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Assessment the carrier frequency of monogenic diseases in populations requiring assisted reproductive technology

BMC Medical Genomics volume 17, Article number: 214 (2024) Cite this article

Abstract

Purpose

The objective of this study is to assess the carrier frequency and pathogenic variation of monogenetic diseases in a population of 114 subjects in Han Chinese from Hebei province who are undergoing assisted reproductive technology through the utilization of Expanded Carrier Screening (ECS).

Methods

The study utilized a panel consisting of 155 severe monogenic recessive genetic diseases for ECS. Next-generation sequencing technology was employed to identify specific variants associated with ECS in a cohort of 114 subjects from 97 couples, comprising 97 females and 17 male spouses.

Results

A total of 114 individuals received ECS. The carrier rate of pathogenic genes in the enrolled population was 44.74% (51/114). Among the 97 females, the carrier rate of pathogenic genes was higher in those without assisted reproduction indicators than in those with assisted reproduction indicators (59.09% vs. 41.33%). However, the carrier rate of pathogenic genes in males without assisted reproductive technology was slightly lower than that with assisted reproductive technology (40% vs. 41.67%). Among both female and male participants, the carrier rate of pathogenic genes between individuals without indicators of assisted reproduction and those with such indicators was 55.55% vs. 41.38%. In 51 carriers, 72.55% (37/51) carried one genetic variant, 25.49% (13/51) carried two genetic variants, and 1.96% (1/51) carried three genetic variants. A total of 38 pathogenic genes were detected in this study, and GJB2 and MMACHC were most common. The carrier rates of the two genes were both 5.26% (6/114). A total of 55 variations were detected, and c.235delC was most frequently found. The carrier rate was 3.51% (4/114). The incidence of couples carrying the same pathogenic genes was 1.03% (1/97).

Conclusions

The findings elucidate the carrier rate of pathogenic genes among 155 severe monogenic recessive genetic diseases and underscore the significance of ECS as a preventive measure against congenital anomalies. When both partners carry the same genetic mutation for a monogenic disease, preventive strategies can be taken in offspring through preimplantation genetic testing (PGT), prenatal genetic testing, or the utilization of donor gametes. ECS is instrumental in assessing reproductive risk, guiding fertility-related decisions, and reducing the prevalence of monogenic recessive genetic disorders in subsequent generations.

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Introduction

Monogenic disorders are one of the causes of malformation and disability in children. Although the incidence of monogenic disorders is relatively low, the overall incidence exceeds 1%, and most monogenic disorders lack effective drugs or treatment options [1]. Expanded carrier screening (ECS) is an effective early intervention strategy to identify individuals or couples at genetic risk for recessive monogenic genetic disorders to reduce the incidence of disability and disease in the neonatal population [2]. The carrier screening program of Tay-Sachs disease that began in 1971 was the prototype for carrier screening for recessive genetic diseases [3].

Advancement in sequencing technology and reduced costs have made ECS increasingly feasible. In 2011, screening was expanded to simultaneously test for 448 Mendelian recessive diseases by next-generation sequencing (NGS) technology [4]. This study showed that the average individual carries 2.8 (from 0 to 7) pathogenic variants in 448 genes associated with severe monogenic recessive disorders in children [4]. The ability of NGS and expanded panels have improved detection rates compared to traditional testing [5,6,7,8]. A study conducted by the ECS revealed that around 5% of couples undergoing assisted reproductive technology are carriers of pathogenic variants of the same genetic disorder [7]. Additionally, pathogenic variants of an X-linked genetic disease were found in 2% of female subjects. The researchers estimate that ECS prevents 1.25% of the births of children with genetic disorders after assisted reproduction [7]. Currently, many professional associations have published guidelines and statements on carrier screening. Carrier screening has evolved from being targeted at specific ethnic groups and diseases to being recommended for all women seeking reproductive assistance and their partners [9,10,11,12,13]. ECS provides couples with the opportunity to explore a wide range of fertility options. Awareness of the potential risks associated with having an affected child may lead couples to pursue preimplantation genetic diagnosis (PGD), prenatal genetic testing, or the utilization of donor gametes as preventive measures against genetic diseases in offspring [7].

