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. 2023 Jul 21;11(10):e2248. doi: 10.1002/mgg3.2248

11q13.3q13.4 deletion plus 9q21.13q21.33 duplication in an affected girl arising from a familial four‐way balanced chromosomal translocation

Qinxin Zhang 1, Yan Wang 1, Jing Zhou 1, Ran Zhou 1, An Liu 1, Lulu Meng 1, Xiuqing Ji 1, Ping Hu 1,✉, Zhengfeng Xu 1,✉
PMCID: PMC10568374  PMID: 37475652

Abstract

Background

We describe a 13‐year‐old girl with a 11q13.3q13.4 deletion encompassing the SHANK2 gene and a 9q21.13q21.33 duplication. She presented with pre‐ and postnatal growth retardation, global developmental delay, severe language delay, cardiac abnormalities, and dysmorphisms. Her maternal family members all had histories of reproductive problems.

Methods

Maternal family members with histories of reproductive problems were studied using G‐banded karyotyping and optical genome mapping (OGM). Long‐range PCR (LR‐PCR) and Sanger sequencing were used to confirm the precise break point sequences obtained by OGM.

Results

G‐banded karyotyping characterized the cytogenetic results as 46,XX,der(9)?del(9)(q21q22)t(9;14)(q22;q24),der(11)ins(11;?9)(q13;?q21q22),der(14)t(9;14). Using OGM, we determined that asymptomatic female family members with reproductive problems were carriers of a four‐way balanced chromosome translocation. Their karyotype results were further refined as 46,XX,der(9)del(9)(q21.13q21.33)t(9;14)(q21.33;q22.31),der(11)del(11)(q13.3q13.4)ins(11;9)(q13.3;q21.33q21.13),der(14)t(9:14)ins(14;11)(q23.1;q13.4q13.3). Thus, we confirmed that the affected girl inherited the maternally derived chromosome 11. Furthermore, using LR‐PCR, we showed that three disease‐related genes (TMC1, NTRK2, and KIAA0586) were disrupted by the breakpoints.

Conclusions

Our case highlights the importance of timely parental origin testing for patients with rare copy number variations, as well as the accurate characterization of balanced chromosomal rearrangements in families with reproductive problems. In addition, our case demonstrates that OGM is a useful clinical application for analyzing complex structural variations within the human genome.

Keywords: balanced chromosomal translocation, optical genome mapping, reproductive problems

Here, we present a 13‐year‐old girl with pre‐ and postnatal growth retardation, global developmental delay, severe language delay, cardiac abnormalities, and dysmorphisms from a family with serious reproductive problems. Optical genome mapping revealing a complex four‐way balanced chromosomal translocation involving five break points at three chromosomes in this family. And the affected proband carries one of the maternally derived chromosomes, der(11)del(11)(q13.3q13.4)ins(11;9)(q13.3;q21.33q21.13).

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1. INTRODUCTION

Balanced chromosomal translocations involve the rearrangement and rejoining of chromosomes after breakage and lead to the generation of de novo derivative chromosomes. Balanced chromosomal translocations are not accompanied by the gain or loss of chromosomal segments (Wilch & Morton, 2018). Carriers with balanced chromosomal translocations lack obvious clinical phenotypes unless the translocation break points disrupt a disease‐causing gene(s). Nonetheless, balanced translocations carried by either parent can cause reproductive problems, including infertility, recurrent miscarriage, and the birth of phenotypically abnormal offspring.

At present, chromosomal microarray analysis (CMA) is the first‐line diagnostic method for detecting disease‐causing copy number variations (CNVs) in phenotypically abnormal offspring or products of conception. Following CMA, cytogenetic diagnostic techniques such as fluorescence in situ hybridization (FISH) or karyotyping are conducted on phenotypically normal parents to test whether the pathogenic CNVs are caused by balanced chromosomal rearrangements in either parent. FISH requires the preparation of specific, custom‐made fluorescence probes for relatively rare CNV regions and is not applicable to highly accurate analyses at a genome‐wide level. Thus, convenient detection of suspected balanced chromosomal rearrangements mainly relies on G‐banded karyotyping. However, the low resolution (~5 Mb) of this technique means that some cryptic translocations and complex balanced translocations involving multiple chromosomal breakpoints may not be accurately identified.

