Contribution of Genomic Imbalance in Prenatal Congenital Anomalies of the Kidney and Urinary Tract: A Multi-Center Cohort Study.

OBJECTIVES: To investigate the diagnostic utility of copy-number variant (CNV) detection by chromosomal microarray analysis (CMA) and genotype-phenotype associations in prenatal congenital anomalies of the kidney and urinary tract (CAKUT). METHODS: This is a retrospective multi-center study of CNV analysis in 457 fetuses with ultrasound-detected CAKUT and normal karyotypes. Cohorts from published studies were included for further pooled analyses (N = 2746). A literature review of single-nucleotide variant (SNV) and small insertions and deletions (Indel) analysis by whole-exome sequencing was performed to investigate monogenic causes. RESULTS: In our multi-center cohort, 5.3% (24/457) of fetuses had pathogenic CNVs (pCNV); 3.9% (14/359) and 10.2% (10/98) in isolated and non-isolated CAKUT, respectively. Fetuses with isolated hyperechogenic kidneys (HEK) had the highest incidence of having pCNVs. In the literature review, 6.6% (180/2746) of fetuses carried pCNVs; 6.1% and 7.5% in isolated and non-isolated CAKUT, respectively. SNV/Indel analysis provided at least 16.5% (63/381) additional diagnostic yield beyond CNV analysis; 12.8% and 23.8% in isolated and non-isolated CAKUT, respectively. CONCLUSION: pCNVs comprise a significant proportion of genetic diagnostic findings in prenatal CAKUT, most commonly detected in fetuses with isolated HEK, MCDK, renal agenesis, and non-isolated CAKUT. Monogenic causes should be considered when karyotyping and CMA are nondiagnostic.

Detection of genomic variants by genome sequencing in foetuses with central nervous system abnormalities.

OBJECTIVE: Clinical validity of genome sequencing (GS) (>30×) has been preliminarily verified in the post-natal setting. This study is to investigate the potential utility of trio-GS as a prenatal test for diagnosis of central nervous system (CNS) anomalies. METHODS: We performed trio-based GS on a prospective cohort of 17 foetuses with CNS abnormalities. Single nucleotide variation (SNV), small insertion and deletion (Indel), copy number variation (CNV), structural variant (SV), and regions with absence of heterozygosity (AOH) were analyzed and classified according to ACMG guidelines. RESULTS: Trio-GS identified diagnostic findings in 29.4% (5/17) of foetuses, with pathogenic variants found in SON, L1CAM, KMT2D, and ASPM. Corpus callosum (CC) and cavum septum pellucidum (CSP) abnormalities were the most frequent CNS abnormalities (47.1%, 8/17) with a diagnostic yield of 50%. A total of 29.4% (5/17) foetuses had variants of uncertain significance (VUS). Particularly, maternal uniparental disomy 16 and a de novo mosaic 4p12p11 duplication were simultaneously detected in one foetus with abnormal sulcus development. In addition, parentally inherited chromosomal inversions were identified in two foetuses. CONCLUSION: GS demonstrates its feasibility in providing genetic diagnosis for foetal CNS abnormalities and shows the potential to expand the application to foetuses with other ultrasound anomalies in prenatal diagnosis.

Genome sequencing in the prenatal diagnosis of structural malformations in the fetus.

Prenatal genetic diagnosis has undergone two pivotal paradigm shifts, initially with the introduction of chromosomal microarray and subsequently with the advent of next-generation sequencing technologies (NGS). NGS technology has given rise to a multitude of applications, with gene panels, exome sequencing (ES), and genome sequencing (GS) emerging as highly promising tests for prenatal genetic investigations. These advanced approaches have demonstrated superior diagnostic rates when compared to conventional testing methods, showcasing the evolution and enhancement of prenatal genetic screening and diagnostic capabilities. With these ground-breaking innovations, NGS technologies have the potential to replace current standard practice in prenatal diagnosis. With the increasing use of prenatal sequencing, the need for better education and guidance on their applications grows. This chapter aims to illustrate the detection scope and feasibility of various NGS-based methods that are currently used in prenatal diagnosis.

Strategic Design and Mechanistic Understanding of Vacancy-Filling Heusler Thermoelectric Semiconductors.