At present, research on ECS in China remains nascent, with a predominant focus on individual diseases. Liao conducted a study that evaluate prospective screening program in China for control of alpha and beta-thalassemia in the population of pregnant couples in Guangzhou [14]. Similarly, Zhao applied NGS-based method in 10,585 self-reported normal couples (34 Chinese ethnic groups from 5 provinces in South China) for spinal muscular atrophy carrier screening [15]. However, there is a lack of established guidelines or expert consensus in this area [14, 15]. ECS-related literature has been known to include research findings, such as Zhao's investigation into a total of 10,476 prenatal/preconception couples from 34 self-reported ethnic groups were simultaneously tested and analyzed anonymously for 11 Mendelian disorders using targeted next-generation sequencing [16] and Fang’s study based on capillary electrophoresis, a first-generation sequencing technology, a prospective screening study of carriers of 15 single-gene diseases was carried out in 327 subjects in Anhui Province, including 84 couples and 159 women of childbearing age [17], which proved the feasibility of ECS. However, the ECS data focused on the Chinese population were quite limited.

Here, the objective of this study was to investigate the carrier frequency and pathogenic variants of monogenic diseases in populations seeking assisted reproductive technology in the Han Chinese population from Hebei province. This was achieved through the implementation of ECS, which included a panel of 155 severe monogenic recessive genetic diseases. In addition to potentially decreasing the incidence of monogenic disorders in newborns. ECS could also provide data support for the design of ECS panel suitable for wide clinical application.

Materials and methods

Study subjects

One hundred fourteen subjects in Han Chinese at department of reproductive medicine, the Second Hospital of Hebei Medical University from Hebei province, were enrolled from April 2021 to March 2023, including 97 female and 17 male spouses. ECS was offered to couples who were planning to undergo assisted reproductive technology (ART) for various reasons unrelated to genetic disorders were enrolled, after pre-test counselling. Individuals known to be carriers of any genetic disease, or with history of a chronic medical disorder or familial genetic disorder were excluded from the study. Prior to examination, all subjects received professional genetic counseling regarding the purpose, significance, limitations, and residual risk of ECS for the target disease. ECS in this study included 155 genetic diseases. This study was approved by the institutional review board of the Second Hospital of Hebei Medical University (Ethics No. 2021-R187), and written informed consent was obtained from all participants.

Disease selection and panel design

A set of oligonucleotide probes was used to capture the target region of genomic DNA, and high-throughput sequencing and bioinformatics analysis were performed to obtain the genetic variation information in the target region. This ECS was accurately conducted for 11,781 pathogenic variants (database version 2021–02) in 147 genes associated with 155 recessive monogenic genetic disorders. The selected conditions met the American College of Medical Genetics and Genomics (ACMG) criteria for performing genetic testing for rare diseases.

DNA extraction and data analysis

Genomic DNA was extracted from 3-5mL of peripheral blood collected in ethylenediaminetetraacetic acid (EDTA) by a QIAamp DNA Blood Mini Kit (Qiagen). Quantity and quality of DNA in each sample was determined by a Nanodrop2000 spectrophotometer and Qubit 3.0 Fluorometer (Thermo Scientific). After the library was constructed, the nucleic acid fragments were detected by MGISEQ-2000 high-throughput sequencing instrument. The pathogenic or suspected pathogenic variants of the target genes were obtained after bioinformatics analysis. Carrier Screening database (11,701, database version: 2021–02) identified pathogenic or suspected pathogenic variants, including 10,974 point variants and small fragment indels (≤ 20 bp). Deletions/duplications of some exons (including deletions/duplications of two or more exons in DMD gene in Duchenne's muscular dystrophy, deletions of exon 7 in SMN1 gene in spinal muscular atrophy, large deletion of HBA/HBB gene in thalassemia: SEA, -α3.7, -α4.2, Chinese, SEA-HPFH, FIL, THAI, Taiwanese).