The above shortcomings mean that a comprehensive and accurate cytogenetic diagnostic technique is needed in clinical practice. Optical genome mapping (OGM) has the potential to accurately detect all types of chromosomal rearrangements >500 bp as a stand‐alone testing platform. Recently, the superiority of OGM in detecting chromosomal rearrangements was confirmed in couples with reproductive problems (Dai et al., 2022; Wang et al., 2020; Zhang et al., 2023). Herein, we report the use of OGM to reveal a complex four‐way balanced chromosomal translocation in a three‐generation family with a history of reproductive problems. The translocation involved five break points at three chromosomes. In addition, we report a girl in this family who inherited a derivative chromosome 11 and presented phenotypic abnormalities.

2. MATERIALS AND METHODS

2.1. Ethical compliance

This study was conducted according to the Declaration of Helsinki principles and approved by the medical ethics committee of Nanjing Maternity and Child Health Care Hospital (2021KY‐118). Peripheral blood samples were collected from the proband and the proband's parents, maternal grandmother, and maternal aunt after written informed consent was obtained for diagnostic testing and research studies. The proband's parents agreed to disclose photographs of the proband's face for research purposes.

2.2. SNP array assay

The human cyto12 single nucleotide polymorphism (SNP) array (Illumina, USA), comprising around 300,000 SNPs, was used to conduct a whole‐genome scan on the proband as previously described (Halder et al., 2012). SNP array tests were performed according to the manufacturer's protocol (Illumina, USA), chromosomal karyotype analysis was carried out using KaryoStudio V 1.3.11 (Illumina, USA), and GenomeStudio V2011.1 (Illumina, USA).

2.3. G‐banded karyotyping

Peripheral blood samples were collected for cell culture followed by karyotyping analysis. G‐banding of metaphase chromosomes was performed using Giemsa staining. For each patient, the numbers of chromosomes in 30 metaphase mitotic figures were counted using optical microscopy (OLYMPUS, Tokyo, Japan), and the karyotypes of 10 cells in mitotic metaphase were analyzed using CytoVision software (Leica Biosystems GmbH, Nussloch, Germany). This procedure was repeated for the two cases of abnormal karyotype. Chromosomal abnormalities were described according to the International System for Human Molecular Cytogenomic Nomenclature (ISCN).

2.4. Optical genome mapping

High molecular weight genomic DNA was isolated using the Bionano Prep™ Blood and Cell Culture DNA Isolation Kit (Bionano Genomics, San Diego, USA) from fresh blood samples collected in EDTA tubes. Ultra‐high molecular weight DNA was fluorescently labeled with DLE‐1 enzyme (Bionano Genomics) using the DLS DNA Labelling Kit (Bionano Genomics). Labeled DNA was loaded onto a Saphyr® chip (for the collection of 1300 Gb of molecules >150 kb) and imaged on the Saphyr® instrument. For each sample, a minimum of 320 Gb of data was acquired, and automatic whole‐genome de novo assembly was performed (Bocklandt et al., 2019). De novo genome assembly and variant calling were performed using Bionano Access (version 1.7) (https://bionanogenomics.com/support/software‐downloads/). For structural variant (SV) calling, we performed in silico DLE1 digestion of the human reference genome (GRCh37, hg19) to generate the reference map. All OGM results were analyzed using CNV algorithms (for chromosomal aberrations >100 Kb) and SV algorithms (for chromosomal aberrations >500 bp) independently. Filtering criteria were based on previous literature recommendations (Dremsek et al., 2021; Mantere et al., 2021) and the experience of our own laboratory. Following the alignment of consensus genome maps with the reference map, SVs were identified using the SV algorithm. The filtering threshold for calling CNVs was confidence >0.95, size >100 kb, with the mask filter turned off. The filtering thresholds for automatic calling SVs were as follows: insertions and deletions, confidence >0, size >500 bp; inversions, confidence >0.7; duplications, confidence = −1; intrachromosomal translocations, confidence >0.3; interchromosomal translocations, confidence >0.65. Minimal break point regions were defined using the boundaries of the DLE mark positions on each chromosome that were the closest to the crossover points.

