F157CPhe→CysCaucasian
S158RSer→ArgCaucasian
Y161CTyr→CysBoth races
R170HArg→HisCaucasian
N186KAsn→LysBoth races
A198PAla→ProBoth races
F200IPhe→IleCaucasian
V201MVal→MetBoth races
I203MIle→MetCaucasian
L206WLeu→TrpCaucasian
E217GGlu→GlyBoth races
A238VAla→ValCaucasian
M244KMet→LysCaucasian
R248TArg→ThrCaucasian
I255NIle→AsnBoth races
M265RMet→ArgCaucasian
M281RMet→ArgCaucasian
N287KAsn→LysChinese
R289XArg→TerminationBoth races
R297WArg→TrpCaucasian
A309GAla→GlyBoth races
L320VLeu→ValCaucasian
R334WArg→TrpBoth races
R334LArg→LeuCaucasian
T338AThr→AlaCaucasian
R347HArg→HisBoth races
A357TAla→ThrChinese
Q372RGln→ArgChinese
E379KGlu→LysCaucasian
L383SLeu→SerCaucasian
V392AVal→AlaCaucasian
A399DAla→AspCaucasian
5T allele-Both races
E407KGlu→LysChinese
K411ELys→GluBoth races
R419IArg→IleChinese
D443YAsp→TyrCaucasian
K464QLys→GlnChinese
T465NThr→AsnBoth races
S466LSer→LeuCaucasian
M469IMet→IleChinese
M469VMet→ValChinese
L475Wfs*52Leu→Trp fs*52Chinese
H484YHis→TyrCaucasian
C491SCys→SerCaucasian
C491FCys→PheChinese
I497VIle→ValBoth races
P499APro→AlaCaucasian
T501NThr→AsnChinese
I507NIle→AsnChinese
I507VIle→ValCaucasian
F508delPhe→DeleteCaucasian
D513GAsp→GlyCaucasian
V520IVal→IleBoth races
E527KGlu→LysChinese
K536XLys→TerminationCaucasian
L541PLeu→ProCaucasian
G542XGly→TerminationCaucasian
E543AGlu→AlaCaucasian
G544VGly→ValCaucasian
G551AGly→AlaCaucasian
G551DGly→AspCaucasian
R553XArg→TerminationBoth races
I556VIle→ValBoth races
S557TSer→ThrChinese
D565GAsp→GlyCaucasian
L568FLeu→PheCaucasian
P574SPro→SerCaucasian
G576AGly→AlaCaucasian
Y577XTyr→TerminationBoth races
T582SThr→SerCaucasian
F587IPhe→IleCaucasian
C592FCys→PheChinese
T604IThr→IleCaucasian
H609RHis→ArgBoth races
G622DGly→AspBoth races
S660XSer→TerminationChinese
W679XTrp→TerminationBoth races
E681VGlu→ValBoth races
E695Gfs*35Glu→Gly fs*35Both races
S753RSer→ArgCaucasian
R766MArg→MetCaucasian
R785QArg→GlnBoth races
R792GArg→GlyCaucasian
E804VGlu→ValCaucasian
I807MIle→MetCaucasian
R810GArg→GlyCaucasian
G817VGly→ValCaucasian
P841RPro→ArgCaucasian
N847SAsn→SerBoth races
R851QArg→GlnBoth races
Y852FTyr→PheCaucasian
I853FIle→PheCaucasian
Q890RGln→ArgCaucasian
D891GAsp→GlyBoth races
N894SAsn→SerCaucasian
S895NSer→AsnBoth races
V920LVal→LeuCaucasian
R933TArg→ThrCaucasian
R933SArg→SerCaucasian
R933GArg→GlyCaucasian
V938LVal→LeuChinese
V938GVal→GlyCaucasian
M952TMet→ThrCaucasian
A959VAla→ValCaucasian
G970DGly→AspBoth races
S977PSer→ProBoth races
D979AAsp→AlaBoth races
L997FLeu→PheBoth races
Y1014CTyr→CysCaucasian
P1021LPro→LeuBoth races
P1021SPro→SerCaucasian
Y1032CTyr→CysCaucasian
L1055ILeu→IleChinese
A1067PAla→ProCaucasian
G1069RGly→ArgBoth races
Q1071XGln→TerminationCaucasian
A1081PAla→ProCaucasian
R1097CArg→CysBoth races
Q1100KGln→LysCaucasian
V1108LVal→LeuCaucasian
G1130AGly→AlaCaucasian
A1136VAla→ValChinese
W1145RTrp→ArgCaucasian
D1152HAsp→HisCaucasian
V1153EVal→GluCaucasian
D1154GAsp→GlyCaucasian
G1208DGly→AspBoth races
T1220IThr→IleBoth races
G1237DGly→AspBoth races
D1270EAsp→GluCaucasian
I1277VIle→ValChinese
W1282XTrp→TerminationCaucasian
A1285VAla→ValCaucasian
P1290SPro→SerCaucasian
N1303KAsn→LysCaucasian
N1303HAsn→HisBoth races
Y1307CTyr→CysCaucasian
Q1309HGln→HisCaucasian
F1337VPhe→ValCaucasian
L1339FLeu→PheCaucasian
K1351ELys→GluCaucasian
Q1352HGln→HisChinese
A1364VAla→ValBoth races
D1377HAsp→HisCaucasian
L1388QLeu→GlnCaucasian
E1401KGlu→LysCaucasian
E1401GGlu→GlyCaucasian
E1409KGlu→LysCaucasian
Q1411XGln→TerminationCaucasian
L1414SLeu→SerCaucasian
E1433KGlu→LysBoth races
E1473XGlu→TerminationCaucasian
T1478RThr→ArgChinese

