یک خانواده ژنتیکی پیچیده با حذف مادرزادی Xp22.2-p21.3 و تکرار ارثی 5q15 طبقه بندی شده به عنوان VUS: تشخیص قبل از تولد، مشاوره ژنتیک و تجزیه و تحلیل بالینی گذشته نگر

خلاصه

Background:

Prenatal genetic diagnosis using copy number variation sequencing (CNV-seq) frequently identifies variants of uncertain significance (VUS), which complicate genetic counseling. Parental verification studies performed after a fetal copy number variant (CNV) is identified may also reveal incidental parental CNVs unrelated to the indication for testing. We report a family in which parental verification revealed both an inherited 5q15 duplication and a previously undiagnosed maternal Xp22.2-p21.3 deletion.

Materials and Methods:

A 36-year-old pregnant woman (G3P1), whose second pregnancy (2021) had been terminated after a positive non-invasive prenatal testing (NIPT) result without confirmatory diagnostic testing and who was subsequently diagnosed with premature ovarian insufficiency (POI), underwent amniocentesis at 18 weeks of gestation because of advanced maternal age and an adverse obstetric history. Amniotic fluid was analyzed by karyotyping and CNV-seq; parental peripheral blood was analyzed by CNV-seq after a fetal CNV was identified.

Results:

Fetal CNV-seq revealed a 480 kb duplication at 5q15 (chr5:g.94580000_95060000dup) encompassing eight protein-coding genes, which was classified as a VUS. Parental verification showed that the duplication was not detected in the father, whereas the mother carried the same 5q15 duplication. Maternal CNV-seq additionally revealed a 16.65 Mb heterozygous deletion at Xp22.2-p21.3 (chrX:g.12210001_28860000del) encompassing 81 protein-coding genes, including 30 OMIM morbid genes (e.g., ARX، CDKL5، PHEX و RS1)؛ این حذف به عنوان بیماریزا طبقه بندی شد. مادر هیچ ویژگی بالینی آشکاری از اختلالات مرتبط با X نداشت. این زوج پس از مشورت تصمیم گرفتند به بارداری ادامه دهند و یک نوزاد کامل متولد شد که هیچ گونه ناهنجاری در بدو تولد تشخیص داده نشد. پیگیری طولی برنامه ریزی شده است.

Conclusion:

This case illustrates two issues in prenatal genomics. First, the 5q15 duplication detected in this family remains a VUS; although its inheritance from an asymptomatic mother is reassuring, it does not establish benignity, and long-term follow-up is required. Second, parental verification performed to trace the origin of a fetal VUS may incidentally identify clinically significant parental CNVs, as occurred in this case with a previously undiagnosed maternal Xp22.2-p21.3 deletion. This incidental finding was relevant to the mother’s own health and reproductive history, provided a plausible explanation for a previous NIPT-positive result, and required separate counseling. We suggest that parental CNV-seq performed after the identification of a fetal VUS be recognized as having the potential to reveal incidental findings and that counseling and consent processes explicitly address this possibility.

Introduction

Non-invasive prenatal testing (NIPT) based on maternal peripheral blood cell-free fetal DNA (cffDNA) is widely applied for fetal common chromosomal aneuploidy screening in clinical obstetrics, but maternal constitutional copy number variation (CNV) is a well-documented critical source of NIPT false-positive results, which has gradually attracted attention in the prenatal genetic field (Snyder et al., 2015; Hartwig et al., 2017). توالی تغییرات تعداد کپی (CNV-seq) با آمنیوسنتز استاندارد طلایی برای تشخیص قطعی قبل از تولد ریزحذف‌های کروموزومی جنینی / میکرودوپلیکاسیون‌ها است. پس از تشخیص CNV غیرطبیعی جنین، غربالگری CNV خون محیطی والدین می‌تواند منبع وراثت واریانت را ردیابی کند و گاهی اوقات یک CNV بیماری‌زای مخفی که قبلاً تشخیص داده نشده بود را در والدین شناسایی کند.Hu and Zhang, 2025).