2.5. Sanger sequencing

LR‐PCR primers were designed to detect the translocation break points. The sequences of the break point PCR primers in this study are listed in Table S1. PCR products were electrophoresed on an agarose gel, and single, clear bands obtained from normal and derivative chromosomes were further analyzed by Sanger sequencing on an ABI3730XL sequencer (Thermo Fisher Scientific).

3. RESULTS

3.1. Clinical report

The proband was a 13‐year‐old girl, the first child born to her parents. She was born at 38 weeks and 4 days gestation with an Apgar score of 8–9; a cesarean section was carried out because of oligohydramnios and fetal growth restriction. Invasive diagnostic tests were not performed during the pregnancy. Her birth measurements were as follows: body weight (BW) = 2300 g (< third centile), body length (BL) = 48.8 cm (28th centile), and head circumference (HC) = 33 cm (23rd centile). Neonatal cardiac ultrasound presented a ventricular septal defect, pulmonary hypertension, and persistent truncus arteriosus. The coagulation parameters on her first day of life were also abnormal: prothrombin time (PT) was 15.9 s (normal range: 9.8–12.1 s), activated partial thromboplastin time (aPTT) was 63.5 s (range: 25–31.3 s), fibrinogen FIB was 1.356 g/L (range: 1.8–3.5 g/L), and factor III was 51.1% (range: 75%–125%). She had no medical therapy follow‐up. And her mother reported that she bruises easily.

The proband was slow in achieving milestones but did not show regression. Specifically, she sat unassisted between 9 and 11 months, crawled at 1 year, began pulling to stand at 18 months, walked independently at 2 years, and climbed stairs at the age of 3 years.

In addition, the proband had noticeable growth retardation and developmental delay. Physical examination at the age of 5 years showed a height of 98.5 cm (< third centile), weight of 13.6 kg (< third centile), and head circumference of 45.2 cm (< third centile). The proband could only use a few words and did not speak in complete sentences; moreover, she was unable to get dressed or eat independently. Evaluation of the girl's mental development status at Nanjing Maternity and Child Health Care Hospital concluded that the patient had no ASD, only global developmental delay (GDD). Despite the severe language delay, the proband showed some social responsiveness, including friendly behavior, a happy demeanor, and good interactions with physicians. The Gesell development scale showed that the development quotients (DQ) for adaptability, gross motor, fine motor, social interaction, and language area were 59, 51, 41, 60, and 33, respectively (DQ >85 is normal). Cranial magnetic resonance imaging and electroencephalography performed to investigate the etiology of the patient's GDD were both normal. Facial dysmorphisms included bilateral epicanthal folds, ptosis, strabismus, low‐set ears, small simple ears with overfolded helices, a broad nasal tip, and slight down‐turned mouth corners (Figure 1a). Additional features included clinodactyly of both fifth fingers and polydactyly (left thumb) (Figure 1a, Table 1).

FIGURE 1.

FIGURE 1

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Clinical information for the proband with an 11q13.2q13.4 deletion plus 9q21.31q22.33 duplication. (a) Photographs of the proband (taken at 13 years of age) show the main clinical features. Left panel: frontal view. Right panel: long slender fingers, clinodactyly of the fifth fingers, and thumb polydactyly of the left hand. (b) The SNP array results of the proband. (c) The pedigree of the proband's family indicates the members affected by reproductive problems.