Screening modes

The mode of screening employed in this study was sequential screening, wherein each individual from the 97 females underwent ECS initially. Among the 97 females, 44 were identified as carriers. Following genetic counseling, the spouses of these female carriers were advised to undergo ECS. Presently, 17 males had undergone ECS, with 7 of them testing positive as carriers.

Genetic counseling

If a couple carried the same autosomal recessive disease gene, or if the woman was a carrier of an X-linked recessive disease, then they were identified as a carrier couple and were at increased risk of having an affected baby. Preimplantation genetic testing or prenatal diagnosis was performed with full informed consent. High-risk couples with subsequent pregnancy outcomes and their newborns were followed up with physical examination, hearing screening, and screening for any other clinical or genetic abnormalities. For miscarriage, stillbirth or neonatal malformation, fetal tissue or neonatal peripheral blood should be collected for detection.

Statistical analysis

The data collected were analyzed by SPSS 23.0 statistical software. Descriptive statistical analysis was performed on 114 subjects who underwent ECS for 155 genetic disorders. The carrier rate of target diseases and pathogenic genes in the region were calculated, and the pathogenic variants detected in this study were analyzed. Count data were presented as n (%) and analyzed using the Fisher's Exact Test. P < 0.05 indicates statistically significant difference.

Results

Overall carrier frequencies

A total of 114 individuals received ECS. As the results were shown in Table 1, the overall carrier rate of pathogenic genes in the enrolled population was 44.74% (51/114). The carrier rate of pathogenic genes in female population was 45.36% (44/97). The carrier rate of pathogenic gene in male population was 41.18% (7/17). There are 75 females had assisted reproduction indicators and the other 22 females had no assisted reproduction indicators (Table 2). In the 75 females, 31 (41.33%) were carriers of pathogenic genes. The number of screened males was 12 and 5 (41.67%) were carriers of pathogenic genes. One couple (1.33%) was identified as carriers of the same disease gene. Among the 22 females without assisted reproduction indicators, 13 (59.09%) were carriers of pathogenic genes. The number of screened males was 5 and 2 (40%) males were carriers of pathogenic genes. None of the couples were identified as both carriers of the same genes. Among the 97 females, the carrier rate of pathogenic genes was higher in those without assisted reproduction indicators than with assisted reproduction indicators (59.09% vs. 41.33%), although this difference was not statistically significant. However, the carrier rate of pathogenic genes in males without assisted reproduction indicator was slightly lower than that with assisted reproduction indicator (40% vs. 41.67%), and the difference was without statistical significance. There was no statistically significant difference in the carrier rate of pathogenic genes between individuals without indicators of assisted reproduction and those with such indicators (55.55% vs. 41.38%), among both female and male participants in the study. Among the 51 carriers, 72.55% (37/51) carried one genetic variant. 25.49% (13/51) carried two genetic variants. 1.96% (1/51) carried three genetic variants (Table 3). In the 75 females had assisted reproduction indicators, 27 individuals (75%) carried a single genetic variant, 8 individuals (22.22%) carried two genetic variants, 1 individual (2.78%) carried three genetic variants. Among the remaining 22 females without assisted reproduction indicators, 10 individuals (66.67%) carried a single genetic variant, 5 individuals (33.33%) carried two genetic variants, and none carried three genetic variants.

Table 1 The positive of carrier status in the 114 tested individuals
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Table 2 Distribution of carrier status in the couples with assisted reproduction indicators or not
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Table 3 Distribution of gene variants among the 51 carriers
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The carrying frequencies of gene

The study identified a total of 38 pathogenic genes, with the top 5 higher carrier rate were GJB2 (5.26%, 6/114), MMACHC (5.26%, 6/114), ARSA (3.51%, 4/114), MUT (3.51%, 4/114) and SLC45A2 (2.63%, 3/114) (Fig. 1A and Table 4). The 5 genetic diseases with the highest carrier rate of pathogenic genes were autosomal recessive deafness type 1A, methylmalonic acidemia and homocysteinemia (cblC Type), metachromatic leukodystrophy, mut-type methylmalonic acidemia and oculocutaneous albinism type 4.

