Newborn Genomic Screening Detects Chromosomal Aneuploidies

doi:10.21203/rs.3.rs-4880901/v1

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Newborn Genomic Screening Detects Chromosomal Aneuploidies

https://doi.org/10.21203/rs.3.rs-4880901/v1

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The application of next-generation sequencing (NGS) technology is increasingly used in newborn screening (NBS) to detect monogenic disorders. However, its capability to identify chromosomal aneuploidies and its potential clinical value have not been fully explored. This study investigates the feasibility of using an NGS panel for aneuploidy screening and examines the incidence of aneuploidies in newborns. We designed an NBS panel targeting 142 genes associated with 128 disorders and conducted chromosomal copy number analysis on 29,601 newborns across eight hospitals in China. The presence of chromosomal aneuploidies was confirmed through karyotyping or genome sequencing, and follow-up visits were conducted to assess prenatal screening outcomes and postnatal phenotypes. Among the 29,601 newborns, 47 were identified with various aneuploidies. Further investigation confirmed 30 of these cases, yielding a positive predictive value (PPV) of 100%. The estimated incidence of aneuploidies among live births was 0.16%, with significant regional discrepancies ranging from 0.04–0.23%. Sex chromosome aneuploidy (SCA) was the most prevalent at 0.15%, while trisomy 21 occurred at a lower rate of 0.01%. The NBS panel demonstrated potential effectiveness and accuracy in detecting chromosomal aneuploidies, suggesting it could play a valuable role in future genetic NBS clinical practice.

Health sciences/Health care/Public health/Population screening

Health sciences/Medical research/Epidemiology

Newborn screening

Targeted genomic sequencing

Aneuploidy

Trisomy 21

Sex chromosome aneuploidy

Chromosomal aneuploidy has profound effects on human development and health, being one of the leading causes of developmental disorders and congenital anomalies. ^{1, 2} The majority of human aneuploid embryos typically undergo early developmental arrest or miscarriage, with an estimated 50% of first trimester miscarriages attributed to chromosomal abnormalities. ^{3, 4} However, specific types such as trisomy 21 (T21, Down syndrome), trisomy 18 (T18, Edwards Syndrome) and trisomy 13 (T13, Patau syndrome) and sex chromosome aneuploidy (SCA), includes monosomy X (Turner syndrome, TS), XXY (Klinefelter syndrome, KS), XXX (triple X syndrome) and XYY (Jacobs syndrome, JS), can result in live births. ^{5, 6} These conditions are associated with a wide range of clinical manifestations, from intellectual disability and developmental delays to various physical anomalies and increased risk of other health issues such as congenital heart defects.^7–10Early screening, diagnosis and intervention for these aneuploidies are critical for easing the burden on pregnant women and improving outcomes.

Non-invasive prenatal testing (NIPT) has become the most widely adopted clinical approach for screening fetal aneuploidies and is now a standard healthcare practice in many countries.¹¹ NIPT offers high sensitivity and specificity for detecting common chromosomal abnormalities. Specifically, recent studies indicate that the sensitivity for T21 and T18 is over 98%, for T13 is approximately 100%, all with a specificity exceeding 99%.¹² Additionally, the detection rate for SCA is also greater than 99%. Despite these high detection rates, some fetal chromosomal aneuploidies may still be missed due to factors such as low fetal DNA fraction (less than 4%), mosaicism, or technical limitations.^13–15 Therefore, although NIPT provide powerful tools for prenatal screening, comprehensive efforts after delivery are still necessary for effective diagnosis and management of fetal aneuploidies.

Recently, there is a growing trend of applying targeted genomic sequencing in newborn screening (NBS).¹⁶ Several research groups have reported important advances in targeted sequencing-based screening for neonatal monogenic diseases ^17–19. Targeted genomic sequencing allows for the simultaneous detection of multiple genetic conditions with high accuracy, making it a promising tool for comprehensive newborn screening. Even though that the efficacy of targeted genomic sequencing in preimplantation genetic testing for aneuploidy has been unequivocally validated^{20, 21}, the application of newborn disease screening panels in neonatal aneuploidy detection remains unexplored and awaits empirical validation.

In this study, we performed targeted genomic sequencing on a prospective cohort of nearly 30,000 newborns utilizing a universal NBS gene panel ¹⁷, followed by a specific bioinformatic pipeline for aneuploidy detection. Our study aims to evaluate the effectiveness of this NBS panel in detecting neonatal aneuploidy. To our knowledge, this represents the first attempt to apply gene panel sequencing for the detection of neonatal aneuploidy.