TABLE 1.

Clinical features of the proband with a 3 Mb deletion at 11q13.3q13.4 plus a 12 Mb duplication at 9q21.13q21.33.

Phenotype Present case
Range 68,656,359–71,935,086
Gender Female
Age 13 years old
Development Global developmental delay
Speech Severe language delay
Eyes Bilateral epicanthal folds, ptosis, strabismus
Ears Low‐set ears, small simple ears with overfolded helices
Nose Broad nasal tip
Mouth Slight down‐turned corners
Hand Long slender fingers, clinodactyly of both fifth fingers, thumb polydactyly of left hand
Cardiac Ventricular septal defect, pulmonary hypertension, and persistent truncus arteriosus
Others Coagulation defect
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After the above examination, the patient was transferred to our department for genetic testing in 2014. SNP array results demonstrated that the girl was carrying a 12 Mb duplication at 9q21.13q21.33, classified as a variant of unknown significance (VOUS), and a pathogenic 3 Mb deletion at 11q13.2q13.4 (Figure 1b). The mother of the proband did not undergo follow‐up parental origin tests until the maternal aunt of the proband was referred to the same department for genetic testing for primary infertility in 2021. At that time, physical examination of the proband showed a height of 138.6 cm (< third centile), weight of 32.1 kg (< third centile), and head circumference of 49.8 cm (< third centile). She was not receiving any speech therapy and showed no improvement in language ability.

A history of reproductive problems was reported in maternal family members (Figure 1c). The mother of the proband had experienced four spontaneous abortions following the proband's birth, after which she had given birth to a boy. The boy (aged 7 years) showed no abnormal developmental problems and was attending primary school. The maternal grandmother also had a history of several spontaneous abortions, all of which had occurred after more than 2 months of pregnancy. The maternal aunt had begun cohabitation with her former husband in 2014 and had not become pregnant, remaining unable to become pregnant after remarrying in March 2021. In October 2021, she presented to our department for genetic diagnosis of primary infertility (Figure 1c). The three female members with reproductive problems but no significant abnormalities in phenotype or intelligence and no history of illness, medication use, or exposure to toxic/harmful substances or radiation during pregnancy.

3.2. SNP array test

As described above, a SNP array test conducted in the proband at 5 years of age identified a pathogenic 3 Mb deletion at 11q13.2q13.4 and a VOUS 12 Mb duplication at 9q21.13q21.33 (Figure 1b). The deleted genomic fragment encompassed a haploinsufficient gene, SHANK2 (OMIM*603290), which is involved in complex neurodevelopmental disorders. Several reports have revealed de novo loss‐of‐function variants in the SHANK2 gene, including microdeletions, nonsense mutations, and frameshift variants in patients with ASD and/or mild to moderate intellectual disability and severe language delay. Dysmorphic facial and hands features have also been observed, especially in patients with microdeletions and exonic deletions (Table S2) (Berkel et al., 2010, 2012; Bowling et al., 2017; Caumes et al., 2020; Doddato et al., 2022; Guo et al., 2018; Leblond et al., 2012, 2014; Marcou et al., 2017; Pinto et al., 2010; Wischmeijer et al., 2011; Zhou et al., 2019).

3.3. G‐banded karyotyping analysis

To determine the parental origins of the CNVs, karyotyping analysis was performed on the parents, maternal grandmother, and maternal aunt. The three females yielded the same karyotyping results, 46,XX,der(9)?del(9)(q21q22)t(9;14)(q22;q24),der(11)ins(11;?9)(q13;?q21q22),der(14)t(9;14) (Figure 2a). The father of the proband was chromosomally normal.

FIGURE 2.

