Prenatal diagnosis of 15q13.3 deletion and duplication syndrome: what do we tell the prospective parents?

Abstract

Objective

This retrospective study analyzed ultrasound findings, single nucleotide polymorphism microarray (SNP array) results, pregnancy outcomes, and postnatal follow-up data in fetuses with 15q13.3 deletions or duplications.

Methods

Six fetuses were diagnosed with 15q13.3 deletions and nine with 15q13.3 duplications via SNP array at the prenatal diagnosis center of a single tertiary medical center from August 2017 to December 2024. Maternal demographics, ultrasound findings, SNP array results, pregnancy outcomes, and follow-up information were comprehensively reviewed and analyzed.

Results

The deletions sizes in the six deletions ranged from 744 Kb to 1.87 Mb, primarily involving genes such as MTMR15, MTMR10, TRPM1, KLF13, OTUD7A, and CHRNA7. The overlapping region was located between 31.9 Mb and 32.5 Mb. In the nine duplication cases, the fragment sizes ranged from 419 Kb to 2.13 Mb, with overlapping region located between 31.9 Mb and 32.4 Mb. Among the six cases of fetal deletions, three (50.0%, 3/6) exhibited ultrasound abnormalities. The observed ultrasound phenotypes primarily consisted of cardiovascular malformations, lateral ventriculomegaly, intrauterine growth retardation, cleft lip and palate, abnormal finger development, and polyhydramnios. In the nine cases with fetal duplications, four (44.4%, 4/9) showed ultrasound abnormalities, predominantly featuring cardiovascular malformations, corpus callosum hypoplasia, enlarged gallbladder, lateral ventriculomegaly, and increased nuchal translucency. Among the six deletions cases, parental origin testing was conducted for five cases, two were identified as maternally inherited and three were de novo. In the nine duplications cases, eight underwent parental origin testing, with five being inherited (three paternal and two maternal) and two were de novo. Follow-up assessments revealed that the Case 7 showed speech and motor developmental delays. Case 8 experienced seizure at four years of age. At 18 months, Case 13 was diagnosed with bilateral strabismus.

Conclusion

This study conducted a preliminary assessment of the genotype and phenotype of fetuses with 15q13.3 deletions/duplications, expanding the phenotypic spectrum of this syndrome. The study suggests that prenatal 15q13.3 deletions and duplications may be associated with cardiac malformations and lateral ventriculomegaly, but lack phenotype specificity. Moreover, it is essential to closely monitor the neuropsychiatric development postnatally in fetuses with 15q13.3 deletions and duplications that exhibit normal phenotypes during the prenatal period.

Take home message

What does this study add to the clinical work？

This study suggests that fetuses with prenatal 1q21.1 deletions may associated with malformations of the urinary system, whereas those with 1q21.1 duplications are likely associated with cardiac malformations.

Introduction

Copy number variations (CNVs) are associated with a variety of genetic diseases. Single nucleotide polymorphism array (SNP array) technology is employed to uncover genetic etiologies in children who exhibit postnatal developmental delays, intellectual disabilities, and multifarious malformations, as well as in fetuses presenting with prenatal structural anomalies [1]. The proximal region of chromosome 15 is particularly unstable due to the presence of low copy repeats (LCRs). These LCRs aggregate and form multiple breakpoints, which facilitate non-allelic homologous recombination, ultimately resulting in the formation of CNVs [2]. Deletions in the 15q11.2q13 region (Breakpoints between BP1-BP3 or BP2-BP3) can lead to disorders such as Prader-Willi Syndrome or Angelman Syndrome [3]. Furthermore, CNVs in the 15q13.3 segment, which includes the CHRNA7, have been reported to be associated with a variety of neuropsychiatric phenotypes, including cognitive deficits, schizophrenia, epilepsy, and autism spectrum disorders [4]. 15q13.3 deletions are classified into two types [5]: (1) between BP4 and BP5 (Type I), which spans approximately 1.3 Mb (chr15:31.1 ~ 32.4 Mb; Hg19), and (2) between D-CHRNA7 and BP5 (Type II), which covers roughly 400 Kb (chr15:32.0 ~ 32.4 Mb; Hg19). Both deletion types are pathogenic CNVs that are known to cause 15q13.3 deletion syndrome (OMIM: 612,001). Additionally, there are two types of 15q13.3 duplications: (1) between BP4 and BP5 (Type I), which, although associated with cognitive impairments and psychiatric disorders in some reports, still lacks robust evidence of pathogenicity, rendering its clinical significance uncertain; (2) between D-CHRNA7 and BP5 (Type II), which can also be observed in the general population and might be considered a normal variation as indicated by current reports [6]. CNVs associated with the 15q13.3 region are commonly documented in children and adult cases, and the clinical phenotypes observed in prenatal diagnostic cases continue to show a lack of consistency [7]. The aim of this study is to investigate the fetal findings, clinical features, and outcomes of pregnancies affected by 15q13.3 deletions and duplications to provide data for prenatal counseling.