Doping narrow-gap semiconductors is a well-established approach for designing efficient thermoelectric materials. Semiconducting half-Heusler (HH) and full-Heusler (FH) compounds have garnered significant interest within the thermoelectric field, yet the number of exceptional candidates remains relatively small. It is recently shown that the vacancy-filling approach is a viable strategy for expanding the Heusler family. Here, a range of near-semiconducting Heuslers, TiFexCuySb, creating a composition continuum that adheres to the Slater-Pauling electron counting rule are theoretically designed and experimentally synthesized. The stochastic and incomplete occupation of vacancy sites within these materials imparts continuously changing electrical conductivities, ranging from a good semiconductor with low carrier concentration in the endpoint TiFe0.67Cu0.33Sb to a heavily doped p-type semiconductor with a stoichiometry of TiFe1.00Cu0.20Sb. The optimal thermoelectric performance is experimentally observed in the intermediate compound TiFe0.80Cu0.28Sb, achieving a peak figure of merit of 0.87 at 923 K. These findings demonstrate that vacancy-filling Heusler compounds offer substantial opportunities for developing advanced thermoelectric materials.

Designs and Applications for the Multimodal Flexible Hybrid Epidermal Electronic Systems.

Research on the flexible hybrid epidermal electronic system (FHEES) has attracted considerable attention due to its potential applications in human-machine interaction and healthcare. Through material and structural innovations, FHEES combines the advantages of traditional stiff electronic devices and flexible electronic technology, enabling it to be worn conformally on the skin while retaining complex system functionality. FHEESs use multimodal sensing to enhance the identification accuracy of the wearer's motion modes, intentions, or health status, thus realizing more comprehensive physiological signal acquisition. However, the heterogeneous integration of soft and stiff components makes balancing comfort and performance in designing and implementing multimodal FHEESs challenging. Herein, multimodal FHEESs are first introduced in 2 types based on their different system structure: all-in-one and assembled, reflecting totally different heterogeneous integration strategies. Characteristics and the key design issues (such as interconnect design, interface strategy, substrate selection, etc.) of the 2 multimodal FHEESs are emphasized. Besides, the applications and advantages of the 2 multimodal FHEESs in recent research have been presented, with a focus on the control and medical fields. Finally, the prospects and challenges of the multimodal FHEES are discussed.

Enhanced Thermoelectric Performance in Vacancy-Filling Heuslers due to Kondo-Like Effect.

To improve thermoelectric efficiency, various tactics have been employed with considerable success to decouple intertwined material attributes. However, the integration of magnetism, derived from the unique spin characteristic that other methods cannot replicate, has been comparatively underexplored and presents an ongoing intellectual challenge. A previous research has shown that vacancy-filling Heuslers offer a highly adaptable framework for modulating thermoelectric properties. Here, it is demonstrated how intrinsic magnetic-electrical-thermal coupling can enhance the thermoelectric performance of vacancy-filling Heusler alloys. The materials, Nb0.75Ti0.25FeCrxSb with 0 ≤ x ≤ 0.1, feature a fraction of magnetic Cr ions that randomly occupy the vacancy sites of the Nb0.75Ti0.25FeSb half-Heusler matrix. These alloys achieve a remarkable thermoelectric figure of merit (zT) of 1.21 at 973 K, owing to increased Seebeck coefficient and decreased thermal conductivity. The mechanism is primarily due to the introduction of magnetism, which increases the density-of-states effective mass (reaching levels up to 15 times that of a free electron's mass) and simultaneously reduces the electronic thermal conductivity. Mass and strain-field fluctuations further reduce the lattice thermal conductivity. Even higher zT values can potentially be achieved by carefully balancing electron mobility and effective mass. This work underscores the substantial prospects for exploiting magnetic-electrical-thermal synergies in cutting-edge thermoelectric materials.

Photothermal therapy: a novel potential treatment for prostate cancer.

Prostate cancer (PCa) is a leading cause of cancer-related death in men, and most PCa patients treated with androgen deprivation therapy will progress to metastatic castration-resistant prostate cancer (mCRPC) due to the lack of efficient treatment. Recently, lots of research indicated that photothermal therapy (PTT) was a promising alternative that provided an accurate and efficient prostate cancer therapy. A photothermic agent (PTA) is a basic component of PPT and is divided into organic and inorganic PTAs. Besides, the combination of PTT and other therapies, such as photodynamic therapy (PDT), immunotherapy (IT), chemotherapy (CT), etc., provides an more efficient strategy for PCa therapy. Here, we introduce basic information about PTT and summarize the PTT treatment strategies for prostate cancer. Based on recent works, we think the combination of PPT and other therapies provides a novel possibility for PCa, especially CRPC clinical treatment.

Decreasing the Carrier Concentration of ZrNiSn: An Opposite Way to the Best N-Type Half-Heusler Thermoelectrics.

