Prenatal diagnosis of 15q11.2 microdeletion fetuses in Eastern China: 21 case series and literature review

Abstract

Objective

15q11.2 microdeletion can lead to syndromes affecting the nervous system. However, 15q11.2 microdeletion has large phenotypic differences and incomplete penetrance, which brings challenges to prenatal diagnosis. We reported 21 cases of 15q11.2 microdeletion fetuses in Eastern China and reviewed literature on the prenatal clinical characteristics related to the deletion variants to provide a basis for prenatal genetic counseling.

Methods

The clinical data of 21 cases of 15q11.2 microdeletion fetuses collected from June 2018 to September 2021 were retrospectively analyzed, and chromosomal microarray analysis was performed. The reported prenatal clinical features of 15q11.2 microdeletion fetuses were reviewed and summarized. A meta-analysis of 20 studies was performed to test heterogeneity, data integration, and sensitivity on the correlation between 15q11.2 microdeletion and neuropsychiatric diseases.

Results

The median age of the women was 29.5 years. The median gestational age at interventional examination was 24 weeks. All fetuses showed deletion variants of the 15q11.2 fragment, and the median deletion range was approximately 0.48 MB. Ultrasound of five cases showed no abnormalities; however, four of them showed a high risk of Down’s syndrome (risk values were 1/184, 1/128, 1/47, and 1/54, respectively). The remaining 16 fetuses showed congenital heart disease (7/16), elevated nuchal translucency (5/16), abnormal brain structure (2/16) and renal disease (2/16). In a literature review of 82 prenatal cases, 44% (36/82) had abnormal ultrasound features, 31% (11/36) showed abnormal nuchal translucency, approximately 28% (10/36) showed abnormal cardiac structure, and 14% (5/36) had brain structural abnormalities. The meta-analysis revealed that the frequency of the 15q11.2 microdeletion mutation in patients with schizophrenia and epilepsy was significantly higher (odds ratio 2.04, 95% confidence interval: 1.78–2.33, p < 0.00001; odds ratio 5.23, 95% confidence interval: 2.83–9.67, p < 0.00001) than that in normal individuals.

Conclusion

More than half of the 15q11.2 microdeletion cases presented no abnormalities in prenatal ultrasound examination. The cases with ultrasound features mainly showed isolated malformations such as elevated nuchal translucency, congenital heart disease, and brain structural abnormalities. Postpartum 15q11.2 microdeletion patients are at an increased risk of suffering from schizophrenia, epilepsy, and other neurological and mental diseases from 15q11.2 microdeletion. Therefore, prenatal diagnosis of 15q11.2 microdeletion not only depends on molecular diagnostic techniques but also requires cautious genetic counseling.

Keywords:

• Prenatal diagnosis
• 15q11.2 microdeletion syndrome
• burnside-butler syndrome
• case series
• genetic counseling

Introduction

Human chromosome 15q11-q13 is located in the subcentromeric region of the long arm of chromosome 15. Copy number variations (CNVs) in this region are associated with human genome imprinting diseases, such as Prader-Willi syndrome (PWS), Angelman syndrome (AS), and Schaaf-Yang syndrome, with a phenotype similar to PWS [1–3]. The clinical manifestations of CNVs in 15q11.2 are mainly related to growth retardation, especially language developmental delay. Other signs include abnormal facial features, cognitive and behavioral abnormalities, and structural changes [4]. There are five breakpoints (BP), which are defined as BP1-BP5, between the 15q11-q13 fragments, and the hot spot associated with the deletion is BP1-BP3. Generally, patients with BP1-BP2 microdeletion have mildly affected phenotypes and no clinical symptoms, while patients with BP1-BP3 deletion can show more serious neurodevelopmental disorders and other symptoms. This is possible because BP1-BP2 contains more genes than distal BP3, including pathological genes that can lead to diseases such as PWS and AS [5,6].