Study design and participants

This is a national multi-center NBS program involving eight hospitals (Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Inner Mongolia Maternity and Child Health Care Hospital, Shijiazhuang Maternity and Child Health Hospital, Jinan Maternity and Child Care Hospital, the First People's Hospital of Yunnan Province, Guangzhou Women and Children's Medical Center, Chongqing Maternal and Child Health Hospital and Hainan Women and Children's Medical Center) representing different regions of China. The recruitment methods, exclusion and inclusion criteria for the newborns have been described in detail in our previous study ¹⁰. Between February 2021 and December 2021, 29,989 newborns were prospectively recruited with written informed consent from their parents. All newborns were tested for biochemical and genetic NBS simultaneously. Approval was obtained from the institutional review board of each center.

The study design encompassed the collection of dried blood spots (DBS) samples from a total of 29,989 newborns. These samples underwent targeted genomic sequencing, and 388 samples that failed quality control (QC) were excluded. To ensure the accuracy of our results, positive cases identified through sequencing underwent follow-up confirmation using karyotyping or genome sequencing methods.

Targeted genomic sequencing

A total of 142 genes associated with 128 disorders were selected as targets of the NBS panel. Targeted genomic sequencing was performed as described before ¹⁰. In brief, Genomic DNA was extracted from neonatal DSB in accordance with the standard protocol outlined in the DNA extraction kit instructions (QIAamp DNA Blood Midi Kit, Qiagen, Hilden, Germany). Sequencing libraries were constructed using custom IDT xGen probes and sequenced (100 paired ends) on MGISEQ-2000 (MGI, Shenzhen, China). The effective sequencing depth of the nuclear genome was ≥ 100X, and the 20X coverage of the target region was ≥ 95%, after removing low-quality reads and low-coverage reads.

Chromosome copy number analysis

Chromosome copy number was analyzed according to a previously published protocol ¹⁵. The clean reads were aligned to the human reference genome (hg19/GRCh37) using the Burrows-Wheeler Aligner (BWA). Aneuploidies were analyzed by BatCNV. The mean depths of given sliding windows based on target regions were calculated, followed by GC bias correction and batch bias correction for sequencing depth for each sample to reduce data fluctuations. Finally, the copy number of continuous chromosome regions was determined by analyzing changes in read depth within the targeted region using a hidden Markov model (HMM). The pipeline of chromosome copy number analysis was is shown in Supplement Figure S1.

Aneuploidy confirmation

The maternal outpatient medical records during pregnancy were firstly checked. If invasive prenatal testing had been performed, the karyotyping or genome sequencing results of amniotic fluid was used for positive aneuploidy confirmation. The remaining positive newborns were recalled for peripheral blood sampling and karyotyping.

Clinical follow-up

Follow-ups were performed by clinicians at each hospital. The clinicians retrieved the information of prenatal screening, pregnancy outcomes and abnormal postnatal presentations from the local medical recording system. For cases where the information was unavailable, the clinicians conducted phone interviews. Follow-up was ended at March 2023.

Demographics of newborns

A total of 29,989 infants were recruited from eight NBS centers throughout China. After excluding data that failed the quality control, 29,601 (98.7%) newborns were included in subsequent chromosome copy number analysis. The demographic characteristics of these newborns were shown in Table 1.

Table 1

The demographic characteristic of 29,601 newborns in this study
Characteristic	No. (%)
Region of China
East^a	9,685 (32.7)
North^b	8,123 (27.5)
West^c	5,994 (20.2)
South^d	5,790 (19.6)
Sex
Male	15357 (51.9)
Female	14226 (48.1)
Unknown	18 (0.1)
Gestational weeks
Preterm (< 37 weeks)	1,309 (4.4)
Early term (37–38 weeks)	9,166 (31.0)
Full term (39–40 weeks)	16,476 (55.7)
Late term (41 weeks)	1,756 (5.9)
Post term (42 weeks and beyond)	40 (0.1)
Unknown	854 (2.9)
Birth weight
≤ 2499 g	974 (3.3)
2500–4000 g	26,361 (89.1)
> 4000 g	1,429 (4.8)
Unknown	837 (2.8)
a Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine; Jinan Maternity and Child Care Hospital.
b Shijiazhuang Maternal and Child Health Care Hospital; Inner Mongolia Maternity and Child Health Care Hospital.
c Guangzhou Woman and Children’s Medical Center; Hainan Woman and Children’s Medical Center.
d Chongqing Health Center for Women and Children; the First People’s Hospital of Yunnan Province.

