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Analysis of Copy Number Variations Of Zhu et al. Orphanet J Rare Dis (2021) 16:258 https://doi.org/10.1186/s13023-021-01888-0 RESEARCH Open Access Analysis of copy number variations of WNT4 gene in a Chinese population with Müllerian anomalies Ying Zhu1,2,3†, Ruyi Wang4,5†, Yun Cheng1,2,3, Yang Han1,2,3, Tengyan Li5, Yunxia Cao1,2,3* and Binbin Wang4,5* Abstract Background: To investigate the genetic contribution of copy number variations (CNVs) in Wingless-type MMTV inte- gration site family, member 4 (WNT4), in a Chinese population with Müllerian anomalies (MA), copy number analysis of WNT4 by Multiplex ligation‐dependent probe amplifcation (MLPA) was performed on 248 female patients. Some studies have shown that heterozygous missense mutation of WNT4 can lead to MA. However, few studies on the relationship between WNT4 CNVs and MA have been performed. Results: Among the 248 Chinese women afected by MA in this study, heterozygous deletion of WNT4 was detected in a single patient. Conclusions: MLPA identifed one heterozygous deletion in WNT4 in a single female patient among 248 Chinese women afected by MA. This study frstly reports CNVs of WNT4 in a large sample of MA patients from the Chinese population, which suggests that CNVs of WNT4 cannot be excluded in the occurrence of MA. This provides a genetic basis for precise treatment in the future. Keywords: Copy number variations, WNT4, Müllerian anomalies, Chinese population Background for Gynaecological Endoscopy (ESHRE/ESGE) in 2013 Müllerian anomalies (MA) are among the most com- [4], Müllerian duct abnormalities can be classifed into mon diseases in gynecology and obstetrics. Tey include 36 diferent combinations as the main class for the uter- various malformations of fallopian tubes, vagina, cervix, ine body (U) and subclasses for the cervix (C) and vagina and corpus uteri [1]. Te estimated incidence of MA is (V). Compared to the classifcation method put forward 5.5% in the general population, but 24.5% in women with by American Fertility Society, ESHRE/ESGE classifed infertility and miscarriage [2, 3]. Tis disease seriously uterine morphology into 7 classes: U0, normal; U1, dys- afects women’s reproductive function and causes a huge morphic; U2, septate; U3,bicorporeal; U4, hemiuterus; social burden. U5, aplastic; U6, unclassifed cases. According to guidance of the European Society of Diferent types of Müllerian duct anomalies have dif- Human Reproduction and Embryology/European Society ferent efects on reproductive function. People with mild symptoms can have normal fertility, but most patients *Correspondence: [email protected]; [email protected] with uterine malformations exhibit serious efects such †Ying Zhu and Ruyi Wang considered as joint frst authors as primary amenorrhea, recurrent abortion, and infer- 1 Reproductive Medicine Center, Department of Obstetrics tility. Septate uterus is one of the milder symptoms in and Gynecology, The First Afliated Hospital of Anhui Medical University, 218 Jixi Road, Shushan, Hefei 230022, China patients with uterine malformation, and the rate of live 4 Graduate School of Peking Union Medical College, Beijing, China births from such patients is about 62.5%. After operation, Full list of author information is available at the end of the article this rate can be signifcantly increased [5]. © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://crea- tivecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdo- main/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zhu et al. Orphanet J Rare Dis (2021) 16:258 Page 2 of 6 To date, many genes related to MA have been found, analyzed by capillary electrophoresis were collected using including many genes of the Wingless-type MMTV inte- an Applied Biosystems 3730xl DNA Analyzer, and the gration site family (WNT4, WNT5A, WANT7, WNT9B) peak area data were output. Relative peak area of WNT4 [6–10]. WNT4 (OMIM: 603490), a transcriptional reg- was compared with that of the reference gene. Dosage ulator, plays an important role in sex determination, quotient (DQ) was used as the signal result of CNVs. Te nephrogenesis, and female reproductive tract develop- classifcation was as follows: normal (0.8–1.2), homozy- ment in the early embryo [6, 11–13]. WNT4−/− female gous deletion (0), heterozygous deletion (0.4–0.65), and mice were reported to show phenotypes of sex reversal, heterozygous duplication (1.3–1.65). Müllerian duct