Subjects and methods

Subjects

In this retrospective study, we searched our electronic database looking for cases where the diagnosis of fetal 15q13.3 deletions/duplications was made using amniocentesis, followed by single nucleotide polymorphism array (SNP array) testing. The testing was done at the prenatal diagnosis center of Longgang Maternal and Child Health Hospital in Shenzhen, from August 2017 to December 2024. The analysis focused on ultrasound abnormalities, SNP array results, parental origin, pregnancy outcomes, and postnatal follow-up. The indications for prenatal diagnosis in pregnant women mainly include fetal ultrasound abnormalities, high-risk serum screening, increased nuchal translucency (NT), lateral ventriculomegaly, advanced maternal age, and adverse pregnancy history. Before undergoing invasive prenatal diagnosis and SNP array testing, pregnant women were fully informed about the research objectives, experimental procedures, and potential risks, and signed an informed consent form. When pregnant women opted to continue with their pregnancies, telephone follow-ups were conducted to monitor the growth and development of the newborns. This study only included cases with 15q13.3 deletions/duplications, excluding cases involving other chromosomal variations. The study was approved by the Ethics Review Committee of Longgang Maternal and Child Health Hospital in Shenzhen (Approval No. LGFYYXLL-028).

Methods

SNP array

Genomic DNA was extracted from 10 mL of amniotic fluid or 2 mL of EDTA-anticoagulated blood using the QIAamp DNA Kit (Qiagen, Germany). DNA concentration was quantified using a microvolume spectrophotometer. PCR amplification was performed, followed by purification with magnetic beads to remove excess enzymes and primers. The purified genomic DNA was then enzymatically fragmented and labeled with terminal deoxynucleotidyl transferase. The labeled DNA fragments were hybridized onto an Affymetrix Cytoscan 750 K Array chip (ThermoFisher, USA) for 18 h. Following hybridization, the array was subjected to automated washing and staining procedures to remove non-specifically bound DNA fragments. Fluorescence signals were finally acquired using a high-resolution chip scanner for subsequent data analysis.

Data analysis

The results obtained were compared with the Database of Genomic Variants (http://dgv.tcag.ca/) to exclude common polymorphic copy number variations (CNVs). The remaining CNVs were analyzed by searching databases such as DECIPHER (https://www.deciphergenomics.org/), ISCA (https://search.clinicalgenome.org/), ClinGen (http://www.ncbi.nlm.nih.gov/projects/dbvar/clingen/), ClinVar (https://clinicalgenome.org/), OMIM (http://omim.org/), and PubMed (http://pubmed.ncbi.nlm.nih.gov/). According to the guidelines of the American College of Medical Genetics and Genomics (ACMG), the clinical significance of these CNVs was assessed to determine their pathogenicity [8, 9].

Follow-up

Telephone follow-ups were conducted within two weeks before and after the expected delivery date provided by the pregnant women. These follow-ups documented any fetal ultrasound abnormalities, whether the pregnancy continued, the mode of delivery, and the phenotypes of the carrier parents after confirming parental origin. After the birth of the child was confirmed, regular telephone follow-ups were conducted every six months to document the child’s postnatal growth and development, focusing on aspects such as language expression. The latest follow-up was conducted on December 31, 2024. The oldest child is 4 years and 5 months old, and the youngest is 13 months old.