NBS panel for aneuploidies detection and Validation

Among 29,601 newborns, 47 were identified as carrying different aneuploidies (Table 2). These aneuploidies comprised three cases of T21 and 44 cases of SCA, which were subclassified as 9 cases of Turner syndrome, 21 cases of Klinefelter's syndrome, eight cases of XXX syndrome, and six cases of XYY syndrome.

Table 2

Chromosomal aneuploidies detected in newborn genetic screening test.
Aneuploidies		NBS Screening positive	Clinical follow-up			PPV (%)
Aneuploidies		NBS Screening positive	Karyotype positive	Karyotype negative	Lost to follow-up	PPV (%)
T21		3	3	-	-	100
SCA	XO	9	4	-	5	100
	XXY/XXYY	21	15	-	6	100
	XXX	8	3	-	5	100
	XYY	6	5	-	1	100
Total		47	30	-	17	100
T21, trisomy 21; SCA, sex chromosome aneuploidy.

Of the positive cases, 30 (63.83%) were successfully followed up (Table 2). All 30 cases underwent karyotype analysis from amniotic fluid cells or peripheral blood (Supplement Table S1). The results from these analyses were consistent with the initial detections of aneuploidies, yielding a positive predictive value (PPV) of 100% for the NBS panel. Furthermore, the NBS panel is also capable of detecting mosaicism aneuploidies. By validation, 4 cases of mosaicism were identified with a minimum mosaic ratio of 40% (Supplement Table S2).

Comparison of NBS panel with other aneuploidies screening methods

The results of prenatal examinations and observations on neonatal abnormal phenotypes were collected from 30 positive cases that were successfully followed up. All these cases had undergone at least one traditional prenatal screening tests, including nuchal translucency (NT) measurement, maternal serum screening (MSS) or ultrasound examination. Only nine cases elected to undergo NIPT.(Table 3 and Supplement Table S1)

Table 3

Comparation of abnormal indication performance between NBS panel with other examinations.
Aneuploidies		NBS Screening positive	Traditional prenatal examinations						NIPT			Neonatal examinations indicators
			NT		MSS		Ultrasound		NIPT			Neonatal examinations indicators
			+	-	+	-	+	-	+	-	N.D.	+	-
T21		3	-	3	-	3	1	2	1	-	2	3	0
SCA	XO	4	-	4	2	2	2	2	2	-	2	3	1
	XXY/XXYY	15	1	14	2	13	2	13	-	-	15	1	14
	XXX	3	1	2	-	3	1	2	3	-	-	-	3
	XYY	5	1	4	1	4	1	4	3	-	2	-	5
Total		30	3	27	5	25	7	23	9	-	21	7	23
T21, trisomy 21; SCA, sex chromosome aneuploidy; “+” positive; “-” negative; NT, nuchal translucency; MSS, maternal serum screening; NIPT, non-invasive prenatal testing; N.D. not detected;

Among the three T21-positive newborns, only one case was indicated prenatally by both NIPT and ultrasound. The other two cases were not detected by traditional prenatal screening tests and did not undergo NIPT, resulting in a missed diagnosis during the prenatal period. However, all three newborns exhibited typical characteristics of Down syndrome that were identifiable after birth (Table 3 ).

Among the 27 SCA-positive newborns, abnormalities were detected in only a few cases by NT (n = 3), MSS (n = 5) and ultrasound (n = 6) (Table 3). All cases that underwent NIPT were accurately identified (n = 8) (Supplement Table S1). After birth, three cases of XO presented with notable abnormal phenotypes, one case of XXY showed testicular abnormalities, and the remaining newborns did not display any indications of chromosomal abnormalities (Table 3). Notably, those who had normal results from traditional prenatal screening tests, did not receive NIPT, and exhibited no abnormal phenotypes after birth, were completely missed in early diagnosis (as shown in Supplement Table S1, #12–22 and # 30).

Incidence of aneuploidies detected in the targeted NBS

The analysis of 29,601 newborns revealed an overall aneuploidy incidence of 0.16% (47/29601). This statistical data provides an overall overview of the occurrence of aneuploidy in newborns. A notable variation in this rate was observed across regions, with the First People's Hospital of Yunnan Province reporting the highest at 0.23%, compared to the lowest of 0.04% at the Shijiazhuang Maternal and Child Health Hospital (Fig. 1A). Excluding T21 cases, the incidence rate of SCA was 0.15% (44/29,601). Specifically, Turner's syndrome (TS, XO) had an incidence of 3.0 per 10,000, while Klinefelter's syndrome (KS, XXY) was the most prevalent SCA, affecting 7.1 per 10,000. The rates for Triple X syndrome (XXX) and XYY syndrome (XYY) were 2.7 and 2.0 per 10,000, respectively (Fig. 1B).