FIGURE 2

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Complex balanced reciprocal translocations in a family exhibiting reproductive problems. (a) The G‐banded karyotyping results of the affected females in this family. (b) A Circos plot of the optical genome mapping results shows a complex four‐way balanced chromosomal translocation; the translocations are indicated by lines in the center of the plot connecting the genomic loci involved. (c) Schematic of the complex 4‐way balanced chromosomal translocation.

3.4. Precise translocation detection by optical genome mapping

To accurately determine the chromosomal rearrangements, samples from the female family members were further subjected to OGM analysis. In this way, we were able to successfully map five break points on three chromosomes, with a total of four rearrangement events (Figures 2b,c and 3). Compared with standard karyotyping, OGM located the break point more precisely. In addition, OGM identified a cryptic break point on chromosome 11 that was ambiguous by G‐banded karyotyping. The average resolution of the five junction regions identified by OGM was 14.2 Kb (range: 1.9–27.0 Kb). All mapped break points are listed in Table 2 and Figure 3. Within these redefined regions, we identified the presence of potentially disrupted genes, including TMC1 (OMIM*606706) in the region of q21.13, NTRK2 (OMIM*600456) in the region of 9q21.33, PHOX2A (OMIM*602753) in the region of 11q13.3, MRPL2 1 (OMIM*611834) in the region of 11q13.3, and KIAA0586 (OMIM*610178) in the region of 14q23.1. Of these genes, TMC1, NTRK2, PHOX2A, and KIAA0586 have previously been associated with diseases.

FIGURE 3.

FIGURE 3

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Optical genome maps and models for each balanced reciprocal translocation. (a–d) Optical genome maps show the precise break point ranges of the balanced reciprocal translocations. The turquoise or blue bars are the sample maps, the green bars are the reference maps, and the vertical lines represent label sites. For each of the translocation break points, the maps are aligned to human reference hg19 chromosomes. Break point resolution was determined by the distance between the matched (arrows) and unmatched labels. Genes around the break points are indicated by horizontal arrows in purple (overlapped genes) and blue (nonoverlapped genes). The schematics on the right show the chromosomal rearrangement events proposed by the optical genome mapping results.

TABLE 2.

Break point definition by OGM and Sanger sequencing.

OGM Sanger sequencing
9q21.13 75335953–75344131 (8.2K) TMC1 Chr9:75340292; 75340282 TMC1
9q21.33 87558410–87574967 (16.6K) NTRK2 Chr9:87567545; 87567547 NTRK2
11q13.3 68641730–68668757 (27.0K) MRPL21 Chr11:68656359; 68656910 –
11q13.4 71933633–71950892 (17.3k) PHOX2A Chr11:71935086; 71935065 –
14q23.1 58899971–58901867 (1.9k) KIAA0586 Chr14:58900486; 58900486 KIAA0586
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3.5. Validation of precise break point locations by Sanger sequencing

To confirm the break points detected by OGM, we performed LR‐PCR and Sanger sequencing. We were able to locate all five break points on three chromosomes and precisely map the rejoining nucleotide sequence positions for all translocation events (Figure 4 and Table S4). Importantly, all finely mapped break points were essentially consistent with the ranges determined by OGM (Table 2 and Figure 4). Within these redefined break points, we confirmed the disruption of three disease‐related genes, TMC1, NTRK2, and KIAA0586.

FIGURE 4.

FIGURE 4

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Break point validation for each balanced reciprocal translocation. (a–e) Chromatograms (generated via Sanger sequencing) of the five junction fragments show the break points (BPs) at the nucleotide level. The dashed lines separate the sequences that match the original chromosomal sequences, and the vertical arrows indicate the location of the break points. Ellipsis dots represent intermediate sequences that are not fully displayed. The horizontal arrows below the chromatograms represent the original direction of the reference sequence. Genome coordinates were obtained from the hg19 human reference genome. The BP at 11q13.3 has a 1.3 Kb insertion that could not be aligned with hg19 but could be aligned with a previously reported nonreference insertion (KY429263.1), leading to the 425 and 901 bp insertions in BRT02 and BRT03, respectively.