Results

Analysis of SNP array testing results for 15 cases of 15q13.3 deletions/duplications

Among 11,850 cases that underwent amniocentesis due to high-risk indications, the detection rate for 15q13.3 deletions is 0.05% (6/11,850), and for 15q13.3 duplications, 0.08% (9/11,850). The sizes of the segments in the six deletion cases ranged from 744 Kb to 1.87 Mb, with breakpoints spanning from 30.8 to 32.8 Mb, primarily involving the genes MTMR15, MTMR10, TRPM1, KLF13, OTUD7A, and CHRNA7. The overlapping region was located between 31.9 and 32.5 Mb, encompassing DEPDC1P1, RNU6-18P, OTUD7A, and CHRNA7. The nine duplication cases had fragment sizes ranging from 419 Kb to 2.13 Mb, with breakpoints between 30.6 and 32.9 Mb. The overlapping region was between 31.9 and 32.4 Mb, containing DEPDC1P1, OTUD7A, and CHRNA7 (Fig. 1). Among the six deletions cases, except for Case 4 which exhibited a Type II deletion, the other five cases were classified as Type I deletions, with breakpoints occurring between BP4 and BP5. In the nine duplications cases, except for Cases 9 and 12 which were Type I duplications, the other seven cases were Type II duplications, with breakpoints located from D-CHRNA7 to BP5. Out of the six deletions cases, five underwent parental origin testing, with two inheriting the mutation maternally and three cases were de novo. In the nine duplications cases, eight underwent parental origin testing, with six cases being inherited (two paternally and four maternally) and two cases were de novo. (Table 1).

Fig. 1.

A schematic diagram depicting the locations and sizes of fragments for 15 cases with 15q13.3 deletions and duplications between BP4 and BP5. Cases 1 to 6 are deletions (Case 4 having breakpoints from D-CHRNA7 to BP5, and the other five located between BP4 and BP5). Cases 7 to 15 are duplications (Cases 9 and 12 having breakpoints between BP4 and BP5, and the others from D-CHRNA7 to BP5). The overlapped region is outlined with a black solid line

Table 1.

Prenatal indications, SNP array results, and follow-up information of 15 cases with 15q13.3 deletions and duplications

Case	Age	GW	High risk/ultrasound findings	SNP array results	Size	Inheritance	Outcome	Follow-up information
1	36	19+2	AMA, VSD	arr[GRCh37]15q13.2q13.3 (30,860,236_32, 621,188) × 1	1.76 Mb	De novo	TOP	N/A
2	31	21+3	Adverse pregnancy history (child with ID)	arr[GRCh37]15q13.2q13.3 (30,868,284_32,611,722) × 1	1.74 Mb	Unknown	TOP	N/A
3	22	18	High risk of NIPT (chromosome 15)	arr[GRCh37]15q13.2q13.3 (30,975,422_32,558,723) × 1	1.58 Mb	De novo	TOP	N/A
4	27	23+5	Left LVW (10.8 mm), FGR, polyhydramnios	arr[GRCh37]15q13.2q13.3 (31,224,221_32,568,261) × 1	1.34 Mb	Inherited (maternal)	TOP	Another daughter (4-year-old) who has the same deletion was diagnosed with delayed language and motor development
5	37	22	AMA, High risk of serum screening (1:140 for T21)	arr[GRCh37]15q13.3 (31,902,632_32,644,043) × 1	744 Kb	De novo	TOP	N/A
6	28	23	Left LVW(11.2 mm), cleft lip and palate, finger dysplasia	arr[GRCh37]15q13.2q13.3 (31,013,669_32,884,261) × 1	1.87 Mb	Inherited (maternal)	TOP	N/A
7	32	20+5	High risk of serum screening (1:150 for T21)	arr[GRCh37]15q13.3 (31,940,425_32,444,043) × 3	504 Kb	Inherited (maternal)	Live birth	Speech and motor delays at 4 years and 5 month old
8	34	28+2	Adverse pregnancy history (child with trisomy 21)	arr[GRCh37]15q13.3 (32,024,760_32,444,043) × 3	419 Kb	Inherited (paternal)	Live birth	Epilepsy at the age of 4
9	27	19	Tricuspid regurgitation, left hydronephrosis, macrogallbladder	arr[GRCh37]15q13.2q13.3 (30,729,041_32,853,574) × 3	2.13 Mb	Inherited (maternal)	TOP	N/A
10	25	29	LVW (11.6 mm)	arr[GRCh37]15q13.3 (31,967,497_32,444,043) × 3	477 Kb	De novo	Live birth	No visible abnormalities
11	32	21+5	History of adverse pregnancy (history of three embryonic demises)	arr[GRCh37]15q13.3 (31,918,970_32,444,043) × 3	525 Kb	Unknown	Live birth	No visible abnormalities
12	19	22	Increased NT(2.5 mm), aortic stenosis	arr[GRCh37]15q13.2q13.3 (30,669,041_32,653,574) × 3	1.99 Mb	Inherited (maternal)	Live birth	Surgery for cardiac malformation after birth
13	33	20+5	High risk of serum screening (1:120 for T21)	arr[GRCh37]15q13.3 (31,967,497_32,854,022) × 3	887 Kb	Inherited (maternal)	Live birth	Strabismus at 18 months
14	38	24+6	AMA, agenesis of the corpus callosum	arr[GRCh37]15q13.3 (31,967,497_32,915,723) × 3	948 Kb	Inherited (paternal)	TOP	N/A
15	33	22	High risk of serum screening (1:90 for T21)	arr[GRCh37]15q13.3 (31,935,698_32,444,043) × 3	508 Kb	De novo	Live birth	No visible abnormalities