بازوی کوتاه کروموزوم X (Xp22) حاوی ژن‌های حساس به دوز متعددی است که در رشد عصبی، رشد اسکلتی و عملکرد تخمدان نقش دارند. حذف های بینابینی بزرگ Xp22.2-p21.3 بر اساس معیارهای ACMG/ClinGen به عنوان CNV های بیماری زا طبقه بندی می شوند. ناقلان مذکر همی زیگوت معمولاً دارای اختلالات رشدی چند سیستمی شدید هستند، در حالی که حاملان زن هتروزیگوت اغلب از نظر بالینی بدون علامت هستند، احتمالاً به دلیل غیرفعال شدن کروموزوم X (XCI). با این حال، وضعیت XCI در مورد حاضر ارزیابی نشد، و این توضیح یک فرضیه باقی می ماند. گزارش شده است که زنان ناقل در معرض افزایش خطر نارسایی زودرس تخمدان (POI) و پیامدهای نامطلوب باروری هستند.Auger et al., 2013; Panay et al., 2024; Tanoshima et al., 2025; Tolmacheva et al., 2025). در مقابل، میکرودوپلیکاسیون بینابینی در 5q15 نادر است و فقط گزارش‌های پراکنده در DECIPHER دارد و در حال حاضر به دلیل جمعیت و شواهد عملکردی ناکافی به عنوان VUS طبقه‌بندی می‌شود.Douyard et al., 2006; Hutchins, 2017).

در این مطالعه، ما موردی را گزارش می‌کنیم که در آن یک تکرار VUS 5q15 جنینی توسط CNV-seq آمنیوتیک در سه ماهه دوم شناسایی شد و غربالگری بعدی والدین حذف Xp22.2-p21.3 مادری را که قبلا تشخیص داده نشده بود، نشان داد. ما روند تشخیص قبل از تولد، تاریخچه باروری مادر، و ملاحظات ژنوتیپ-فنوتیپ را برای دو CNV توصیف می کنیم و در مورد پیامدهای مشاوره ژنتیکی و مدیریت حاملگی های مثبت NIPT بحث می کنیم. از آنجا که XCI به طور تجربی ارزیابی نشده است و تکرار 5q15 همچنان یک VUS است، تفاسیر ارائه شده در زیر به صراحت به عنوان مشاهدات، شواهد پشتیبان یا فرضیه ها، در صورت لزوم، در نظر گرفته شده است.

Case presentation

Clinical history

The proband was a 36-year-old woman (G3P1) born in 1987. Her menstrual cycles were regular before 2021. In 2017, she delivered a healthy full-term female infant by spontaneous vaginal delivery; neither the proband nor her daughter underwent genetic testing, and the daughter has been followed to 7 years of age with unremarkable physical growth and neurodevelopment.

In April 2021, her second pregnancy returned a positive NIPT result. According to the couple’s account, no confirmatory invasive testing was performed, and the pregnancy was terminated electively. The NIPT report and any fetal material from that pregnancy were not available to us, as both the screening and the termination were performed at other institutions. Because the fetal chromosomal status was never established, whether the NIPT result was a true positive, a false positive related to the maternal constitutional CNV, or a false positive of other origin cannot be determined retrospectively. As discussed below, termination of pregnancy based on a screening result alone is not consistent with current guidance.

In September 2024, she conceived spontaneously. At 18 weeks of gestation, she was enrolled for prenatal diagnosis because of advanced maternal age (≥35 years) and adverse obstetric history. Amniocentesis was performed for karyotyping and CNV-seq. After the fetal CNV-seq result was available, both parents underwent peripheral blood CNV-seq on the same occasion to determine the inheritance of the fetal 5q15 duplication; the father was 38 years old, with no congenital malformations or developmental disorders. This testing was performed solely for segregation analysis of the fetal variant. The pregnancy was continued after genetic counseling. Serial prenatal ultrasonography showed no fetal structural anomalies. A male infant was delivered vaginally at 39 weeks of gestation. No abnormalities were identified during the routine neonatal examination at birth. Longitudinal follow-up is planned.