4. DISCUSSION

In this study, we reported the case of an affected girl with a 9q21.13q21.33 duplication and 11q13.3q13.4 deletion from a family with serious reproductive problems. OGM revealed a complex four‐way balanced chromosomal translocation involving five break points at three chromosomes in this family. Combining LR‐PCR and Sanger sequencing, we characterized the location of the translocation break point with single‐nucleotide resolution. Moreover, we showed that the five break points interrupted three genes: TMC1, NTRK2, and KIAA0586.

The affected proband inherited one of the maternally derived chromosomes, der(11)del(11)(q13.3q13.4)ins(11;9)(q13.3;q21.33q21.13), leading to the duplication of 9q21.13q21.33 and deletion of 11q13.3q13.4. These two CNVs are relatively rare. Two patients with de novo deletions of 11q13.2q13.4 region have been reported previously (Marcou et al., 2017; Wischmeijer et al., 2011), as well as one patient with deletion of 11q13.3q13.4 (Leblond et al., 2014). These patients shared similar phenotypic features, including GDD, intellectual disability, severe language delay, facial dysmorphic features, and clinodactyly of both fifth fingers. The deleted region includes 32 protein‐coding genes, 26 of which are OMIM genes. Among them, SHANK2 is a haploinsufficient gene. De novo variants of the SHANK2 gene have been found in patients with neurodevelopmental disorders, including four cases of exonic deletion (Berkel et al., 2010; Leblond et al., 2012; Pinto et al., 2010), three cases of frameshift variants (Bowling et al., 2017; Caumes et al., 2020), four cases of nonsense variants (Berkel et al., 2010; Doddato et al., 2022; Guo et al., 2018; Zhou et al., 2019), and one case of gene disruption resulting from a translocation (Leblond et al., 2014). Consistent with our patient, all reported patients exhibited severe language delay, which represents a key SHANK2‐related feature. In addition, in contrast to our case, nearly all previous patients showed autism; however, it is worth noting that a recent study has shown that ASD is not necessarily a constant clinical feature (Doddato et al., 2022). Additional features such as clinodactyly of both fifth fingers were frequently observed, consistent with 11q13 microdeletion patients and our proband (Table S2).

The 12 Mb 9q21.13q21.33 duplication segment includes 35 protein‐coding genes, 31 of which are OMIM genes. Although this segment lacks established triplosensitive regions or genes, one report has described a case of a maternally inherited 7.5 Mb duplication on chromosome 9q21.31q22.33 that caused intrauterine growth restriction with feeding refusal and mild facial dysmorphism (Travan et al., 2015). Many features, such as intrauterine growth restriction, language delay, low‐set ears, and long, thin fingers were also present in our patient. Another study described a patient with a 9q21.12q22.1 duplication who presented with low birth weight and complex heart anomalies, consistent with our proband's phenotypes (Table S3) (Lindgren et al., 1994). However, delineation of a common phenotype is hampered by the lack of reported cases, and additional reports of 9q21.13q21.33 duplications will be required for more robust genotype–phenotype correlations (Table S3).

Based on the above analyses and clinical feature comparisons, we propose that the complex features of our patient result from both the de novo CNVs. The 11q13.3q13.4 deletion may have contributed mainly to the GDD, language delay, and clinodactyly of the fifth fingers, while the 9q21.13q21.33 duplication may have contributed mainly to the intrauterine growth restriction and cardiac abnormalities. Moreover, either or both de novo CNVs could have contributed to the facial phenotypes. Interestingly, our patient also presented some phenotypes that have not been reported in previous cases, such as polydactyly and coagulation defects. Thus, additional cases with similar CNVs are required to explain these additional phenotypes (Tables S2 and S3).