Fig. 1
figure 1

Distribution of 38 pathogenic genes (A) and 55 loci variation (B) in the study. n, There are n carriers in this pathogenic gene (A). n, There are n carriers in this loci variation (B)

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Table 4 The top 5 higher carrier rates of pathogenic genes for each target disease in the 114 subjects who underwent ECS
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Pathogenic variants

A total of 55 loci variation were identified, with their respective gene and chromosome locations detailed in Table 5. 8 variants were detected in ≥ 2 subjects, accounting for 28.79% (19/66) of all detected variants (Fig. 1B). The variants detected in more than 3 individuals were c.235delC in GJB2 (3.51%, 4/114) and c.658_660delAAG in MMACHC (2.63%, 3/114) (Table 6).

Table 5 55 pathogenic genetic variants were identified, along with their corresponding gene and chromosome locations
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Table 6 8 pathogenic genetic variants were detected in ≥ 2 subjects
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High-risk couples and genetic counseling

High-risk couples carrying the same pathogenic genes were analyzed. One high-risk couple (1.03%, 1/97) was detected. In this couple, the female was first screened as a carrier of ARSA gene (c.1344_1345insC) for metachromatic leukodystrophy, and then her spouse was sequenced by ECS. Her spouse also carried variant of ARSA gene (c.736C > T) (Table 7). After genetic counseling, this high-risk couple opted not to utilize preimplantation genetic testing for monogenic diseases. Due to the severe oligoasthenospermia of the male partner, the patient requested conception through intracytoplasmic sperm injection (ICSI) with assisted reproductive technology. Subsequent amniocentesis during pregnancy confirmed the fetus to be genetically normal, free of inherited pathogenic variants from parents (Fig. 2). At present, the high-risk pregnant woman has delivered a boy with normal phenotype, and the results of neonatal physical examination are normal.

Table 7 Diseases and mutations for couples carried variants in the same gene (high risk) after ECS
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Fig. 2
figure 2

Single-gene inherited disease was verified by Sanger sequencing. The pathogenic variant of ARSA; NM_000487.5; c.1344_1345insC; p.Gly449Argfs*124 was inherited from mother. The pathogenic variant of ARSA; NM_000487.5; c.736C > p.Arg246Cys was inherited from father. The fetus was genetically normal and did not inherit these variants from parents

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Discussion

ECS is to detect whether the subjects carry pathogenic or suspected pathogenic variants associated with monogenic recessive genetic disorder before or during the first trimester of pregnancy. ECS can assess fertility risk, guide fertility decisions, and decrease the incidence of monogenic recessive genetic disorders in offspring [18]. In this study, carriers of 155 monogenic gene recessive genetic diseases were screened in couples of requiring assisted reproductive technology in Han Chinese from Hebei province, with a total of 114 patients received ECS. The overall carrier rate of pathogenic genes in the enrolled population was 44.73% (51/114). Guo et al. found that 32.6% (East Asian) to 62.9% (Ashkenazi Jewish) of individuals were variant carriers in at least one of the 415 genes. For couples, screening for all 415 genes identified 0.17% to 2.52% of couples at risk for having a child affected by these disorders [19]. In the study of Xi et al., 46.73% of the individuals were found to be the carriers of at least 1 of the 135 diseases [20]. These are consistent with our results. In the research conducted by Chen et al. it was found that 64.83% of the patients were identified as carriers of at least one of 342 genetic diseases [21]. The high carrier rate is attributed to the presence of 622 pathogenic/likely pathogenic variants, which include single nucleotide variants (SNVs), insertions/deletions (Indels), and copy number variations (CNVs). Lazarin et al. conducted pan-ethnic carrier screening for 108 diseases, with the carrier rate of 24% [22]. Fang et al. performed an ECS in the population of childbearing age for 15 diseases, the carrier rate was 20.31% [17]. Zhao et al. performed carrier screening of 11 diseases in a multi-ethnic population in China, and the carrier rate was 27.49% [16]. Singh et al. conducted ECS for genetic disorders in North Indian population, identifying that 26% participants were carrier of one or more disorders [23]. The variations in results may be attributed to differences in geographical regions, racial demographics, population characteristics, sample sizes, types of diseases screened, and sequencing technologies utilized. Bristow et al. further proposed that carrier rates among different ethnic groups differ based on the content of the screening panel, highlighting the importance of expanding panel content and incorporating preconception carrier screening into standard assisted reproduction protocols through a comparative analysis of two panels within a single fertility clinic [24].