N-type ZrNiSn-based alloys reach a record thermoelectric figure of merit zT ≈1.2 by increasing the carrier concentration to 4-5 × 1020 cm-3 . In this work, It is reported that a comparable zT can also be realized in trace Ru-doped ZrNiSn-based alloy at even lower temperature by decreasing the carrier concentration. Compared to the previously reported Co doping, the doping of Ru results in a more effective reduction in carrier concentration, and thus higher Seebeck coefficient, lower electronic thermal conductivity, and enhanced thermoelectric performance. The electronic specific heat coefficient of the ZrNi1- x Rux Sn sample remains constant with increasing Ru content, indicating no obvious change in the density of states effective mass. Theoretical calculations show that the doping of Ru has negligible effect on the bottom of conduction band. The lattice thermal conductivity is further reduced by alloying Ti and Hf at the Zr site, and the bipolar diffusion is suppressed by doping of 0.5 at.% Sb. As a result, Ti0.25 Zr0.5 Hf0.25 Ni0.99 Ru0.01 Sn0.995 Sb0.005 reaches not only a zT value of 1.1 at 773 K but also a record average zT value of 0.8 in 300 to 873 K, demonstrating the effectiveness of trace Ru doping on boosting the thermoelectric performance of ZrNiSn-based alloys.

Prenatal diagnosis of polycystic kidney caused by biallelic hypomorphic variants in the PKD1 gene.

Heterozygous loss-of-function variants in the PKD1 gene are commonly associated with adult-onset autosomal dominant polycystic kidney disease (ADPKD), where the formation of renal cysts depends on the dosage of the PKD1 gene. Biallelic null PKD1 variants are not viable, but biallelic hypomorphic variants could lead to early-onset PKD. We report a non-consanguineous Chinese family with recurrent fetal polycystic kidney and negative findings in the coding region of the PKHD1 gene or chromosomal microarray analysis. Trio exome analysis revealed compound heterozygous variants of uncertain significance in the PKD1 gene in the index pregnancy: a novel paternally inherited c.7863 + 5G > C and a maternally inherited c.9739C > T, p.(Arg3247Cys). Segregation analysis through long-range PCR followed by nested PCR and Sanger sequencing confirmed another affected fetus had both variants, while the other two normal siblings and the parents carried either variant. Thus, these two variants, both of which were hypomorphic as opposed to null variants, co-segregated with prenatal onset polycystic kidney disease in this family. Functional studies are needed to further determine the impact of these two variants. Our findings highlight the biallelic inheritance of hypomorphic PKD1 variants causing prenatal onset polycystic kidney disease, which provides a better understanding of phenotype-genotype correlation and valuable information for reproductive counseling.

Identification of cryptic balanced translocations in couples with unexplained recurrent pregnancy loss based upon embryonic PGT-A results.

PURPOSE: The goal of this study is to determine whether any balanced translocation (BT) had been missed by previous karyotyping in patients with unexplained recurrent pregnancy loss (uRPL). METHODS: This case series included 48 uRPL-affected couples with normal karyotypes. The embryos from these couples have all undergone preimplantation testing for aneuploidies (PGT-A). Based on the PGT-A's results, 48 couples could be categorized into two groups: 17 couples whose multiple embryos were detected with similar structural variations (SVs, segmental/complete) and 31 couples without such findings but who did not develop any euploid embryo despite at least three high-quality blastocysts being tested. The peripheral blood sample of each partner was then collected for mate-pair sequencing (MPseq) to determine whether any of them were BT carriers. RESULTS: MPseq analyses identified 13 BTs in the 17 couples whose multiple embryos had similar SVs detected (13/17, 76.47%) and three BTs in the 31 couples without euploid embryo obtained (3/31, 9.7%). Among the 16 MPseq-identified BTs, six were missed due to the limited resolution of G-banding karyotyping analysis, and the rest were mostly owing to the similar banding patterns and/or comparable sizes shared by the two segments exchanged. CONCLUSION: A normal karyotype does not eliminate the possibility of carrying BT for couples with uRPL. The use of PGT-A allows us to perceive the "carrier couples" missed by karyotyping analysis, providing an increased risk of finding cryptic BTs if similar SVs are always detected on two chromosomes among multiple embryos. Nonetheless, certain carriers with translocated segments of sub-resolution may still go unnoticed.

Single-cell analysis reveals specific neuronal transition during mouse corticogenesis.