We performed targeted genome sequencing on nearly 30,000 newborns, providing an opportunity to assess the potential utility of these data in detecting aneuploidies. Previous studies have demonstrated the effectiveness of this approach for screening monogenic diseases using this approach. In this article, we conducted an in-depth analysis of the effectiveness of the NBS-targeted gene panel in aneuploidy screening. This study not only expands the scope of our original study but also provides a new perspective and methodology for early detection of neonatal aneuploidy.

Chromosomal aneuploidy screening, crucial for assessing fetal and newborn health, is primarily conducted in the prenatal stage. Among various prenatal screening methods, such as NIPT, NT measurement, MSS, and ultrasonography, NIPT demonstrates remarkable performance in detecting aneuploidies, particularly for trisomies 13, 18, and 21. However, its efficacy in detecting SCAs is less optimal, with widely varying sensitivities reported.¹¹ For instance, the sensitivity for X-monosomy ranges from 83.2–98.8%, while for other SCAs, it varies between 76.3% and 100%.^{11, 23–25} Furthermore, the PPV of NIPT for SCAs is reported to be less than 50%, substantially lower than the PPV of 91.8% for T21.¹² Despite its high accuracy, NIPT is not universally offered to all pregnant women but is typically reserved for those at high risk. This underscores the limitations of prenatal screening in fully guaranteeing newborn health. Moreover, aneuploidy detection is not a standard for newborns unless they exhibit overt phenotypic abnormalities or complex conditions. Many individuals with SCAs are not diagnosed early.²⁶

The gradual emergence of newborn genetic screening provides an opportunity to integrate aneuploidy screening into the process, which can be achieved by adding additional analysis without modifying the wet lab procedure. The potential value of newborn aneuploidy screening lies in its ability to serve as a secondary line of detection. While current prenatal screening methods are effective, they are not infallible, and some cases of aneuploidy, particularly SCAs, may be missed. Newborn screening ensures that cases not caught prenatally can still be identified early. This early detection is crucial for providing timely interventions and support to affected families, significantly improving outcomes for children with these conditions. Screening helps families make informed decisions and plan for necessary medical care and support, reducing the long-term burden on healthcare systems.

Our study, employing NBS-targeted gene panel sequencing, identified 47 potential cases of aneuploidy among 29,601 newborns. Of these, 30 were reliably confirmed through subsequent validation, demonstrating a remarkable PPV of 100% in aneuploidy detection. It is important to note that this PPV is based on the 30 confirmed cases out of the 47 initially detected. Therefore, while the PPV for the confirmed cases is 100%, it does not represent the entire cohort. This underscores the need for a complete follow-up of all detected cases to accurately determine the true PPV. Furthermore, the method proved capable of detecting mosaic aneuploidy at a minimum ratio of 40% in this study. This robust performance underscores the feasibility and efficacy of using gene panel sequencing for aneuploidy identification.

The analysis of 29,601 newborns revealed an overall aneuploidy incidence of 0.16% (47/29,601). This statistical data provides an overall overview of the occurrence of aneuploidy in newborns. A notable variation in this rate was observed across regions, with the First People's Hospital of Yunnan Province reporting the highest at 0.23% compared to the lowest of 0.04% at the Shijiazhuang Maternal and Child Health Hospital. Excluding T21 cases, the incidence rate of SCA was 0.15% (44/29,601). Specifically, Turner syndrome (TS, XO) had an incidence of 3.0 per 10,000, while Klinefelter syndrome (KS, XXY) was the most prevalent SCA, affecting 7.1 per 10,000. The rates for Triple X syndrome (XXX) and XYY syndrome were 2.7 and 2.0 per 10,000, respectively.

The rate of T21 (0.01%) in our study is significantly lower than that reported in recent national studies from Brazil ²⁷, the United States ²⁸, and Norway²⁹, which range from 0.04–0.15% (i.e., 4–15 per 10,000 births). This notable decrease in T21 occurrence can be attributed to the widespread use of NIPT. In contrast, the incidence of SCA in our study (0.15%) was comparable to previous reports⁵. However, a recent study in Zhejiang, China, reported an SCA incidence ranging from 1.70 to 7.30 cases per 10,000 births,³⁰ which is lower than the 15 cases per 10,000 newborns observed in our research. This discrepancy might be due to the Zhejiang study only including cases diagnosed during prenatal diagnosis or within 7 days of postpartum, whereas our study screened all enrolled newborns, providing a more accurate and comprehensive picture of SCA incidence.