Interestingly, among the 97 females in our study, the carrier rate of pathogenic genes was higher in those without assisted reproduction indicators than in those with assisted reproduction indicators (59.09% vs. 41.33%). Although the difference was without statistical significance, this indicates that there is a higher carrier rate in women without requiring assisted reproductive technology. Potential explanations for the disparities in the findings may be attributed to variations in geographical locations, along with small sample sizes. In 2013, the American College of Medical Genetics and Genomics (ACMG) linked the utility of carrier screening to reproductive decisions, including PGT-M, sperm/egg donation, adoption, prenatal diagnosis, special care for children, etc. [25]. Consequently, it is imperative to conduct carrier screening for monogenic diseases in couples with reproductive requirements, regardless of whether they are utilizing assisted reproductive technologies. In the context of genetic testing, information on diagnosis, treatment, management, or disease prevention based on test results would benefit patients or their families [26]. Studies have shown that most ECS participants are willing to pay for genome sequencing, and participants who are not willing to pay anything or pay a small amount may have financial resource issues, and willingness to pay is related to income levels and religious beliefs [27]. Therefore, the expansion of the scope of ECS also needs to consider the economic issues of the participants.

A total of 38 pathogenic genes were detected in our study. The 5 genetic diseases with the highest carrier rate of pathogenic genes were autosomal recessive deafness type 1A, methylmalonic acidemia and homocysteinemia (cblC Type), metachromatic leukodystrophy, mut-type methylmalonic acidemia and oculocutaneous albinism type 4. This test only screened the target loci of the target genes related to the disease in the scope of the test, and the data analysis was only for the pathogenic or suspected pathogenic variants (excluding variants of unknown clinical significance) that are currently related to the disease. Ignoring variants of unknown significance (VUS) in ECS may miss high-risk couples. Even though only 10% of couples currently classified as pathogenic/likely pathogenic variants (P/LP) and VUS carriers (P/LP*VUS) may be at risk. The P/LP*cVUS is eventually reclassified as P/LP*P/LP, and the ECS yield will increase by≈20%. Although the current understanding of VUS precludes VUS reporting in ECS, these findings highlight the importance of VUS reclassification [28].The fertility risk assessment of diseases outside the scope of the test was not included. There may be a residual risk of carrying other genes or pathogenic variants that are not within the detection range. It cannot exclude the possibility that de novo variants may cause related diseases in the offspring of the subjects. Exact estimates of the number of pathogenic variants per individual are currently imperfect. Even assuming correct design and performance, negative results do not completely eliminate the risk to future generations. These limitations must be included in the informed consent form and clearly explained to the patient and the clinician who orders such testing. Finally, informed consent must include pretrial individual decisions about any potential unanticipated findings.

The study examined the prevalence of couples who possess identical pathogenic genes, identifying one high-risk couple (1.03%, 1/97). Despite receiving genetic counseling, this couple opted not to undergo Preimplantation Genetic Testing for Monogenic Disorders (PGT-M) to screen for embryos free of associated monogenic diseases. Subsequent amniocentesis during the pregnancy confirmed the fetus to be genetically normal and free of abnormal variants inherited from the parents. However, there are some limitations to this study. First, the limited number of identified disease-causing loci and disease included in this study prevented the identification of pathogenic variants and emerging variants that were outside the scope of detection, which may increase residual risk. Pre- and post-test needs to be emphasized to counseling inform subjects of the benefits and limitations in this study. Furthermore, the study is constrained by a small sample size. Additionally, the decreased representation of males in screen-positive patients undergoing sequential screening may result in a lower rate of testing for high-risk couples.