GW gestational week, SNP Single nucleotide polymorphism, AMA Advanced maternal age, VSD ventricular septal defect, ID intelligence disability, NT nuchal translucency, FGR fetal growth retardation, NIPT non-invasive prenatal testing, LVW lateral ventricle widened, TOP termination of pregnancy, N/A not applicable

Ultrasound manifestations of fetuses with 15q13.3 deletions

Among the six cases of fetuses with 15q13.3 deletions, three (50.0%, 3/6) exhibited abnormal ultrasound findings. The detected ultrasound phenotypes primarily included cardiovascular malformations, lateral ventriculomegaly, intrauterine growth retardation, cleft lip and palate, abnormal finger development, and polyhydramnios (Tables 1 and 2). Case 6 was particularly special, presenting with complex multi-organ malformations, including left lateral ventriculomegaly (width 11.2 mm), cleft lip and palate, and abnormal development of the left fingers (Fig. 2). The pregnant woman carried a similar deletions segment, but displayed a normal clinical phenotype. She describes herself as introverted and is employed as a waitress. In Case 4, the deletion was maternally inherited. The mother is clinically normal, has a high school education, and works in office administration. The pregnant woman has a 4-year-old daughter who also carries this deletion segment. While the mother reports her daughter's clinical phenotype as normal, she observed that her daughter began walking and speaking 5 months later than her peers.

Table 2.

Ultrasound features of fetuses with 15q13.3 deletions

Ultrasound findings	Cases
Widened lateral ventricles	2
Ventricular septal defect	1
Fetal growth restriction	1
Cleft lip and palate	1
Deformed fingers	1
Polyhydramnios	1
Total	7

Fig. 2.

Ultrasound findings of Case 6 showed multiple structural malformations. A Left widened lateral ventricles, with a width of 11.2 mm. B Fetal cleft lip and palate. C Malformation of the left fingers, with the middle finger having one phalanx and the other fingers having two phalanges

Ultrasound findings of fetuses with 15q13.3 duplications

Among the nine fetuses with duplications, four (44.4%, 4/9) presented with abnormal ultrasound findings. Specifically, two of these fetuses showed cardiovascular malformations, mainly tricuspid regurgitation and aortic stenosis. Additionally, individual cases were identified with corpus callosum hypoplasia, an enlarged gallbladder, lateral ventriculomegaly, increased nuchal translucency (NT), and polyhydramnios (Tables 1 and 3). Case 9 was particularly notable, as the fetus exhibited complex multi-organ malformations, including tricuspid regurgitation, left hydronephrosis, and an enlarged gallbladder (Fig. 3). The mother also carried a similar duplication segment, but had a normal clinical phenotype. She completed high school and is employed in sales.

Table 3.

Ultrasound features of fetuses with 15q13.3 duplications

Ultrasound findings	Cases
Cardiovascular abnormalities	2
Tricuspid regurgitation	1
Aortic stenosis	1
Corpus callosum dysgenesis	1
Widened lateral ventricles	1
Gallbladder enlargement	1
Increased NT	1
Hydronephrosis	1
Total	7

Fig. 3.