Specimen collection and testing

Amniotic fluid was collected at 18⁺³ هفته های بارداری مقدار کمی برای کاریوتایپینگ باند G کشت داده شد. DNA ژنومی از مقدار باقیمانده برای تجزیه و تحلیل CNV-seq و STR با عمق کم در سطح ژنوم طبق پروتکل استاندارد استخراج شد. هنگامی که نتیجه CNV-seq جنین در دسترس قرار گرفت، نمونه‌های خون وریدی محیطی مادر و پدر به طور همزمان گرفته شد و به موازات CNV-seq مورد تجزیه و تحلیل قرار گرفت، با تنها نشانه بالینی برای تعیین اینکه آیا تکرار 5q15 جنین ارثی است یا de novo. بنابراین، هر دو والدین برای یافتن یک جنین مورد آزمایش قرار می گیرند. حذف مادری Xp22.2-p21.3 از قبل مشکوک بالینی نبود. آن را در طول تجزیه و تحلیل CNV-seq مادر برای تجزیه و تحلیل جداسازی انجام شد شناسایی شد.

CNV classification

Genomic DNA was extracted using the Amp Genomic DNA Kit (TIANGEN Biotech, Beijing, China) according to the manufacturer’s instructions.

For library construction, genomic DNA was fragmented to an average size of 200 bp, and 2.5 ng of fragmented DNA was used as the starting template. Barcoded sequencing adaptors were ligated to the DNA fragments, followed by PCR amplification. The PCR product was purified using magnetic beads (Beckman AMPure XP, United States). Libraries that passed quality control were pooled and sequenced on the NextSeq 550AR platform (Annoroad Technology, China), generating 8–10 million 40 bp single-end reads per sample.

After sequencing quality control and trimming, short reads were aligned to the human reference genome hg19 (GRCh37) using BWA (version 0.7.12). Unique reads were counted for each 100 kb window. GC bias in per-window read counts was corrected using the LOWESS model. A normal-karyotype database (NKD), derived from 1,000 samples with normal G-banded karyotype, was used as the background. Copy number changes were identified by standardized Z-score analysis using an in-house R script (R version 3.4.0); a Z-score threshold of >3 for duplications and

For STR linkage analysis, 21 autosomal STR loci plus the amelogenin locus were amplified using the Microreader™ 21 ID System (Suzhou Microread Genetics, Suzhou, China) according to the manufacturer’s instructions and analyzed on an Applied Biosystems 3500 Dx Genetic Analyzer (Thermo Fisher Scientific, Waltham, MA, United States). STR analysis was performed to confirm sample identity and exclude maternal contamination.

CNV coordinates are reported according to hg19 (GRCh37). CNVs were classified according to the 2019 ACMG/ClinGen joint consensus criteria, with reference to OMIM, DECIPHER, DGV, the ClinGen dosage map, and published literature, into pathogenic, likely pathogenic, VUS, likely benign, and benign categories.

Methods and results

Fetal findings

Amniotic fluid CNV-seq revealed a 480 kb interstitial duplication at 5q15: seq [hg19]dup (5)(q15)chr5:g.94580000_95060000dup، شماره کپی = 3 (Figure 1). ناحیه تکرار شده حاوی هشت ژن کد کننده پروتئین است: MCTP1، FAM81B، SKIC3، ARSK، GPR150، RFESD، SPATA9 و RHOBTB3. هیچ CNV غیر طبیعی دیگری در اتوزوم ها یا کروموزوم های جنسی مشاهده نشد. کاریوتایپ باند G آمنیوسیت‌های کشت‌شده، کاریوتایپ طبیعی مردانه، 46، XY را نشان داد.

Interpretation of the fetal 5q15 duplication

The duplication was classified as a VUS. DECIPHER contains one overlapping case (ID331577) with an autistic behavioral phenotype, and no triple-dose sensitive genes have been documented in the duplicated region. The DGV database contains no polymorphic record for this fragment.

Parental findings

Parental CNV-seq was performed in parallel on both parents to trace the origin of the fetal 5q15 duplication.