Because the phenotype severity of patients with BP1-BP2 microdeletion varies greatly and has the characteristics of imperfect penetrance, prenatal diagnosis and genetic counseling are more challenging [7,8]. BP1-BP2 deletion syndrome, also known as Burnside-Butler syndrome (BBS), has piqued the interest of many researchers since Butler et al. reported in 2004 that regional deletion variation is related to susceptibility to abnormal phenotypes of the nervous system [9]. Although more than 200 cases of BBS have been reported, prenatal diagnosis is still relatively rare. This is mainly owing to the lack of prenatal ultrasound soft index of BBS and CNV pathogenicity evaluation evidence [7]. Kang et al. [10] showed that only 12 of 31 prenatal cases with 15q11.2 BP1-BP2 microdeletion had ultrasound abnormalities, which were manifested as fetal cardiovascular malformations, elevated nuchal translucency (NT), soft markers, and oligohydramnios. Therefore, further study of prenatal diagnosis of 15q11.2 microdeletion can clarify the abnormal prenatal characteristics, which will help improve prenatal screening measures and inform reproductive decision-making.

Herein, we performed prenatal diagnosis, using interventional diagnostic indicators, in 21 pregnant women from Eastern China. Chromosomal microarray analysis (CMA) revealed varying degrees of 15q11.2 microdeletion in the 21 fetuses. In contrast to previously published case series studies, our study placed more emphasis on the prenatal ultrasound features associated with 15q11.2 microdeletion. Moreover, we analyze the association between the 15q11.2 microdeletion and mental illnesses, such as schizophrenia and epilepsy, through meta-analysis to provide data that can potentially guide prenatal genetic counseling.

Patients and methods

Subjects

We selected patients who underwent prenatal diagnosis at the Genetic Medicine Diagnosis and Treatment Center of Fujian Maternal and Child Health Hospital between June 2018 and September 2021. All the pregnant women included met the indications for interventional prenatal diagnosis. All pregnant women received genetic counseling and signed an informed consent form before the procedure. The study protocol was approved by the Medical Ethics Committee of Fujian Maternal and Child Health Hospital.

Ultrasound examination

The IE33 ultrasound machine (Philips Ultrasound, WA, USA) equipped with a C5-1 PureWave transducer was used for transabdominal ultrasound exploration, and the probe frequency was set at 2–5 MHz. Ultrasound operators were sonographers with early pregnancy screening qualifications and Chinese prenatal ultrasound qualifications.

Interventional prenatal puncture

Samples of amniotic fluid and umbilical cord blood were collected under ultrasound guidance. Amniotic fluid was collected from 16 to 28 weeks of gestation, while umbilical vein blood was collected from 28 to 33 weeks of gestation.

Cytogenetic examination

Fetal cell culture, chromosome preparation, G-banding, and karyotype analyses were performed according to conventional standards. Karyotype naming was based on the International Nomenclature of Human Genetics (ISCN 2015).

Genomic DNA extraction

The Genomic DNA Extraction MiniKit (Qiagen, Hilden, Germany) was used for genomic DNA extraction from amniotic fluid and umbilical cord blood cells. A NanoDrop micro-ultraviolet spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA) was used to measure the concentration and purity of the extracted genomic DNA.

CMA detection

CMA was performed using a CytoScan 750K (Thermo Fisher Scientific, Santa Clara, CA, USA) gene chip. Experiments were carried out according to the manufacturer’s instructions. Original chip data obtained from scanning were analyzed using various genomic variation databases, including the informant Mendelike Genetic Database (https://omim.org/), DECIPHER (https://www.deciphergenomics.org/), ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/), ClinGen Dose-sensitivity database (https://dosage.clinicalgenome.org), and the ISCA database (http://dbsearch.clinicalgenome,org/search/). Published studies retrieved from PubMed (http://www.ncbi.nlm.nih.gov/pubmed/) were used to analyze and evaluate the clinical significance of CNV in accordance with the guidelines of the American College of Medical Genetics.