Genes interrupted by translocation may also contribute to some of the phenotypic features. In this family, three genes were interrupted—TMC1, NTRK2, and KIAA0586. The KIAA0586 gene encodes a centrosomal protein required for ciliogenesis and hedgehog signaling. Biallelic mutations in KIAA0586 cause Joubert syndrome 23 (OMIM#616490) and short‐rib thoracic dysplasia 14 (OMIM#616546) in an autosomal‐recessive manner (Bachmann‐Gagescu et al., 2015; Zhao et al., 2021). The TMC1 gene encodes a 6‐pass integral membrane protein that is a major component of the mechano‐electrical transducer channel in cochlear hair cells and is subject to numerous mutations that cause deafness (Ballesteros & Swartz, 2022). TMC1 gene mutations causing human deafness are divided into two categories: those referred to as DFNA36 (OMIM#606705), which are autosomal dominant, and those termed DFNB7 (OMIM#600974), which are autosomal recessive. Nonsense and frameshift mutations of TMC1 predicted to cause a loss of normal protein function through protein truncation are often detected in DFNB7/11 patients (Kraatari‐Tiri et al., 2022; Nishio & Usami, 2022). Our patient carried a break point in intron 8 of TMC1, which interrupted the open reading frame. Thus, it is reasonable that the females we reported here had no deafness phenotype and that there was no deafness in the proband's family. NTRK2 is associated with developmental and epileptic encephalopathy 58 (OMIM#617830), as well as obesity, hyperphagia, and developmental delay (OMIM#613886) (Hamdan et al., 2017; Yeo et al., 2004; Yoganathan et al., 2021). The TrkB protein is mainly expressed in the central nervous system and is involved in neuronal proliferation and migration. Dominant NTRK2 mutations have been described in association with hyperphagic obesity associated with developmental delay, and functional studies have implicated haploinsufficiency as the likely pathogenic mechanism of the disease (Gray et al., 2007; Yeo et al., 2004). However, in the family reported here, there were no obesity‐related issues in the females carrying the disrupted NTRK2 gene. Thus, the developmental delay of the proband is unlikely to have been caused by interruption of NTRK2. Additionally, rearrangement of the NTRK2 gene region seems to be a common event in the genome. When NTRK2 is fused to unrelated genes, the resulting NTRK2 fusion proteins can act as carcinogenic drivers, promoting the growth and survival of cancer cells (Amatu et al., 2016; Manea et al., 2022; Solomon et al., 2019). NTRK2 gene fusions have been observed in various cancers, including astrocytoma (López et al., 2019), low‐grade glioma (Pattwell et al., 2020), and pediatric glioma (Barritault et al., 2021). Although our reported family female members had a break in the NTRK2 coding sequence, NTRK2 was not fused with other genes. Based on the above analysis, the interrupted genes may not contribute to the phenotype of this proband, or the reproductive problems observed within the family.

For the past several decades, karyotyping has been used routinely to detect balanced SVs in couples with reproductive problems. However, the low resolution of karyotyping analysis (~5 Mb) may affect the accuracy of the results as the locations and sizes of SVs are imprecise, and some balanced SVs are cryptic (Dai et al., 2022; Zhang et al., 2023). Recent studies have applied OGM to patients with SVs, suggesting that this technology may be becoming the next‐generation cytogenetic tool of choice. Zhang et al. reported that OGM successfully detected 11 cryptic reciprocal translocations in couples with normal karyotypes who had abortions/affected offspring (Zhang et al., 2023). In this report, we used OGM to refine the complex translocation events. Although the sequence around the break points still required verification, the obtained break point ranges of a few kilobases were sufficient to determine whether the break points were in known disease‐related genes.