fs, frame shift.

Table 2

Characteristics of CFTR hotspot mutations in CAVD patients.

MutationAmino acid changeMolecular changeClassClinical manifestation*Mostly detected inFrequency (%)Reference
R117HArg→HisDefective protein conductanceIVCAVD and CFTR-RDS, CFCaucasian3.3–11Sharma et al. (2014), Dork et al. (1997)
L206WLeu→TrpDefective protein conductanceIVCAVD and CFTR-RDS, CFCaucasian5.3Casals et al. (2000)
R334WArg→TrpDefective protein conductanceIVCAVD and CFTR-RDS, CFCaucasian8Grangeia et al. (2004)
F508delPhe→DeleteDefective protein processingIICF, CFTR-RDS, CAVDCaucasian12–33Kanavakis et al. (1998), Jarvi et al. (1998)
G542XGly→TerminationDefective protein productionICF, CFTR-RDS, CAVDCaucasian4–7.6Grangeia et al. (2004), Safinejad et al. (2011)
I556VIle→ValDefective protein conductanceIVCAVD and CFTR-RDS, CFChinese3.1–4.8Luo et al. (2021), Li et al. (2012)
Q1352HGln→HisDefective protein conductanceIVCAVD and CFTR-RDS, CFChinese2.1–6.9Luo et al. (2021), Li et al. (2012), Yuan et al. (2019)
5T alleleReduced protein synthesisVCAVD, CFTR-RDS, CFAll races10–43.7Wang et al. (2002), Lissens et al. (1999)
Chinese27.54–44.4Luo et al. (2021), Wu et al. (2004)

*Most to least common.

CFTR screening strategy for Chinese patients with CAVD

Can a Caucasian-based CFTR genetic blocking strategy be applied to Chinese patients with CAVD?