Literature review of 15q11.2 microdeletion prenatal cases

PubMed (http://www.ncbi.nlm.nih.gov/pubmed/) and Europe PMC databases (http://www.europepmc.org/) were used to search relevant literature using the keywords "15q11.2" and “prenatal diagnosis.” The language was limited to English, and the fetal data of 15q11.2 microdeletion during prenatal diagnosis, including clinical characteristics and variation information, were collected and sorted out.

Correlation analysis between 15q11.2 microdeletion and behavioral characteristics through meta-analysis

PubMed (http://www.ncbi.nlm.nih.gov/pubmed/) and Europe PMC database (http://www.europepmc.org/) were searched, and the references included in the literature were also screened. The language was limited to English, and the following keywords were used "15q11.2 microdeletion syndrome," "schizophrenia," “epilepsies,” and “autism spectrum disorders (ASD).” All included studies adopted the Newcastle-Ottawa scale evaluation criteria used by the non-randomized research methodology group of the Cochrane Collaboration Network for training [11,12]. The Statistical Analysis System software RevMan 5.2 (The Nordic Cochrane Center, The Cochrane Collaboration, Copenhagen, Denmark) for system evaluation was used for meta-analysis [13]. The forest map and I² statistic test were used to assess the heterogeneity of binary variables, and the odds ratio (OR) and 95% confidence interval (CI) of each study and combined effect were calculated. The Mantel-Haenszel method and Z-test were used to estimate the combined effect and test the hypothesis, and the funnel chart was used to explain publication bias. The detailed process can be found in Supplementary Materials 1.

Results

Cytogenetic examination results

Karyotype analysis was performed in 21 fetuses, of which one case suggested balanced chromosome translocation [46, XN,t(1;4)(p36.2;q31.3)], while the other 20 cases showed no obvious abnormality.

CMA test results

All 21 fetuses contained microdeletions of different lengths in 15q11.2, with a median deletion range of approximately 0.48 (0.30–0.83) MB, of which nine were verified by CMA of both parents (four inherited from fathers with normal phenotype, and five inherited from mothers with normal phenotype) (Figure 1(a)).

Figure 1. Distribution of deletion range and abnormal characteristics of prenatal examination of 21 fetuses with 15q11.2 microdeletions in this study. (a) Human chromosome 15 q11-q13 is located in the proximal centromeric region of the long arm. BP1-BP2 region contains four genes, all of which are related to nervous system functions. The median deletion range of 21 fetuses was 0.48 Mb, the maximum was 0.83 Mb, and the minimum was 0.3 Mb. (b) Among the 21 fetuses, five had no abnormal features detected by ultrasound, while the other cases had abnormal features of varying degrees, mainly prenatal detection of high risk of down’s syndrome (24%, 5/21), tricuspid regurgitation (24%, 5/21), and elevated NT (24%, 5/21). the other features were left ventricular hyperechoic focus (10%, 2/21), brain structure abnormality (10%, 2/21), and renal disease (10%, 2/21).

Statistical results of case series phenotype

The median age of the 21 pregnant women was 29.5 (24–39) years, and the median gestational age at genetic examination was 24 (18–33) weeks. All 21 cases were single gestations, of which 5 cases had no abnormality in ultrasound examination, and 4 cases showed a high risk of Down’s screening during prenatal diagnosis (Patients 4,8,9,17). Prenatal ultrasound examination of the other fetuses showed that 43% (7/16) had congenital heart disease (CHD) in varying degrees, including 5 cases of tricuspid regurgitation (Patients 2,5,13,16,20), 2 cases of left ventricular hyperechoic foci (Patients 5,19) and 1 case of ventricular septal defect (Patient 1). Approximately 31% (5/16) of the fetuses had thickened NT. Two fetuses had abnormal brain structures, including Dandy–Walker-like malformation (Patient 1) and bilateral ventriculomegaly (Patient 7). Two fetuses had nephrotic manifestations, including 1 case with left renal accessory artery (Patient 13) and 1 case with right pelvic ectopic kidney with dysplasia and a left renal collecting system slightly separated (Patient 14) (Figure 1(b)). After full genetic counseling to inform the patients of the possible risks, 18 of the 21 women with fetal 15q11.2 microdeletions successfully gave birth. Further, 14 of 18 follow-ups with patients were conducted via telephone 3 months after they gave birth. All children grew and developed normally. In three cases, the patients selected induced labor. # Patient 1 selected induced labor because of Dandy–Walker-like malformation, and the forehead showed a depression deformity after induced labor; #Patient 7 chose induced labor owing to bilateral ventriculomegaly malformation; #Patient 21 chose to induce labor to avoid the risk of mental illness, as her first child has a history of autism. Fours cases did not have follow-up records. The detailed clinical and variantion information for case series is presented in Table 1.