Ultrasound findings of Case 6 showed multiple structural malformations. A Moderate tricuspid regurgitation. B Left-sided hydronephrosis. C Fetal gallbladder enlargement

Pregnancy outcomes and follow-up information

All six cases with deletions chose to terminate their pregnancy. Follow-up revealed that in Case 4, the pregnant woman has a 4-year-old daughter who also carries a similar deletion segment and exhibits delays in motor and speech development. Of the nine cases with duplications, two opted for termination, while seven decided to continue the pregnancy. Follow-up for Case 7 showed that at the age of 4 years and 5 months, the child demonstrated delays in speech and motor development; The duplicated segment was maternally inherited from a mother with a normal clinical phenotype. Case 8 began experiencing epileptic seizures at the age of 4; the father carries a similar duplications segment but has a normal clinical phenotype. The prenatal ultrasound findings for Case 12 were confirmed postnatally, the child was diagnosed with aortic stenosis and underwent surgery at the age of 3, with a good prognosis currently. At 18 months, Case 13 was found to have strabismus during a physical examination; the mother carries a similar duplications segment and has a normal clinical phenotype (Tables 1 and 4).

Table 4.

Five abnormal phenotypes of 15q13.3 deletions and duplications were found during follow-up

	Sibling of Case 4 (deletions)	Case 7 (duplications)	Case 8 (duplications)	Case 12 (duplications)	Case 13 (duplications)
Age at diagnosis	4 years	4 years 5 months	4 years	3 years	18 months
Gender	Female	Male	Female	Female	Male
Developmental delay	Speech and gross motor delay	Speech and motor skill delays	No	No	No
Seizures/epilepsy	No	No	Epilepsy was diagnosed at the age of 4	No	No
Cardiovascular malformation	No	No	No	Aortic stenosis; surgical prognosis is favorable	No
Eye abnormalities	No	No	No	No	Bilateral strabismus

Discussion

In cases involving genetic deletions and duplications, the clinical phenotype of patients may not be clearly identifiable before birth, and there is often a lack of consistent correlation between prenatal and postnatal manifestations [10]. Syndromes that are clearly defined in adults do not always provide conclusive evidence for prenatal diagnosis, and the prenatal clinical phenotypes cannot be easily predicted based solely on the location and size of genetic variations [11].The 15q13.3 region is characterized by a cluster of multiple low copy repeat sequences, making this subchromosomal area a hotspot for non-allelic homologous recombination (NAHR). Consequently, the segment between 30.5 and 32.5 Mb is particularly susceptible to recurrent deletions and duplications [12]. The 15q13.3 deletion/duplication syndrome, which features complex genomic variations and pathogenic mechanisms, exhibits a wide spectrum of clinical phenotypes [13]. In children and adults, the main clinical features typically include intellectual disability, developmental delays, epilepsy, and neuropsychiatric problem, while congenital malformations are uncommon [14]. However, phenotypes like developmental delays and neuropsychiatric disorders are age dependent and cannot be detected prenatally [15]. In this study, the deletions/duplications regions for 15 cases were located within the 30.5–32.5 Mb range and primarily included genes such as KLF13, OTUD7A, and CHRNA7. Among the six deletions, three (50.0%, 3/6) exhibited abnormal ultrasound findings, predominantly involving cardiovascular malformations, lateral ventriculomegaly, intrauterine growth retardation, cleft lip and palate, abnormal finger development, and polyhydramnios. Since all the fetuses with deletions were terminated, postnatal clinical phenotypes could not be assessed in this group. In the nine duplications, four (44.4%, 4/9) presented ultrasound abnormalities, mainly cardiovascular malformations, corpus callosum hypoplasia, enlarged gallbladder, lateral ventriculomegaly, and increased nuchal translucency (NT). This study further demonstrates that the prenatal ultrasound phenotypes of 15q13.3 deletions/duplications exhibit significant heterogeneity and differ considerably from the clinical phenotypes observed in children or adult patients.