In summary, our study represents the inaugural exploration of ECS within a Han Chinese cohort undergoing assisted reproductive technology from Hebei province.The findings elucidate the prevalence of 155 monogenic disorders among carriers and underscore the value of ECS as a preventive strategy against congenital anomalies. Future investigations with a more extensive sample size are warranted to enhance our understanding of ECS utility. Ultimately, we advocate for the integration of ECS into clinical practice, emphasizing the necessity of genetic counseling for informed decision-making.

Availability of data and materials

The datasets generated during the current study are available in the Genome Sequence Archive (Genomics, Proteomics & Bioinformatics 2021) [29] in National Genomics Data Center (Nucleic Acids Res 2022) [30], China National Center for Bioinformation / Beijing Institute of Genomics, Chinese Academy of Sciences (GSA-Human: HRA006687) that are publicly accessible at https://ngdc.cncb.ac.cn/gsa-human.

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Acknowledgements

The authors thank all the patients who participated in this study.

Funding

This study was supported by S&T Program of Hebei (21377721D, 21377720D, 22377795D). Hebei Natural Science Foundation (H2022206019). Medical Science Research Project of Hebei Province (20211494, 20240414). China Health Promotion Foundation. National Key R&D Program of China (2021YFC2700605). Hebei Provincial Government Funded Clinical Medicine Excellent Talent Program (2021). Science Foundation Project of The Second Hospital of Hebei Medical University (2HN202408).

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Authors and Affiliations

  1. Department of Reproductive Medicine, Hebei Key Laboratory of Infertility and Genetics, Hebei Clinical Research Center for Birth Defects, Hebei Medical Key Discipline of Reproductive Medicine, Hebei Collaborative Innovation Center of Integrated Traditional and Western Medicine On Reproductive Disease, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China

    Xiuhua Xu, Ziwei Wang, Luyi Lv, Zhiming Zhao, Baojun Shi & Gui-min Hao

  2. Hebei Industrial Technology Research Institute of Genomics in Maternal & Child Health, Clin Lab, BGI Genomics, Shijiazhuang, 050000, China

    Sijie He

  3. Cardiovascular Platform, Institute of Health and Disease, Hebei Medical University, Shijiazhuang, 050000, China

    Xiuhua Xu & Qian Li

  4. Department of Neurology, The 980th Hospital of the People’s Liberation Army Joint Logistics Support Force (Bethune International Peace Hospital), Shijiazhuang, China

    Gang Li

Authors
  1. Xiuhua Xu
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  2. Sijie He
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  3. Gang Li
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  4. Ziwei Wang
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  5. Luyi Lv
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  6. Zhiming Zhao
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  7. Qian Li
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  8. Baojun Shi
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  9. Gui-min Hao
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Contributions

Conceptualization, XH.X. and GM.H.; methodology, XH.X., SJ.H., ZW.W. and G.L; software, SJ.H.and G.L; validation,XH.X., ZW.W., and LY.L.; formal analysis, XH.X.and Q.L.; investigation, ZM.Z. and BJ.S.; resources, XH.X.and GM.H.; data curation, XH.X.; writing—original draft preparation, XH.X.; writing—review and editing, SJ.H.and GM.H.; visualization, XH.X.; supervision, GM.H.; project administration, BJ.S.; funding acquisition, XH.X.,GM.H.,BJ.S. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Gui-min Hao.

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Ethics approval and consent to participate

The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board of Second Hospital of Hebei Medical University (Ethics No. 2021-R187). Informed consents were obtained from the participants/patients involved in this study.

Competing interests

The authors declare no competing interests.

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Xu, X., He, S., Li, G. et al. Assessment the carrier frequency of monogenic diseases in populations requiring assisted reproductive technology. BMC Med Genomics 17, 214 (2024). https://doi.org/10.1186/s12920-024-01989-2

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BMC Medical Genomics

ISSN: 1755-8794

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