Table 1. Prenatal case data of 21 BP1-BP2 microdeletion fetuses in this study.

Case	Age	Gestational age	Prenatal fetal ultrasound and clinical features	Karyotype analysis results	CMA results	Size	Origin	Pregnancy outcomes
1	34Y	33W	Dandy-Walker malformation; VSD; Screening for DS high risk, test value 1/112	46,XN,t(1;4) (p36.2;q31.3)	arr[hg19] 15q11.2 (22,770,421–23,277,436)x1	0.48	pat	TP
2	28Y	28W	TR; EB	46,XN	arr[hg19] 15q11.2 (22,770,421–23,286,423)x1	0.49	pat	TD
3	32Y	29W	Cystic hygroma; Screening for DS high risk, test value 1/87	46,XN	arr[hg19] 15q11.2 (22,770,421–23,082,237)x1	0.28	/	TD
4	33Y	20W	Screening for DS high risk, test value 1/184	46,XN	arr[hg19] 15q11.2 (22,770,421–23,625,785)x1	0.81	/	TD
5	35Y	21W	Left ventricular hyperechoic foci; TR	46,XN	arr[hg19] 15q11.2 (22,770,421–23,277,436)x1	0.48	/	TD
6	37Y	23W	Absent nasal bone	46,XN	arr[hg19] 15q11.2 (22,770,421–23,276,833)x1	0.48	pat	TD
7	31Y	27W	Bilateral ventriculomegaly	46,XN	arr[hg19] 15q11.2 (22,770,421–23,625,785)x1	0.81	pat	TD
8	34Y	26W	Screening for DS high risk, test value 1/128	46,XN	arr[hg19] 15q11.2 (22,770,421–23,276,833)x1	0.48	/	TD
9	24Y	21W	Screening for DS high risk, test value 1/47	46,XN	arr[hg19] 15q11.2 (22,770,421–23,625,785)x1	0.81	/	TD
10	29Y	19W	NT 2.5mm	46,XN	arr[hg19] 15q11.2 (22,770,421–23,281,886)x1	0.48	/	TD
11	25Y	19W	NT 3.1mm; Uneven echo of bilateral choroid plexus	46,XN	arr[hg19] 15q11.2 (22,770,421–23,082,237)x1	0.29	/	TD
12	30Y	18W	NT 3.2mm	46,XN	arr[hg19] 15q11.2 (22,770,421–23,282,798)x1	0.49	/	TD
13	28Y	19W	TR; Left accessory renal artery	46,XN	arr[hg19] 15q11.2 (22,770,421–23,277,436)x1	0.48	/	TD
14	28Y	24W	Right pelvic ectopic kidney with dysplasia; Mild separation of left renal collecting system	46,XN	arr[hg19] 15q11.2 (22,770,421–23,277,436)x1	0.48	/	TD
15	26Y	22W	Choroid plexus cyst	46,XN	arr[hg19] 15q11.2 (22,770,421–23,615,769)x1	0.81	/	TP
16	32Y	24W	Elevated NT; Mild TR; Systemic skin thickening; Fetal ascites	46,XN	arr[hg19] 15q11.2 (22,770,421–23,195,725)x1	0.41	mat	TD
17	39Y	26W	Screening for DS high risk, test value 1/54	46,XN	arr[hg19] 15q11.2 (22,770,421–23,082,237)x1	0.3	mat	TD
18	28Y	25W	Elevated NT	46,XN	arr[hg19] 15q11.2 (22,770,421–23,277,436)x1	0.48	mat	TD
19	38Y	26W	Left ventricular hyperechoic foci	46,XN	arr[hg19] 15q11.2 (22,770,421–23,277,436)x1	0.48	mat	TD
20	29Y	32W	Mild TR; Small gallbladder	46,XN	arr[hg19] 15q11.2 (22,770,421–23,277,436)x1	0.48	mat	TD
21	34Y	26W	Reproductive history of autistic children	46,XN	arr[hg19] 15q11.2 (22,770,422–23,082,237)x1	0.48	/	TP