Background: Currently, the mechanism(s) underlying corticogenesis is still under characterization. Methods: We curated the most comprehensive single-cell RNA-seq (scRNA-seq) datasets from mouse and human fetal cortexes for data analysis and confirmed the findings with co-immunostaining experiments. Results: By analyzing the developmental trajectories with scRNA-seq datasets in mice, we identified a specific developmental sub-path contributed by a cell-population expressing both deep- and upper-layer neurons (DLNs and ULNs) specific markers, which occurred on E13.5 but was absent in adults. In this cell-population, the percentages of cells expressing DLN and ULN markers decreased and increased, respectively, during the development suggesting direct neuronal transition (namely D-T-U). Whilst genes significantly highly/uniquely expressed in D-T-U cell population were significantly enriched in PTN/MDK signaling pathways related to cell migration. Both findings were further confirmed by co-immunostaining with DLNs, ULNs and D-T-U specific markers across different timepoints. Furthermore, six genes (co-expressed with D-T-U specific markers in mice) showing a potential opposite temporal expression between human and mouse during fetal cortical development were associated with neuronal migration and cognitive functions. In adult prefrontal cortexes (PFC), D-T-U specific genes were expressed in neurons from different layers between humans and mice. Conclusion: Our study characterizes a specific cell population D-T-U showing direct DLNs to ULNs neuronal transition and migration during fetal cortical development in mice. It is potentially associated with the difference of cortical development in humans and mice.

Low-Pass Genome Sequencing-Based Detection of Paternity: Validation in Clinical Cytogenetics.

Submission of a non-biological parent together with a proband for genetic diagnosis would cause a misattributed parentage (MP), possibly leading to misinterpretation of the pathogenicity of genomic variants. Therefore, a rapid and cost-effective paternity/maternity test is warranted before genetic testing. Although low-pass genome sequencing (GS) has been widely used for the clinical diagnosis of germline structural variants, it is limited in paternity/maternity tests due to the inadequate read coverage for genotyping. Herein, we developed rapid paternity/maternity testing based on low-pass GS with trio-based and duo-based analytical modes provided. The optimal read-depth was determined as 1-fold per case regardless of sequencing read lengths, modes, and library construction methods by using 10 trios with confirmed genetic relationships. In addition, low-pass GS with different library construction methods and 1-fold read-depths were performed for 120 prenatal trios prospectively collected, and 1 trio was identified as non-maternity, providing a rate of MP of 0.83% (1/120). All results were further confirmed via quantitative florescent PCR. Overall, we developed a rapid, cost-effective, and sequencing platform-neutral paternity/maternity test based on low-pass GS and demonstrated the feasibility of its clinical use in confirming the parentage for genetic diagnosis.

Fertility preservation in pediatric healthcare: a review.

Survival rates for children and adolescents diagnosed with malignancy have been steadily increasing due to advances in oncology treatments. These treatments can have a toxic effect on the gonads. Currently, oocyte and sperm cryopreservation are recognized as well-established and successful strategies for fertility preservation for pubertal patients, while the use of gonadotropin-releasing hormone agonists for ovarian protection is controversial. For prepubertal girls, ovarian tissue cryopreservation is the sole option. However, the endocrinological and reproductive outcomes after ovarian tissue transplantation are highly heterogeneous. On the other hand, immature testicular tissue cryopreservation remains the only alternative for prepubertal boys, yet it is still experimental. Although there are several published guidelines for navigating fertility preservation for pediatric and adolescent patients as well as transgender populations, it is still restricted in clinical practice. This review aims to discuss the indications and clinical outcomes of fertility preservation. We also discuss the probably effective and efficient workflow to facilitate fertility preservation.

A pilot investigation of low-pass genome sequencing identifying site-specific variation in chromosomal mosaicisms by a multiple site sampling approach in first-trimester miscarriages.