Most break point junctions have blunt ends, microhomology, inserted sequences, or inversions. In our sample, the break point junctions showed a 1 bp insertion at BRT03‐02, blunt ends at BRT01, BRT02‐1, and BRT02‐2, and 2–3 bp microhomologies at BRT03‐1, BRT04, and BRT05 (Table S4). Weckselblatt and Rudd reported that blunt ends mostly derive from nonhomologous end‐joining (NHEJ) or fork stalling and template switching (FoSTeS), while 1–15 bp microhomologies are derived from NHEJ, FoSTeS, or microhomology‐mediated break‐induced replication (MMBIR). Moreover, the presence of inserted sequences at break points is indicative of replicative mechanisms such as FoSTeS and MMBIR (Weckselblatt & Rudd, 2015). However, NHEJ is considered the major mechanism responsible for the formation of balanced chromosomal alterations (Burssed et al., 2022; Chiang et al., 2012; Moysés‐Oliveira et al., 2019). Repetitive sequences such as Alu, long interspersed nuclear elements, low copy repeats, and palindromic AT‐rich repeats are breakage hotspots and have been associated with the chromosomal rearrangements formed via NHEJ (Burssed et al., 2022; Edelmann et al., 2001; Emanuel, 2008; Inoue et al., 2002; Kurahashi & Emanuel, 2001; Shaw & Lupski, 2005). In our study, the BRT01 and BRT04 junctions exhibited blunt ends and microhomologies at AT‐rich repeats within the 9q21.13 break point. Therefore, we strongly suspect NHEJ to be the mechanism involved in these rearrangements.

In summary, our case emphasizes the requirement for the timely testing of parental origin for patients with rare CNVs as well as the accurate cytogenetic analysis of complex chromosome rearrangements in families with reproductive problems. Meanwhile, we believe the OGM will be a strong cytogenetic tool for defining chromosomal rearrangements in the future.

AUTHOR CONTRIBUTIONS

Qinxin Zhang: Funding acquisition and original draft; Yan Wang and Jing Zhou: The clinical information collection and editing the final article; Ran Zhou, An Liu, Lulu Meng, and Xiuqing Ji: Data analysis, genetic analysis, and validation; Ping Hu: Conceptualization and funding acquisition; Zhengfeng Xu: Conceptualization, Supervision, and funding acquisition. All authors agreed to be accountable for and ensure any questions relating to the accuracy, integrity of this work, and read and approved the final article.

FUNDING INFORMATION

This work was supported by the National Key R&D Program of China (2021YFC1005301 and 2022YFC2703400), and the National Natural Science Foundation of China (82101943 and 81971398).

CONFLICT OF INTEREST STATEMENT

The authors declare that they have no conflict of interest.

ETHICS STATEMENT

The research Ethics Committee of Nanjing Maternity and Child Health Care Hospital approved the study (2021KY‐118) in accordance with the Helsinki Declaration of 1975, as revised in 2000.

PATIENT CONSENT

Informed consent was obtained from all study participants at the time of providing samples.

Supporting information

Table S1

Click here for additional data file. (17.1KB, docx)

Table S2

Click here for additional data file. (51.7KB, xlsx)

Table S3

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Table S4

Click here for additional data file. (16.8KB, docx)

ACKNOWLEDGMENTS

We thank all the patients who participated in this study.

Zhang, Q. , Wang, Y. , Zhou, J. , Zhou, R. , Liu, A. , Meng, L. , Ji, X. , Hu, P. , & Xu, Z. (2023). 11q13.3q13.4 deletion plus 9q21.13q21.33 duplication in an affected girl arising from a familial four‐way balanced chromosomal translocation. Molecular Genetics & Genomic Medicine, 11, e2248. 10.1002/mgg3.2248

Qinxin Zhang, Yan Wang, and Jing Zhou contributed equally to this work.

Contributor Information

Ping Hu, Email: njfybjyhuping@163.com.

Zhengfeng Xu, Email: zhengfeng_xu_nj@163.com.

DATA AVAILABILITY STATEMENT

All the data generated or analyzed in this study are included in this published article.

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Associated Data

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Supplementary Materials

Table S1

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Table S2

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Table S3

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Table S4

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Data Availability Statement

All the data generated or analyzed in this study are included in this published article.

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