In individuals with developmental delays, intellectual disabilities, and autism spectrum disorders, deletion segments in the 15q13.3 region that include only the CHRNA7 and OTUD7A genes have been identified [16]. This finding suggests that at least one of these genes may play a role in the neuropsychiatric manifestations associated with recurrent deletions in this region. CHRNA7 encodes a synaptic ion channel protein that facilitates neuronal signal transmission and is prominently expressed in the thalamic reticular nucleus [17]. It encodes the α7 subunit of the nicotinic acetylcholine receptors, playing a crucial role in regulating the thalamocortical pathway [18]. Research suggests that deletions in the CHRNA7 gene could be a potential pathogenic factor for the phenotypes linked to epilepsy and schizophrenia. OTUD7A encodes a deubiquitinating enzyme located in the dendritic spines of cortical neurons. This enzyme acts as a protease, specifically targeting and cleaving ubiquitin bonds on proteins undergoing degradation [19]. Additionally, OTUD7A is found in the postsynaptic densities of the brain, underscoring its may play a key role in synaptic development and maturation. Pathogenic variants that lead to the loss of OTUD7A function have been identified in patients with schizophrenia [20]. Garrett et al. identified a homozygous missense mutation in OTUD7A in a patient with epileptic encephalopathy and a biallelic deletion of OTUD7A in another patient presenting with severe hypotonia, intellectual disability, and epileptic seizures [21]. The OTUD7A gene plays a crucial role in brain-specific protein modules and may be involved in brain-specific synaptic signaling. Whole genome or whole exome sequencing has been performed in studies on over 6000 patients with neurodevelopmental disorders who did not have the 15q13.3 deletions. They identified eight de novo mutations within the breakpoint interval (BP4–BP5), including three in the OTUD7A gene, two of which were found in siblings diagnosed with autism spectrum disorder (ASD) [20]. Kozlova et al. conducted targeted sequencing on genes within schizophrenia-associated copy number variations (CNVs) for 1,779 patients with schizophrenia and 1418 control subjects. They discovered three patients with rare variants in the OTUD7A gene, located in the chromosome 15q13.3 deletions region known to be associated with various neuropsychiatric phenotypes [22]. In a genome-wide association study on venous thromboembolism, OTUD7A was identified as one of the candidate genes, and it was hypothesized to be potentially related to cardiac diseases [23]. KLF13 belongs to a family of transcription factors and contains three classic zinc finger DNA-binding domains [24]. Studies have reported on the characteristics of mice with a heterozygous regional knockout of the 15q13.3 area, which includes the KLF13 gene. They observed significant defects, including changes in epilepsy susceptibility, autism-related behavioral phenotypes, and auditory sensory processing, indicating a gene dosage dependency [25]. It is hypothesized that a homozygous knockout of 15q13.3 would result in more pronounced behavioral and physiological defects in mice compared to heterozygous deletions. Although there is obvious genetic heterogeneity, studies have reported that klf13 gene mutation is the cause of congenital heart disease. Research indicates that defects in the KLF13 gene lead to familial patent ductus arteriosus, ventricular septal defects, and bicuspid aortic valve [26].

The penetrance of the 15q13.3 deletions is estimated at approximately 80% [12]. Its prevalence in the general population is about 1 in 40,000 (0.0025%). As reviewed by the Clinical Genome consortium, the small CNV in the 15q13.3 recurrent region (D-CHRNA7 to BP5) (includes CHRNA7, OTUD7A) is pathogenic for the deletion and probably has no effect (or negligible effect) on the duplication. This is because a partial duplication of a gene in most cases produces an inactive copy, in addition to the well-known fact that the effect of deletions is usually much more severe than that of duplications. Among groups with developmental delays, intellectual disabilities, and neuropsychiatric disorders, the detection rate ranges from about 1 in 450 to 1 in 600 (0.17–0.22%) [12, 27]. This is significantly higher than the 0.05% (6/11,850) detection rate observed in this study, a difference that may be attributed to variations in the populations examined. This study included prenatal fetuses, whereas most literature focused on children or adults, with the majority displaying neuropsychiatric abnormal phenotypes. The 15q13.3 deletions exhibit a wide range of non-specific phenotypes, some of which are mild or have no apparent clinical symptoms. The most common but non-specific phenotypes include developmental delays and intellectual disabilities (over 60%), neuropsychiatric developmental abnormalities (over 50%), and epilepsy (30%) [4, 5, 28]. Congenital malformations are not common, but there are case reports of cardiac structural abnormalities, hearing impairments, and eye problems [23]. Ziats et al. conducted neuropsychiatric behavioral assessments on 18 carriers identified with the 15q13.3 deletions, finding that 33.3% (6/18) exhibited delays in speech and motor development, 27% (5/18) had epilepsy, and two cases (11.1%, 2/18) had a history of cardiac malformations [29]. Lowther et al. reported that in seven Canadian adult cases with the 15q13.3 deletions, 57.1% (4/7) exhibited delays in speech and motor development, one case had epilepsy, and one case had an eye disease [30]. In this study, among six prenatal cases with the 15q13.3 deletions, two exhibited lateral ventriculomegaly, while the others presented with one case each of ventricular septal defect, intrauterine growth retardation, cleft lip and palate, and abnormal finger development. Additionally, follow-up revealed that Case 4 had a 4-year-old daughter experiencing delays in speech and motor development. Furthermore, Case 6 presented with complex multi-organ malformations, underscoring that the clinical phenotypes of fetuses with the 15q13.3 deletions can significantly differ from those observed in children or adults.