aplasia, hyperandrogenism, and follicle depletion [6, 14]. Many studies have also shown that the heterozygous Analysis of CNV pathogenicity missense mutation of WNT4 can lead to MA and hyper- Te pathogenicity of CNVs was evaluated in accordance androgenism in humans [15–18]. However, few studies with the CNV interpretation scoring metric from the have been performed on the relationship between WNT4 American College of Medical Genetics and Genomics copy number variations (CNVs) and MA. Terefore, here (ACMG) [19]. Online databases including the Database we detected the copy number of WNT4 in 248 female of Genomic Variants (DGV, http:// dgv. tcag. ca/ dgv/ app/ patients with MA. home/) and the Genome Aggregation Database (Gno- mAD, http:// gnomad. broad insti tute. org/) were used to Materials and methods retrieve the frequency of CNVs. Public databases, includ- Participants ing PubMed (https:// pubmed. ncbi. nlm. nih. gov/) and 248 unrelated MA patients were recruited from the Online Mendelian Inheritance in Man (OMIM, https:// Reproductive Medicine Center of the First Afliated Hos- www. omim. org/), were used to evaluate the signifcance pital of Anhui Medical University. All patients were Chi- of CNVs of WNT4. nese, ranging in age from 22 to 48 years (29.32 ± 4.87). All patients showed a normal karyotype of 46, XX and had been diagnosed with abnormal Müllerian ducts Results using physical examination, ultrasonographic investiga- MLPA results of MA patients tions, hysteroscopy and laparoscopy. Te study protocol One deletion was identifed in WNT4 in a single female was approved by the Ethics Committee of the National patient among the 248 Chinese women afected by MA in Research Institute for Family Planning, and written this study (Fig. 1). Te DQ values of three probe recogni- informed consent was obtained from all participants. tion sequences were all between 0.4 and 0.65, refecting a heterozygous deletion of WNT4 (Table 1). DNA extraction Genomic DNA was extracted from the peripheral blood of 248 patients using the QIAamp DNA Blood Mini Kit Clinical characteristics of the patient with CNVs (Qiagen, Hilden, Germany). Te patient with a single copy of WNT4 was 28 years old, had regular menstruation, and exhibited normal levels MLPA assay of estradiol (E2) and testosterone (T). She sufered from Tree probes designed in-house targeted the region of secondary infertility, having been diagnosed with partial the WNT4 gene. Te frst probe covered exon 1 and exon septate uterus but no renal abnormalities. She had under- 2, second probe covered exon 3 and exon 4, third probe gone transcervical incision of septa (TCIS) in 2016 (see covered exon 5. Fluorescence data on the PCR products Table 1 for details). Fig. 1 Copy number variations on WNT4 exons. WNT4 has 5 exons, one MA patient carried heterozygous deletion of WNT4. Gray slash symbols deletion Zhu et al. Orphanet J Rare Dis Orphanet (2021)16:258 JRare et al. Table 1 CNVs of WNT4 gene and clinical features in congenital uterine anomaly patients Patient No Copy number status Dosage quotient Age (years) BMI (kg/m2) FSH (IU/l) LH (IU/l) E2 (pmol/l) P (nmol/l) PRL (ng/ml) T (nmol/l) 1 Heterozygous deletion of exons 1–5 0.51 (ex1–ex2) 28 20 6.06 3.23 75.5 1.43 15.54 0.4 0.61 (ex3–ex4) 0.45 (ex5) BMI body mass index (normal range 18.5–23.9 kg/m2), FSH follicle stimulating hormone (normal range 2.5–10.2 mIU/ml), LH luteinizing hormone (normal range: 1.9–12.5 mIU/ml), E2 estradiol (normal range 40–253 pmol/l), P progesterone (normal range 0.6–1.9 nmol/l), PRL prolactin (normal range 2.8–29.2 ng/ml); T testosterone (normal range 0.48–2.64 nmol/l) Page 3of6 Page Zhu et al. Orphanet J Rare Dis Orphanet (2021)16:258 JRare et al. Table 2 CNV Interpretation Scoring Metric of ACMG Patient no Copy number status Contain protein- Haploinsufcient Number of protein- Analysis of public Inheritance pattern Total score Classifcationf coding elements genesb coding RefSeq genes databases and for patient (Score)e (Score)a (Score)c literature (Score)d 1 Heterozygous deletion 1A, Yes (0) Skip 3A, 1 (0) 4E, reported phenotype 5F, inheritance pattern 0.1 VUS of WNT4 is highly specifc and is unknown (0) relatively unique to WNT4. But the inherit- ance pattern of the variant is unknown (0.1) a Gene type of WNT4: protein coding, Accession: NM_030761.5 (https:// www. ncbi. nlm. nih. gov/) # The haploinsufciency evaluation of WNT4 has not been established (https:// dosage.
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