Y: year; W: week; VSD: ventricular septal defect; TR: tricuspid regurgitation; EB: echogenic bowel; DS: Down syndrome; TP: termination of pregnancy; TD: term delivery; NT: nuchal translucency; mat: inherited from mother; pat: inherited from father.

Literature review results

A total of six studies comprising 82 prenatal cases related to 15q11.2 microdeletion were collected [10, 14–18]. The median deletion range of 15q11.2 was 0.63 Mb, the maximum deletion was 7.8 Mb, and the minimum deletion was 0.43 Mb. Approximately 44% (36/82) of fetuses showed abnormal features on ultrasound (Figure 2(a)). Among them, around 31% (11/36) of the fetuses showed abnormal NT values (9 cases were higher, 2 cases were lower than normal values); approximately 27.7% (10/36) showed abnormal cardiac structure, including 4 cases of ventricular septal defect, 2 cases of single ventricular artery, and 2 cases of hyperplastic left heart syndrome; about 13.8% (5/36) showed different degrees of intrauterine growth retardation (IUGR); and around 8.3% (3/36) showed microcephaly and 2 cases of brain structural abnormalities (1 case of vermis hypoplasia, 1 case of thin pellucid membrane). Other abnormalities were mostly sporadic; for example, 4 fetuses (11.1%) showed bone abnormalities such as talipes equinovarus or cleft lip and palate (Figure 2(b)). See Supplementary Material 2 for details.

Figure 2. Literature review of prenatal abnormal features in fetuses with 15q11.2 microdeletions. (a) The clinical data of 82 fetuses were collected. More than half of the fetuses had no abnormal features on ultrasound. (b) The main abnormal features of fetuses with 15q11.2 microdeletions were abnormal nuchal translucency, cardiac and vascular malformations, abnormal brain structure (such as microcephaly and vermis hypoplasia), and intrauterine growth retardation of different degrees. Other abnormal features were sporadic (for example, skeletal abnormalities such as talipes equinovarus and/or orofacial cleft in four fetuses).

Meta-analysis results

After literature screening, a total of 24 studies were included in the analysis [19–40]. Among these, 12 studies involved 77,787 patients with schizophrenia and 228,091 healthy controls with 427 (0.5%, 427/77,787) and 596 (0.3%, 596/228,091) 15q11.2 microdeletions, respectively [19–30]. Statistical analysis showed a significant difference in the combined effect (OR: 2.04, 95% CI: 1.78–2.33, p < 0.00001). Another four studies involved 2,311 patients with epilepsy and 23,970 healthy controls with 25 (1.1%, 25/2,311) and 64 (0.3%, 64/23,970) 15q11.2 microdeletions, respectively [31–34]. Statistical analysis showed that there was a significant difference in the combined effect (OR: 5.23, 95% CI: 2.83–9.67, p < 0.00001). In another set of four studies, there was a total of 32,891 patients with ASD and 17,966 healthy controls, with 172 (0.5%, 172/32,891) and 51 (0.3%, 51/17,966) cases of 15q11.2 microdeletions detected, respectively [35–38]. Statistical analysis showed that the combined effect (OR: 2.01, 95% CI: 1.39–2.91, p = 0.0002) was statistically significant (Figure 3). The meta-analysis showed that the probability of carrying 15q11.2 microdeletion in patients with an abnormal nervous system was significantly higher than that in normal people, which indicated that having 15q11.2 microdeletion was more likely to lead to schizophrenia, ASD, and epilepsy.