Maternal CNV-seq revealed two constitutional CNVs

Paternal CNV-seq showed no abnormal copy number variants on chromosome 5 or chromosome X; in particular, the 5q15 duplication identified in the fetus was not detected in the father.

Discussion

Maternal Xp22.2-p21.3 deletion

The Xp22.2-p21.3 deletion detected in the proband is a large interstitial deletion classified as pathogenic. Male hemizygous carriers of deletions in this region are reported to develop severe clinical manifestations, including intractable epilepsy, profound intellectual disability, and multiple congenital malformations, and some affected male infants die during early infancy. In contrast, heterozygous female carriers are often clinically asymptomatic, and the proband had no overt clinical features associated with the deleted region.

Skewed X-chromosome inactivation has been proposed as an explanation for the absence of somatic manifestations in female carriers of large Xp deletions (Auger et al., 2013; Orstavik, 2009). با این حال، هیچ آنالیز XCI یا آنالیز بیان اختصاصی آلل در این مطالعه انجام نشد. بنابراین، این مکانیسم یک فرضیه باقی می ماند و در این مورد نشان داده نشده است. مطابق با گزارش‌های قبلی، فنوتیپ تولیدمثلی پروباند شامل POI بود. ژن های موجود در ناحیه حذف شده، مانند ZFX، USP9X و PGRMC1، در رشد فولیکول و بقای تخمک نقش دارند. ناکافی بودن این ژن ها ممکن است به اختلال در ذخیره تخمدان کمک کند.Peluso, 2013; Byun et al., 2025; Xue et al., 2025). با این حال، چندین خط از شواهد خاص بیمار در این مورد در دسترس نبود: ارزیابی عملکردی ژن های حذف شده انجام نشد، وضعیت XCI مشخص نشد، ذخیره تخمدان به طور سیستماتیک قبل و بعد از تشخیص حذف ارزیابی نشد، و هیچ شواهد مولکولی وجود نداشت که مستقیماً فنوتیپ بیمار را به یک ژن حذف شده خاص مرتبط کند. بنابراین، حذف ممکن است توضیح دهد یا به طور قابل قبولی به POI proband کمک کند، اما هیچ انتساب مکانیکی قطعی نمی توان ایجاد کرد. POI پروباند پس از 12 ماه مقاربت محافظت نشده و بدون لقاح پس از بارداری در سال 2021 تشخیص داده شد. یک رابطه زمانی در این مورد نباید به عنوان علت و معلول تفسیر شود. کاهش مربوط به سن در ذخیره تخمدان یک مورد دیگر است و سهم نسبی سن، حذف Xp مادر و سایر عوامل را نمی توان با استفاده از داده های موجود تشخیص داد.

2021 NIPT-positive result and clinical considerations

The nature of the 2021 NIPT-positive result is unknown because the report was not available and no fetal material was retained. Therefore, the condition for which pregnancy screened positive, the fetal karyotype, and the CNV status of that pregnancy cannot be documented. Any relationship between the maternal Xp deletion and that result is therefore inferential. Maternal constitutional CNVs are a recognized source of false-positive NIPT results (Snyder et al., 2015) و حذف مادری Xp22.2-p21.3 به اندازه 16.65 مگابایت به اندازه کافی بزرگ است که یک عامل قابل قبول باشد. با این حال، این یک فرضیه باقی می ماند که نمی توان آن را به صورت گذشته آزمایش کرد. به همین ترتیب، جنین 2021 ممکن است از نظر کروموزومی نرمال بوده یا دارای یک ناهنجاری غیرمرتبط بوده باشد. هیچ یک از این دو احتمال را نمی توان رد کرد.

Several aspects of the 2021 management differ from current guidance, and we note them as general principles rather than as a judgment on the care provided. First, NIPT is a screening test, and a positive result requires confirmatory invasive testing before any irreversible reproductive decision. Second, for couples with a known parental constitutional chromosomal abnormality, invasive prenatal diagnosis is generally preferred over NIPT as the primary approach, because maternal CNVs can distort screening results. Third, when an abnormal prenatal result is obtained, multidisciplinary consultation involving obstetrics, clinical genetics, and pediatrics should precede decisions about whether to continue the pregnancy. These principles are consistent with existing prenatal screening guidance.