STUDY QUESTION: Can multiple-site low-pass genome sequencing (GS) of products of conception (POCs) improve the detection of genetic abnormalities, especially heterogeneously distributed mosaicism and homogeneously distributed mosaicism in first-trimester miscarriage? SUMMARY ANSWER: Multiple-site sampling combined with low-pass GS significantly increased genetic diagnostic yield (77.0%, 127/165) of first-trimester miscarriages, with mosaicisms accounting for 17.0% (28/165), especially heterogeneously distributed mosaicisms (75%, 21/28) that are currently underappreciated. WHAT IS KNOWN ALREADY: Aneuploidies are well known to cause first-trimester miscarriage, which are detectable by conventional karyotyping and next-generation sequencing (NGS) on a single-site sampling basis. However, there are limited studies demonstrating the implications of mosaic genetic abnormalities in first-trimester miscarriages, especially when genetic heterogeneity is present in POCs. STUDY DESIGN, SIZE, DURATION: This is a cross-sectional cohort study carried out at a university-affiliated public hospital. One hundred seventy-four patients diagnosed with first-trimester miscarriage from December 2018 to November 2021 were offered ultrasound-guided manual vacuum aspiration (USG-MVA) treatment. Products of conception were subjected to multiple-site low-pass GS for the detection of chromosomal imbalances. PARTICIPANTS/MATERIALS, SETTING, METHODS: For each POC, multiple sites of villi (three sites on average) were biopsied for low-pass GS. Samples with maternal cell contamination (MCC) and polyploidy were excluded based on the quantitative fluorescence polymerase chain reaction (QF-PCR) results. The spectrum of chromosomal abnormalities, including mosaicism (heterogeneously distributed and homogeneously distributed) and constitutional abnormalities was investigated. Chromosomal microarray analysis and additional DNA fingerprinting were used for validation and MCC exclusion. A cross-platform comparison between conventional karyotyping and our multiple-site approach was also performed. MAIN RESULTS AND THE ROLE OF CHANCE: One hundred sixty-five POCs (corresponding to 490 DNA samples) were subjected to low-pass GS. Genetic abnormalities were detected in 77.0% (127/165) of POCs by our novel approach. Specifically, 17.0% (28/165) of cases had either heterogeneously distributed mosaicism (12.7%, 21/165) or homogeneously distributed mosaicism (6.1%, 10/165) (three cases had both types of mosaicism). The remaining 60.0% (99/165) of cases had constitutional abnormalities. In addition, in the 71 cases with karyotyping performed in parallel, 26.8% (19/71) of the results could be revised by our approach. LIMITATIONS, REASONS FOR CAUTION: Lack of a normal gestational week-matched cohort might hinder the establishment of a causative link between mosaicisms and first-trimester miscarriage. WIDER IMPLICATIONS OF THE FINDINGS: Low-pass GS with multiple-site sampling increased the detection of chromosomal mosaicisms in first-trimester miscarriage POCs. This innovative multiple-site low-pass GS approach enabled the novel discovery of heterogeneously distributed mosaicism, which was prevalent in first-trimester miscarriage POCs and frequently observed in preimplantation embryos, but is currently unappreciated by conventional single-site cytogenetic investigations. STUDY FUNDING/COMPETING INTEREST(S): This work was supported partly by Research Grant Council Collaborative Research Fund (C4062-21GF to K.W.C), Science and Technology Projects in Guangzhou (202102010005 to K.W.C), Guangdong-Hong Kong Technology Cooperation Funding Scheme (TCFS), Innovation and Technology Fund (GHP/117/19GD to K.W.C), HKOG Direct Grant (2019.050 to J.P.W.C), and Hong Kong Health and Medical Research Fund (05160406 to J.P.W.C). The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Mate-pair genome sequencing reveals structural variants for idiopathic male infertility.

Currently, routine genetic investigation for male infertility includes karyotyping analysis and PCR for Y chromosomal microdeletions to provide prognostic information such as sperm retrieval success rate. However, over 85% of male infertility remain idiopathic. We assessed 101 male patients with primary infertility in a retrospective cohort analysis who have previously received negative results from standard-of-care tests. Mate-pair genome sequencing (large-insert size library), an alternative long-DNA sequencing method, was performed to detect clinically significant structural variants (SVs) and copy-number neutral absence of heterozygosity (AOH). Candidate SVs were filtered against our in-house cohort of 1077 fertile men. Genes disrupted by potentially clinically significant variants were correlated with single-cell gene expression profiles of human fetal and postnatal testicular developmental lineages and adult germ cells. Follow-up studies were conducted for each patient with clinically relevant finding(s). Molecular diagnoses were made in 11.1% (7/63) of patients with non-obstructive azoospermia and 13.2% (5/38) of patients with severe oligozoospermia. Among them, 12 clinically significant SVs were identified in 12 cases, including five known syndromes, one inversion, and six SVs with direct disruption of genes by intragenic rearrangements or complex insertions. Importantly, a genetic defect related to intracytoplasmic sperm injection (ICSI) failure was identified in a patient with non-obstructive azoospermia, illustrating the additional value of an etiologic diagnosis in addition to determining sperm retrieval rate. Our study reveals a landscape of various genomic variants in 101 males with idiopathic infertility, not only advancing understanding of the underlying mechanisms of male infertility, but also impacting clinical management.