Figure 3. Meta-analysis process and results. (a) Flow chart of literature collection. (b-d) Statistical analysis of the combined effect showed that schizophrenia, epilepsy, and autism spectrum disorder (ASD) were significantly different from the healthy control group (odds ratio [or]: 2.04, 95% confidence interval [CI]: 1.78–2.33, p < 0.00001; or: 5.23, 95% CI: 2.83–9.67, p < 0.00001; or: 2.01, 95% CI: 1.39–2.91, p = 0.0002). the results showed that carrying 15q11.2 microdeletion was more likely to lead to schizophrenia, epilepsy, and ASD.

Discussion

A large number of tandem repeats exist in the long arm of human chromosome 15, and the proximal and distal regions are highly homologous during evolution [7,8]. However, the structure of the imprinted gene region of 15ql1-q13 is not stable. According to the position of the starting point of the genome, five break points, namely BP1-BP5, can be formed in the 15 long-arm regions. According to different breakpoints, CNVs can be divided into three categories: 15q11.2 (BP1-BP2), 15q11.2-q13.1 (BP2-BP3), and 15q13.2–13.3 (BP4-BP5) [7]. Typically, the BP1-BP2 deletion syndrome (BBS) manifests with mild or partially observable symptoms, complicating clinical diagnosis and genetic counseling [5]. The current study investigated the prenatal characteristics of 21 BP1-BP2 microdeletion cases in Eastern China. Based on CMA technology, the 21 fetuses in this case series were identified as having BP1-BP2 microdeletion, with a median size of 0.48 Mb. Additionally, most of the ultrasound findings indicated isolated malformations. Approximately 43% of the fetuses showed CHD, mainly involving ventricular septal defects and tricuspid regurgitation, and around 31% showed elevated NT. In addition, two fetuses exhibited varying degrees of nephrotic diseases, which is rare in fetuses with BBS. In previously reported cases, a left double kidney malformation was observed in only one fetus [10]. Prenatal diagnosis of BBS is exceptionally rare worldwide, particularly within the Chinese population. This study focuses on the prenatal ultrasound features of BP1-BP2 microdeletion and integrates these findings with those from published case series to delineate the phenotype characteristics. These insights aim to provide clinicians with valuable clinical data for more effective prenatal diagnoses.

We summarized reported prenatal cases of BP1-BP2 microdeletions and screened a total of 82 prenatal cases in the literature [10, 14–18]. Approximately 44% of the cases had abnormal features detected in prenatal ultrasound, which were mainly isolated structural malformations, such as cardiac and cardiovascular structural malformations, elevated NT, abnormal brain structure, and IUGR to varying degrees, and skeletal malformations. This is similar to the phenotypic distribution and frequency observed in this case series. In addition, approximately 56% of the fetuses in the meta-analysis had no abnormal features detected on ultrasound. In the current case series, five cases had no abnormalities on ultrasound examination, and the prenatal diagnosis was made only because of the high risk of Down’s syndrome during screening. the fetus with BP1-BP2 microdeletion has no specific imaging findings, making it difficult to screen from routine examination and for doctors and pregnant women to decide on fetal outcomes. In this study, three pregnant women had difficulty in making a decision to induce labor because they knew that BP1-BP2 microdeletion was a disease risk. Two of these patients were aware that the fetus had severe brain development abnormalities. One patient with autism had a child-bearing history, but the family refused to undergo genetic testing for their first child.