5q15 microduplication

The 5q15 duplication remains a VUS. It was maternally inherited, and the mother had normal intelligence and physical growth without autistic features or developmental delay. This observation is reassuring but does not establish benignity as the available evidence on phenotype, penetrance, expressivity, and dosage sensitivity is limited and the number of reported cases is very small.

ACMG/ClinGen classification rationale

The duplication was evaluated according to the 2019 ACMG/ClinGen joint consensus criteria. The following evidence categories were considered.

Gene content and dosage sensitivity

The duplicated region contains eight protein-coding genes (MCTP1، FAM81B، SKIC3، ARSK، GPR150، RFESD، SPATA9 و RHOBTB3). هیچ یک از این ژن ها به عنوان یک ژن حساسیت تریپلوئید تایید شده توسط ClinGen توضیح داده نشده است و هیچ ورودی OMIM تایید نمی کند که دوز بالا از این ژن ها باعث بیماری انسان می شود. MCTP1 با بیماری عصبی عضلانی پراکنده از طریق انواع اشتباه تک نقطه ای مرتبط است، اما شواهدی وجود ندارد که افزایش تعداد کپی MCTP1 را با بیماری انسانی مرتبط کند.Shin et al., 2005; Tarchini et al., 2018; Riggs et al., 2020).

Population data

No record of this fragment as a polymorphism was found in the DGV database, indicating that it is not a common population polymorphism. However, the absence of a DGV record does not by itself establish pathogenicity.

Case-level evidence

DECIPHER contains two overlapping cases. Case ID331577 carries a 480 kb overlapping duplication with an autistic behavioral phenotype, and case ID341303 carries a 289.65 kb partially overlapping duplication inherited from the mother, with fetal growth retardation. These observations are based on small numbers of cases and cannot be weighted heavily.

Inheritance

The duplication was inherited from the mother, who had a normal phenotype. This is supportive but not sufficient to reclassify the variant as benign, because incomplete penetrance and variable expressivity cannot be excluded.

Based on these considerations, the variant cannot be classified as pathogenic or likely pathogenic. Because the available evidence is insufficient to classify it as benign or likely benign, and because pathogenicity cannot be excluded as further evidence accumulates, it is classified as a VUS. An inherited VUS remains a VUS unless sufficient evidence supports its reclassification; the normal phenotype of a single carrier does not establish benignity.

The central clinical message of this case is that a prenatal genetic investigation undertaken for one indication—characterizing a fetal VUS—can yield information of independent clinical relevance for a parent. Three elements are interlinked: the fetal 5q15 duplication required parental verification to establish inheritance; that verification incidentally identified a maternal pathogenic Xp22.2-p21.3 deletion; and the maternal deletion in turn provides a plausible, though unproven, explanation for the previous NIPT-positive result and for the proband’s reproductive phenotype. Each element carries distinct counseling and management implications, and none can be resolved by the fetal finding alone.

Parental segregation testing versus opportunistic genomic screening

In this case, parental CNV-seq was performed to determine the origin of a fetal VUS, which is the standard indication for parental segregation testing. The maternal Xp deletion was identified incidentally during this targeted analysis. It is important to distinguish this from opportunistic genomic screening, in which parental genomes are examined more broadly in the absence of a specific indication. Segregation testing and opportunistic screening differ in their objectives, the scope of analysis, the likelihood of incidental findings, and the ethical and counseling requirements they entail.

The incidental identification of a pathogenic maternal CNV raises several ethical considerations. These include the scope of consent for parental testing, the possibility of findings unrelated to the fetal indication, the mother’s right to know or not to know, and the implications for other family members, including the couple’s 7-year-old daughter. In this case, the finding was considered clinically actionable for the mother’s reproductive and long-term health, and the couple was counseled accordingly. We recommend that consent for parental verification explicitly address the possibility of incidental findings, that the scope of analysis be defined in advance where feasible, and that a clear pathway for disclosure and follow-up be established. Whether broader genomic screening of parents should be offered routinely after a fetal VUS is a separate question that requires further ethical and health-services research and is not resolved by this case.