The principles of newborn screening should focus on detecting serious conditions where early intervention can significantly improve prognosis.³¹ Traditional newborn screening is designed to identify conditions that, if untreated, would lead to severe health problems or death. However, the inclusion of SCAs in newborn screening panels is a subject of debate. While SCAs may not immediately threaten life, they can lead to significant developmental and health issues that benefit from early diagnosis and management.¹⁰ The value of screening for SCAs in the context of current prenatal testing practices lies in the ability to provide a safety net for cases missed prenatally, ensuring no child with a potentially manageable condition is left undiagnosed. This addition can complement prenatal screening, offering a more comprehensive approach to genetic health in the neonatal period.

Limitations

This study has two notable limitations. Firstly, the validation process did not cover all detectable chromosomes. Consequently, it remains uncertain whether the method can accurately detect chromosomal abnormalities beyond SCA and T21. Future research should aim to broaden the validation scope by utilizing samples such as clinically discarded specimens of umbilical cord blood, amniotic fluid, or villus tissue that have been previously confirmed to exhibit chromosomal abnormalities, thereby encompassing a wider spectrum of chromosomal aberrations. Secondly, the follow-up conducted in this study was insufficient, preventing the accurate calculation of sensitivity, specificity, and PPV. Therefore, more comprehensive follow-up assessments are required to ensure the robustness of the findings.

This study successfully employed NBS panel sequencing technology for the analysis of aneuploidy in newborns, demonstrating a high PPV of 100% among the confirmed cases. This high PPV indicates the potentially high efficacy and precision of this method in detecting chromosomal abnormalities. Our findings revealed an overall aneuploidy incidence of 0.16% among the nearly 30,000 newborns screened, with significant regional variations. This novel approach not only offers a promising new pathway for neonatal screening but also underscores the capability of genetic screening to simultaneously detect both single-gene disorders and chromosomal abnormalities. Moreover, our findings provide a more precise understanding of the incidence of neonatal aneuploidy within the framework of existing prenatal screening practices. Despite its limitations, this research represents a significant step forward in advancing neonatal screening methods. Future studies should focus on expanding the cohort size and improving follow-up rates to validate these findings further. Additionally, exploring the integration of this screening method into routine newborn screening programs and assessing its long-term impact on health outcomes will be crucial.

Funding

This study was supported by Application Technology Research and Development Project of Inner Mongolia Autonomous Region (2020GG0119 and 2021GG0130), Health science and technology project of Inner Mongolia Autonomous Region (202201137 and 202201138).

Data Availability

Due to privacy and ethical considerations, the raw data supporting this study are not publicly available. Detailed methods and comprehensive results are presented in the article.

Acknowledgments

We would like to express our gratitude to the institutions involved in this study. Their support and resources were invaluable to this research. We also acknowledge the assistance of our colleagues across these institutions who provided helpful insights and discussions, contributing significantly to the enhancement of this research.

Author Contribution

D. H, M. S, J. X, and B. Z. (Bo) conceived the study and participated in its design, data collection, analysis, and interpretation. D. H also drafted the manuscript.

C. H, J. F, J. M, B. Z. (Baosheng), and Y. H participated in the design of the study, and helped to revise the manuscript critically.

T. C, M. T, Y. Z, Y. Y, L. J, and X. L carried out the experiments, participated in data acquisition and analysis, and helped to draft the manuscript.

X. W, H. Z, L. H, and A. L take overall responsibility for the study. They conceived the project, participated in its design and coordination, and helped to draft and revise the manuscript. All authors read and approved the final manuscript. D. H, M. S, J. X and B. Z. (Bo) contributed equally to this work.

Ethical Approval

This study received ethical approval from the institutional review boards of the participating hospitals. Informed consent was obtained from all participants prior to their inclusion in the study.

Competing Interests

The authors declare no competing interests.

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There is no duality of interest

TableS1.docx
Prenatal screening information in follow-up data of aneuploidy cases.
TableS2.docx
NBS panel mosaic detection results and verification comparison.
FigureS1.jpg
The pipeline of chromosome copy number analysis. he newborn genetic screening test was carried out on a panel spans a l Mb target region of of the human genome.

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Newborn Genomic Screening Detects Chromosomal Aneuploidies

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Abstract

Figures

Introduction

Materials and Methods

Study design and participants

Targeted genomic sequencing

Chromosome copy number analysis

Aneuploidy confirmation

Clinical follow-up

Results

Demographics of newborns

NBS panel for aneuploidies detection and Validation

Comparison of NBS panel with other aneuploidies screening methods

Incidence of aneuploidies detected in the targeted NBS

Discussion

Limitations

Conclusion

Declarations

References

Additional Declarations

Supplementary Files

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