TEDD: a database of temporal gene expression patterns during multiple developmental periods in human and model organisms.

Characterization of the specific expression and chromatin profiles of genes enables understanding how they contribute to tissue/organ development and the mechanisms leading to diseases. Whilst the number of single-cell sequencing studies is increasing dramatically; however, data mining and reanalysis remains challenging. Herein, we systematically curated the up-to-date and most comprehensive datasets of sequencing data originating from 2760 bulk samples and over 5.1 million single-cells from multiple developmental periods from humans and multiple model organisms. With unified and systematic analysis, we profiled the gene expression and chromatin accessibility among 481 cell-types, 79 tissue-types and 92 timepoints, and pinpointed cells with the co-expression of target genes. We also enabled the detection of gene(s) with a temporal and cell-type specific expression profile that is similar to or distinct from that of a target gene. Additionally, we illustrated the potential upstream and downstream gene-gene regulation interactions, particularly under the same biological process(es) or KEGG pathway(s). Thus, TEDD (Temporal Expression during Development Database), a value-added database with a user-friendly interface, not only enables researchers to identify cell-type/tissue-type specific and temporal gene expression and chromatin profiles but also facilitates the association of genes with undefined biological functions in development and diseases. The database URL is https://TEDD.obg.cuhk.edu.hk/.

The Burden and Benefits of Knowledge: Ethical Considerations Surrounding Population-Based Newborn Genome Screening for Hearing.

Recent advances in genomic sequencing technologies have expanded practitioners' utilization of genetic information in a timely and efficient manner for an accurate diagnosis. With an ever-increasing resource of genomic data from progress in the interpretation of genome sequences, clinicians face decisions about how and when genomic information should be presented to families, and at what potential expense. Presently, there is limited knowledge or experience in establishing the value of implementing genome sequencing into newborn screening. Herein we provide insight into the complexities and the burden and benefits of knowledge resulting from genome sequencing of newborns.

Investigation of Chromosomal Structural Abnormalities in Patients With Undiagnosed Neurodevelopmental Disorders.

Background: Structural variations (SVs) are various types of the genomic rearrangements encompassing at least 50 nucleotides. These include unbalanced gains or losses of DNA segments (copy number changes, CNVs), balanced rearrangements (such as inversion or translocations), and complex combinations of several distinct rearrangements. SVs are known to play a significant role in contributing to human genomic disorders by disrupting the protein-coding genes or the interaction(s) with cis-regulatory elements. Recently, different types of genome sequencing-based tests have been introduced in detecting various types of SVs other than CNVs and regions with absence of heterozygosity (AOH) with clinical significance. Method: In this study, we applied the mate-pair low pass (∼4X) genome sequencing with large DNA-insert (∼5 kb) in a cohort of 100 patients with neurodevelopmental disorders who did not receive informative results from a routine CNV investigation. Read-depth-based CNV analysis and chimeric-read-pairs analysis were used for CNV and SV analyses. The region of AOH was indicated by a simultaneous decrease in the rate of heterozygous SNVs and increase in the rate of homozygous SNVs. Results: First, we reexamined the 25 previously reported CNVs among 24 cases in this cohort. The boundaries of these twenty-five CNVs including 15 duplications and 10 deletions detected were consistent with the ones indicated by the chimeric-read-pairs analysis, while the location and orientation were determined in 80% of duplications (12/15). Particularly, one duplication was involved in complex rearrangements. In addition, among all the 100 cases, 10% of them were detected with rare or complex SVs (>10 Kb), and 3% were with multiple AOH (≥5 Mb) locating in imprinting chromosomes identified. In particular, one patient with an overall value of 214.5 Mb of AOH identified on 13 autosomal chromosomes suspected parental consanguinity. Conclusion: In this study, mate-pair low-pass GS resolved a significant proportion of CNVs with inconclusive significance, and detected additional SVs and regions of AOH in patients with undiagnostic neurodevelopmental disorders. This approach complements the first-tier CNV analysis for NDDs, not only by increasing the resolution of CNV detection but also by enhancing the characterization of SVs and the discovery of potential causative regions (or genes) contributory to could be complex in composition NDDs.

Corrigendum: SVInterpreter: A Comprehensive Topologically Associated Domain Based Clinical Outcome Prediction Tool for Balanced and Unbalanced Structural Variants.

[This corrects the article DOI: 10.3389/fgene.2021.757170.].