Pregnancy decision-making and neonatal follow-up

After detailed genetic counseling covering the available evidence and uncertainties related to the 5q15 duplication, the couple decided to continue the pregnancy. Serial systematic obstetric ultrasonography, including nuchal translucency scanning, second-trimester structural anomaly screening, and third-trimester fetal growth assessment, revealed no fetal malformations or growth restriction. A male infant was delivered at 39 gestational weeks with normal birth weight. No congenital abnormalities were identified on routine physical examination at discharge. Because the 5q15 duplication remains a VUS, the long-term neurodevelopmental outcome cannot be inferred from the current follow-up data; longitudinal follow-up is planned to monitor growth, neurodevelopment, language, and behavior. A long-term follow-up plan has been formulated to monitor the child’s neurodevelopment, language, and behavioral development up to 6 years of age to accumulate real-world clinical evidence regarding this VUS duplication.

Clinical value of parental CNV verification

This case illustrates the clinical value of parental peripheral blood CNV-seq verification after the detection of an abnormal fetal CNV during prenatal diagnosis. First, it clarifies the inheritance pattern of the variant and distinguishes de novo CNV های بیماری زا از انواع ارثی. CNV های خوش خیم یا VUS ارثی ممکن است خطر مورد انتظار پیامدهای نامطلوب جنین را کاهش دهد و ممکن است تصمیم گیری برای ادامه بارداری را تعیین کند. در این مورد، تکثیر 5q15 جنین به عنوان یک واریانت ارثی از مادر بدون علامت تایید شد. دوم، غربالگری والدین ممکن است CNV های بیماری زا والدین را که قبلاً تشخیص داده نشده بودند، همانطور که در این مورد با حذف Xp مادر رخ داده است، شناسایی کند. این یافته پیامدهایی برای سابقه باروری مادر و سلامت طولانی مدت و مشاوره ژنتیک آگاهانه برای خانواده دارد. سوم، مبنایی را برای در نظر گرفتن آزمایش ژنتیکی سایر اعضای خانواده فراهم می کند. دختر بزرگتر پروبند که در سال 2017 به دنیا آمد، تحت CNV-seq قرار نگرفت. بر اساس این مورد، آزمایش را می توان با خانواده به عنوان یک ملاحظات به جای یک دستورالعمل رسمی برای تعیین اینکه آیا حذف Xp بیماری زا از مادر و/یا تکرار 5q15 به ارث برده است یا خیر، با خانواده مورد بحث قرار داد، و این امکان را فراهم می کند که خطرات باروری در مراحل اولیه ارزیابی شود.آرزوها

Considerations for clinical practice

Conclusion

This case illustrates several points. First, a maternal constitutional pathogenic CNV was identified incidentally during parental verification performed after a fetal VUS was detected. This finding was relevant to the mother’s reproductive history and long-term health. Second, the 2021 NIPT-positive result may have been related to the maternal Xp deletion, but the condition screened positive, the NIPT report, and any fetal material were unavailable, so this remains inferential and the fetal chromosomal status of that pregnancy is unknown. Third, the 5q15 duplication detected in the fetus and mother remains a VUS; its inheritance from an asymptomatic mother is reassuring but does not establish benignity, and long-term follow-up of the child is warranted. Fourth, the absence of somatic features in the mother is consistent with previous reports of female carriers of large Xp deletions, but XCI was not assessed, and the mechanism remains hypothetical; the association between the deletion and POI is supported by the location of several ovarian-function genes in the deleted region, but direct functional evidence was not obtained. Parental CNV-seq after a fetal CNV finding can clarify inheritance and may occasionally reveal clinically significant parental variants; the consent process should reflect this possibility. The management suggestions above are aligned with existing guidance and are not intended to replace it.