In the past, the diagnosis of CAVD and fertility interventions were limited. Couples affected by CBAVD experienced infertility caused by obstructive azoospermia. Over the past three decades, CBAVD patients have been able to father children thanks to assisted reproduction techniques (ARTs), such as intracytoplasmic sperm injection (ICSI). However, the disease-causing genes could have been transmitted to the offspring, leading to the inheritance of CFTR-related diseases. As early as 1996, Asangla Ao et al. reported the clinical experience of using PGD to intervene in the reproduction of offspring by screening the F508del hotspot mutation to avoid CF in offspring and found that the pregnancy rate after PGD in these patients was similar to that in other patients with infertility (Ao et al. 1996). Subsequently, reproductive centers in major hospitals gradually performed genetic counseling related to the application of PGD (Harper et al. 2002). Girardet et al. summarized 10 years of PGD experience in relation to CF and found that for couples at risk for hereditary CF disease, the application rate was as high as 98%, and all follow-up offspring were free from CF disease (Girardet et al. 2015). Therefore, to prevent the inheritance of pathogenic genes, it is gradually acknowledged that couples with infertility, especially those including individuals who are diagnosed with CF disease or CFTR-RDs, should undergo screening of CFTR genes and apply PGD for assisted reproduction before performing ARTs, such as in vitro fertilization (IVF) (Wong et al. 2004). Different screening methods are not contradictory. Salvado et al. proposed the application of microarray analysis to screen the F508del hotspot mutation, which has economic benefits (Salvado et al. 2004). Field et al. proposed routine screening for CFTR mutations in patients with infertility (Field & Martin 2011). Bieth et al. combined a variety of strategies to screen CAVD patients with a high risk of CFTR mutations, at least in hotspot mutations. Non-Caucasians should undergo comprehensive screening, and if conditions permit, next-generation sequencing (NGS) can even be performed, with relevant genes other than CFTR screened at the same time (e.g. ADGRG2, SLC9A3, and PANK2) (Bieth et al. 2021). Most of these recommendations are based on studies of CF disease in Caucasians. Can we draw lessons from these experiences for genetic counseling of Chinese patients with CAVD before seeking assisted reproduction? Han-Sun Chiang et al. reported a case in which the Caucasian father had iCBAVD with F508del in trans with p.L375F mutations and his Chinese female partner of Taiwanese descent had a negative CFTR screen. The two healthy offspring of the couple conceived by ICSI were heterozygous with each of the above mutations (Chiang et al. 2008). Han-Sun Chiang et al. argued that the CFTR gene should be screened in patients with infertility before assisted reproduction, especially in patients diagnosed with CBAVD. Hongxiang Wang et al. stated that there were no hotspot mutations other than the 5T allele in Chinese CBAVD patients; thus, NGS of the whole CFTR and ADGRG2 genes may be an appropriate genetic testing method. Although the majority of CFTR mutations in Chinese individuals are of the mild or heterozygous type with severe mutations, according to Mendelian genetic rules, it is still possible to give birth to offspring with CF disease, and the probability of offspring suffering from CAVD is higher. Therefore, we believe that, in view of the lack of strategic research on CFTR gene screening in Chinese individuals at present, we can learn from the screening strategy of Caucasians.

CFTR and ICSI

Obstructive azoospermia caused by CFTR gene mutation is relatively clear, but whether the generation and function of spermatozoa in the testis are affected has been controversial in the past. Later, Xu et al. showed that CFTR inhibitor or antibody significantly reduces the sperm capacitation due to decreased HCO3-dependent events and suggested that CFTR mutations with impaired CFTR function may lead to reduced sperm fertilizing capacity and male infertility other than CBAVD (Xu et al. 2007). Subsequent clinical cohort studies were consistent with these findings. Patients with CBAVD have been found to have a significantly increased risk of abortion and stillbirth with ICSI-assisted reproduction and a reduced live birth rate compared to patients with non-CBAVD obstruction, presumably due to CFTR mutations (Lu et al. 2014). Another study showed that those patients with CF have lower sperm quality, greater difficulty with sperm retrieval, and worse ICSI outcomes compared with CBAVD-only patients (McBride et al. 2021).

Screening strategies for Chinese patients with CF-related CAVD and iCAVD, and consideration of female partners for carrier screening

In our previous study, we calculated the genetic correlations of the disease-causing genes and the probability of the possible phenotype. Then, we studied the screening strategy for the CFTR gene in Caucasians (Daudin et al. 2000) and proposed a systematic strategy for screening Chinese CBAVD couples (Feng et al. 2019) in consideration of the particular genetic pattern of Chinese individuals. The method is also applicable to CF-related CAVD and isolated CAVD (iCAVD). This article summarizes and optimizes this strategy (see Fig. 2), and in general, we do not recommend CFTR gene screening in patients with infertility who are excluded as having CAVD after a detailed examination. When a patient is diagnosed with CF-related CAVD or iCAVD, we recommend at least comprehensive screening of the CFTR gene or NGS of this gene and other CAVD-related genes, if permitted. For couples seeking fertility assistance, it is recommended that the prospective mother be screened for at least the 5T alleles. If conditions allow, or if the couple has plans for PGD, the prospective mother can be screened in the same way as the prospective farther, considering economic conditions and risk tolerance. Of course, genetic counseling can be considered regardless of whether the screening results are negative or positive.

Figure 2
Figure 2

Screening strategies for Chinese CAVD couples. A guideline flowchart of screening strategies for Chinese couples with CAVD. Not applicable means there is no need for further screening of CAVD-related genes or other treatments; CS means comprehensive screening of all CAVD-related genes, including CFTR, ADGRG2, SLC9A3 and PANK2; NGS means next-generation sequencing; and IVF and ICSI mean in vitro fertilization and intracytoplasmic sperm injection, respectively.