The BP1-BP2 region contains four genes: NIPA1, NIPA2, CYFIP1, and TUBGCP5 [7]. Currently, the OMIM database only records that NIPA1 defects can lead to spastic paraplegia type 6 (OMIM #600363). Goytain et al. [39] reported that NIPA1 mediates Mg²⁺ transport and is highly expressed in the brain tissue. Defects in NIPA1 are mainly characterized by limb spasms and high foot arch. Although the other three genes were not mapped to any Mendelian disease, they were all related to nervous system abnormalities. For example, NIPA2 mutations may lead to childhood absence epilepsy (CAE) [34]. CYFIP1 is mainly expressed in the brain and plays an important role in maintaining dendritic complexity and stabilizing mature axonal processes. Its gene product interacts with FMRP, encoded by fragile X syndrome (FXS)-related genes, which is one of the most common causes of intellectual disability [40]. Lastly, TUBGCP5 is associated with attention deficit hyperactivity disorder and obsessive-compulsive disorder [38]. Therefore, BP1-BP2 microdeletion cases, whether prenatal or postnatal, may have complex phenotypic characteristics, especially an increased risk of resulting in neurodevelopmental abnormalities.

Owing to the gene functions in the BP1-BP2 region mentioned above, BBS characteristics are closely related to developmental disorders and behavioral abnormalities; however, these clinical features may gradually manifest as the children age. Previously, it was reported that BP1-BP2 microdeletion carriers may manifest developmental retardation/intellectual disability (DD/ID), epilepsy, ASD, schizophrenia, CHD, and variable malformations [7, 41]. Notably BP1-BP2 microdeletions have a high distribution frequency in the normal population. Rosenfeld et al. [8] studied more than 20,000 patients with DD/ID and healthy individuals. Using Bayesian analysis, they found that the possibility of an abnormal phenotype caused by BP1-BP2 microdeletions is only approximately 10.4%, and around 90% of carriers may have normal phenotypes. This further explains that some of the microdeletions in children or fetuses with BBS are inherited from non-phenotype parents, which indicates that the phenotypes of the population carrying BP1-BP2 deletion variants are very different.

Most pregnant women without obvious ultrasound indications may have BP1-BP2 microdeletion in the fetus and should be subjected to genetic testing based on factors such as advanced age, prenatal anxiety, and family history. Fetuses carrying BP1-BP2 microdeletion do not necessarily have abnormal clinical manifestations after delivery; however, as they grow older, there is a high risk of neurological phenotypes, resulting in changes in clinical interpretation of gene reports and making clinical diagnosis more challenging, especially in prenatal diagnosis. In general, the literature suggests that BP1-BP2 microdeletions have an important impact on neurocognitive function, but the effect is mild. The meta-analysis performed in this study further proves that microdeletions are related to the phenotype of mental disorders, including schizophrenia and epilepsy, providing data to help in prenatal counseling, genetic diagnosis, and family planning.

In summary, we reported the prenatal ultrasound features and genetic diagnosis of 21 fetuses with BP1-BP2 microdeletion and reviewed the reported literature on BP1-BP2 microdeletion fetuses. More than half of the fetuses with BP1-BP2 microdeletions showed no abnormal characteristics on prenatal ultrasound imaging. The main phenotypes of BBS fetuses with ultrasonic features were isolated malformations, such as CHD, elevated NT, and abnormal brain structure. However, these features are nonspecific; therefore, prenatal diagnosis still needs to rely on molecular diagnostic techniques. In addition, there are still some limitations to this study, mainly due to our failure to conduct long-term follow-up for postnatal infants, especially an in-depth evaluation of nervous system development, including the evaluation and follow-up of growth and development, intelligence, behavioral characteristics, and cognitive ability. In conclusion, prenatal diagnosis of BP1-BP2 microdeletions is difficult, and clinical prenatal consultation should be performed with caution.

Ethical approval

The studies involving human participants were reviewed and approved by the Medical Ethics Committee of Fujian Provincial Maternal and Child Health Hospital (2014042). The participants provided their written informed consent to participate in this study.

Author contributions

LX and MC designed the study. XJ wrote the manuscript. NL and HH revised the article. BL and WZ analyzed CMAs and interpreted the data. All authors contributed to the article and approved the submitted version.

Acknowledgments

The authors are very grateful to all the families who participated in the study.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The raw data supporting the conclusion of this article will be made available by the authors.

Additional information

Funding

This work was sponsored by the Fujian Provincial Natural Science Foundation [2021J01407] and Fujian Provincial Health Technology Project [2020GGA020].