References

• AugerJ.BonnetC.ValdugaM.PhilippeC.Bertolo-HouriezE.Beri-DexheimerM.et al (2013). De novo بازآرایی پیچیده کروموزوم X آشکارسازی حذف ارثی CSF2RA از مادر در یک دختر مبتلا به پروتئینوز آلوئولار ریوی. Am. Journal Medical Genetics. Part A161A (10) 2594—2599. 10.1002/ajmg.a.36097

• ByunS.YoonS. H.HongY. J.JangH. S.SeoB. J.ChoiG. T.et al (2025). Expression patterns of escape genes in Turner Syndrome fibroblasts and induced pluripotent stem cells. Int. Journal Molecular Sciences26 (3) 975. 10.3390/ijms26030975

• DouyardJ.HawleyP.ShahamM.KimonisV. (2006). Duplication of 5q15-q23.2: case report and literature review. Birth defects research. Part A, Clin. Molecular Teratology76 (4) 272—276. 10.1002/bdra.20244

• HartwigT. S.AmbyeL.SørensenS.JørgensenF. S. (2017). Discordant non-invasive prenatal testing (NIPT) – a systematic review. Prenat. Diagnosis37 (6) 527—539. 10.1002/pd.5049

• HuF.ZhangG. (2025). Prenatal diagnosis and genetic counseling of a Chinese family with inherited multiple chromosomal microduplications. Psychiatr. Genetics35 (3) 69—74. 10.1097/YPG.0000000000000391

• HutchinsJ. R. (2017). Genomic database searching. Methods Molecular Biology Clift. N.J.1525، 225—269. 10.1007/978-1-4939-6622-6_10

• PanayN.AndersonR. A.BennieA.CedarsM.DaviesM.EeC.et al (2024). Evidence-based guideline: premature ovarian insufficiency. Hum. Reproduction Open2024 (4) hoae065. 10.1093/hropen/hoae065

• OrstavikK. H. (2009). X chromosome inactivation in clinical practice. Hum. Genetics126 (3) 363—373. 10.1007/s00439-009-0670-5

• PelusoJ. J. (2013). Progesterone receptor membrane component 1 and its role in ovarian follicle growth. Front. Neuroscience7، 99. 10.3389/fnins.2013.00099

• RiggsE. R.AndersenE. F.CherryA. M.KantarciS.KearneyH.PatelA.et al (2020). Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet. Medicine Official Journal Am. Coll. Med. Genet.22 (2) 245—257. 10.1038/s41436-019-0686-8

• ShinO. H.HanW.WangY.SüdhofT. C. (2005). Evolutionarily conserved multiple C2 domain proteins with two transmembrane regions (MCTPs) and unusual Ca2+ binding properties. J. Biological Chemistry280 (2) 1641—1651. 10.1074/jbc.M407305200

• SnyderM. W.SimmonsL. E.KitzmanJ. O.CoeB. P.HensonJ. M.DazaR. M.et al (2015). Copy-number variation and false positive prenatal aneuploidy screening results. N. Engl. Journal Medicine372 (17) 1639—1645. 10.1056/NEJMoa1408408

• TanoshimaM.TanoshimaR.TakaseH.YamamotoD.AokiS.SakakibaraH.et al (2025). Karyotype and phenotype association in Turner syndrome with non-mosaic X chromosome structural rearrangements: systematic review. Congenit. Anomalies65 (1) e70002. 10.1111/cga.70002

• TarchiniB.Longo-GuessC.TianC.TadenevA. L. D.DevanneyN.JohnsonK. R. (2018). A spontaneous mouse deletion in Mctp1 uncovers a long-range cis-regulatory region crucial for NR2F1 function during inner ear development. Dev. Biology443 (2) 153—164. 10.1016/j.ydbio.2018.09.011

• TolmachevaE. N.KashevarovaA. A.FonovaE. A.SalyukovaO. A.SeitovaG. N.NazarenkoL. P.et al (2025). Prevalence of CNVs on the X chromosome in patients with neurodevelopmental disorders. Mol. Cytogenetics18 (1) 3. 10.1186/s13039-025-00703-w

• XueS.ShiW.HaoL. (2025). A rare variant of USP9X associated with female-restricted X-linked syndromic intellectual disability. Mol. Biology Reports53 (1) 88. 10.1007/s11033-025-11251-2