Compared to cases with the 15q13.3 deletions, those with the 15q13.3 duplications exhibit relatively lower penetrance. They share several clinical phenotypes with the 15q13.3 deletions, including delays in speech and motor development, epilepsy, and various neuropsychiatric developmental abnormalities [10, 31, 32]. However, the primary distinction is that the 15q13.3 duplications has lower penetrance and its phenotypes exhibit greater variability [33]. Research on five carriers of the Type II 15q13.3 duplications revealed that the most common clinical features included speech delay, autistic behaviors, and hypotonia. Three of these patients (60%, 3/5) exhibited developmental delays or intellectual disabilities, one patient (20%, 1/5) experienced epileptic seizures, and three patients (60%, 3/5) displayed abnormal EEG results, although no consistent clinical phenotype was identified [12]. Zhou et al. reported a case involving a father and son, both carriers of the 15q13.3 duplications, who were diagnosed with severe schizophrenia [34]. In this study, among nine fetuses with the duplications, four (44.4%, 4/9) showed ultrasound abnormalities, primarily including cardiovascular malformations, corpus callosum hypoplasia, gallbladder enlargement, and lateral ventriculomegaly. Furthermore, among seven cases followed up, three exhibited delays in speech and motor development, epilepsy, and eye diseases. Case 9, which presented with complex multi-organ malformations, demonstrates the incomplete penetrance and broad phenotypic spectrum associated with 15q13.3 duplications.

The primary strength of this study is our comprehensive analysis of the diversity of prenatal clinical phenotypes associated with the 15q13.3 deletion/duplication syndrome. This has broadened the spectrum of clinical phenotypes and initiated a preliminary discussion on the correlation between genotype and phenotype. However, there are still some limitations. Firstly, although this study includes more cases and provides abundant clinical information compared to previous individual case reports, it has not yet identified specific clinical phenotypic features for the syndrome. Secondly, those pregnant with 15q13.3 deletion often choose to terminate their pregnancy after consultation, and none of the fetuses with deletions had postnatal follow-up. Thirdly, as the subjects in this study were generally young, accurately assessing their neuropsychiatric conditions poses a challenge. Lastly, as the study population was ultrasound preselected without healthy controls, the reported phenotype detection rates may be subject to selection bias.

Conclusion

In summary, in this study, we broadened the clinical phenotype spectrum of fetuses with 15q13.3 deletions/duplications and performed preliminary assessments of prenatal ultrasound findings and postnatal clinical phenotypes during the follow-up period at a tertiary hospital prenatal center. Fetuses with 15q13.3 deletions or duplications may be linked to cardiac structural anomalies, lateral ventriculomegaly, and intrauterine growth retardation, but these associations lack specificity. Fetuses with 15q13.3 deletions/duplications that appear phenotypically normal prenatally are often associated with postnatal delays in speech and motor development, as well as epilepsy. Moreover, it is crucial to closely monitor the neuropsychiatric development of fetuses with 15q13.3 deletions and duplications after birth.

Author contributions

All authors have materially participated in this study and manuscript preparation. Xiaojin Luo, Hongyan Niu and Hongqing Liu collected all clinical data and carried out all the molecular and cytogenetic analyses. Xiaohang Chen, Fei Zhou, and Shuxian Zeng participated in the data analysis and drafted the manuscript. Yuhe Fu, Jinxing Liu, and Yanyun Guo designed the work and drafted and revised the manuscript. All authors approved the final article.

Funding

The study was supported by Shenzhend Longgang Science and Technology Development Foundation (Grant No.LGKCYLWS2020106) and the Foundation of Longgang District Key Laboratory of Birth Defects Prevention (No. LGKCZSYS2018000010).

Data availability

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Declarations

Conflict of interest

The authors declare no competing interests.

Ethical approval and consent to participate

This study was approved (No. LGFYYXLL-028) by the Ethics Committee of Longgang District Maternity and Child Heathcare Hospital of Shenzhen City. All patients provided written informed consent for the use of their biological samples for research purposes, in accordance with the institutional review board’s requirements and the Helsinki’s Declaration.

Consent for publication

Consent for publication has been obtained from the patient and/or their legal guardians.