Citation: Reproduction 164, 3; 10.1530/REP-21-0315

Other issues

Is genetic screening required for deep intron regions and adjacent intergenic regions of CFTR ?

Pathogenic mutations of the CFTR gene are mainly detected in the exon region because it encodes a functional protein, and some pathogenic mutations are detected in the promoter region and splicing sites, which affect the regulation of CFTR expression and transcription integrity. However, few researchers screen deep intron regions and adjacent intergenic regions because the functions of these regions are not very clear, and they are much longer, making sequencing analysis difficult. Audrézet et al. pointed out that 99% of the pathogenic mutation sites can be found in exons, promoters, and splicing sites, meaning that only 1% of the pathogenic mutations should be in the intron region (Audrézet et al. 2015). To date, only seven mutations of the intron region and adjacent intergenic regions have been reported to have pathogenic functions (Bergougnoux et al. 2019), including one mutation beyond 10 kb at the tail of the CFTR gene (Chiba-Falek et al. 1998). Although some scholars believe that these mutations should be included in CF diagnostic testing and carrier screening strategies (Bergougnoux et al. 2019), sequencing of intron regions and adjacent intergenic regions is not recommended at present in terms of efficiency ratio and economic effect.

Is genetic screening required for other CAVD-related genes?

There are some other genes proven to be associated with CAVD, in which pathogenic mutations were detected in patients with iCBAVD, such as the recently discovered X-linked ADGRG2 gene (Patat et al. 2016) and CNVs involving the PANK2 (Lee et al. 2009) and SLC9A3 genes (Chiang et al. 2019, Wu et al. 2019). These new findings partially bridge the gap in the explanation of genetic etiology in patients with no CFTR mutations. We also treated a family with CAVD but no CFTR mutations were detected and then performed NGS to identify a pathogenic mutation in ADGRG2. At present, with the expansion and deepening of research on these genes, there has been continuous research participation and reporting of new mutations and functional verification (Yang et al. 2017, Pagin et al. 2020). The author believes that for patients with CF-related CAVD and iCAVD, if they are free of CFTR mutations, screening for other CAVD-related genes can be performed, but not as a part of routine clinical testing.

Conclusions

A review of the literature published over recent decades has revealed that the CFTR gene mutation spectrum shows significant ethnic differences. Unlike Caucasian populations, which are characterized by predominantly hotspot and severe mutations, CFTR mutations in Chinese Han patients with CAVD are heterogeneous and dominated by mild mutations. Therefore, considering the strategy of sequencing screening, we recommend a more suitable screening strategy for the Chinese Han population. However, from the genetic perspective of the inheritance of pathogenic genes, mild mutations also have the potential to cause a severe phenotype by combinations of inherited alleles. Therefore, couples with infertility, especially those with CAVD, should undergo as comprehensive a CFTR screening as possible. Regarding the controversial issue of sequencing scope, other CAVD-related genes discovered in recent years can be used as a complement to CFTR sequencing negativity; in other words, further studies are encouraged to discover their values.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This work was supported by the National Natural Science Foundation of China (grant no. 81771565).

Author contribution statements

J F, Y Z and X Y collected data and drafted the manuscript; Y Z and X Y read and helped to revise the manuscript; J F and Y Z conceived and designed the study. All authors read and approved the final manuscript.

Acknowledgements

The authors would like to thank Prof Zuping He for his valuable suggestions on this review, the fundings, and The Third Affiliated Hospital, Sun Yat-Sen University.

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    Distribution of mutations in the CFTR gene detected in patients with CAVD on transcripts. This graph summarizes the CFTR gene mutations in the transcript (and 5T allele). The size of a pie on a lollipop indicates the gene frequency of the mutation, and the hotspot mutations has been labeled accordingly.

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    Screening strategies for Chinese CAVD couples. A guideline flowchart of screening strategies for Chinese couples with CAVD. Not applicable means there is no need for further screening of CAVD-related genes or other treatments; CS means comprehensive screening of all CAVD-related genes, including CFTR, ADGRG2, SLC9A3 and PANK2; NGS means next-generation sequencing; and IVF and ICSI mean in vitro fertilization and intracytoplasmic sperm injection, respectively.

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