
==== Front
Heliyon
Heliyon
Heliyon
2405-8440
Elsevier

S2405-8440(24)12589-3
10.1016/j.heliyon.2024.e36558
e36558
Research Article
Prenatal diagnosis of 17q12 copy number variants in fetuses via chromosomal microarray analysis - A retrospective cohort study and literature review
Huang Ruibin a1
Ma Chunling ab1
Chen Huanyi a1
Fu Fang a
Han Jin a
Liu Liyuan ab
Li Lushan a
Yan Shujuan a
Lu Jianqin a
Zhou Hang a
Wang You ab
Guo Fei a
Jing Xiangyi a
Li Fucheng a
Zhen Li a
Li Dongzhi a
Li Ru linra020@126.com
a⁎⁎
Liao Can canliao6008@163.com
a⁎
a Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510620, Guangdong, China
b The First Clinical Medical College, Southern Medical University, Guangzhou, 510515, Guangdong, China
⁎ Corresponding author. Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China. canliao6008@163.com
⁎⁎ Corresponding author. Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China. linra020@126.com
1 These authors contributed equally to this work.

19 8 2024
15 9 2024
19 8 2024
10 17 e3655814 4 2024
12 8 2024
19 8 2024
© 2024 Published by Elsevier Ltd.
2024

https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Purpose

17q12 copy number variants (CNVs) have variable presentations and incomplete penetrance, challenging prenatal counseling and management. This study aims to investigate the intrauterine phenotype.

Methods

We included 48 fetuses diagnosed with 17q12 microdeletion or microduplication by chromosomal microarray analysis.

Results

For 17q12 deletion, renal anomalies were found in 35 fetuses (35/37, 94.6 %), with hyperechogenic kidneys (HEK, 28/37, 75.7 %) and multicystic dysplastic kidneys (17/37, 45.9 %) being the most common findings. Duodenal obstruction (DO) was most frequently combined in 17q12 duplication fetuses. In addition, cardiac abnormalities were the first reported prenatal phenotype in 17q12 duplication fetuses.

Conclusion

Our study shows that HEK and DO are the most predominant presentations of 17q12 deletion and duplication, respectively, and cardiac structural abnormalities may be associated with the latter. Although 17q12 CNVs have incomplete penetrance and variable expressivity and may be mainly involved in neurodevelopmental disorders, their short-term prognosis appears positive.

Keywords

17q12 microdeletion
17q12 microduplication
Chromosomal microarray analysis
Prenatal diagnosis
Copy number variants
==== Body
pmc1 Introduction

Copy number variants (CNVs) of chromosome 17q12, including microdeletion and microduplication, are associated with a broad range of clinical phenotypes, and the expressivity is highly variable. The 17q12 region, spanning approximately 1.4 Mb at genomic coordinates 17q12: 34,815,072–36,192,492 (hg19), is considered a hotspot for CNVs due to its flanking by segmental duplications (low copy repeats), making it susceptible to nonallelic homologous recombination (NAHR) [1,2]. Previous studies have shown their prevalence to be approximately 1/14,000 and 1/2675, respectively [3,4]. For 17q12 deletion, HNF1B (OMIM *189,907), LHX1 (OMIM *601,999), and ACACA (OMIM *200,350) are considered the primarily affected genes. HNF1B variants are the common genetic causes of renal, genitourinary, and endocrine abnormalities, while HNF1B heterozygous pathogenic sequence variants may also cause renal cysts and diabetes syndrome (RCAD, OMIM #137920) [5]. LHX1 is a candidate gene for Mayer-Rokitansky-Kuster-Hauser syndrome (MRKHS, OMIM %277,000), a disorder characterized by abnormalities in the female genital tract [6]. Besides, the protein encoded by LHX1 is a transcription factor essential for developing the kidney and urogenital systems. The ACACA gene encodes the alpha form of acetyl-CoA carboxylase [7]. Although the 17q12 duplication contains the same genes as the 17q12 deletion, it is unclear whether or how mutations of these genes lead to the phenotype associated with the 17q12 duplication.

The postnatal phenotype of 17q12 deletion and duplication have been well documented. The former (17q12 deletion) is characterized by a variable combination of the following three phenotypes: structural or functional abnormalities of the kidneys and urinary tract (e.g., hyperechogenic kidneys (HEK), multicystic dysplastic kidney (MCDK), renal cysts), maturity-onset diabetes of the young type 5 (MODY5), and neurodevelopmental or neuropsychiatric disabilities (e.g., developmental delay (DD), intellectual disability (ID), autism spectrum disorder (ASD), and so on) [2]. In contrast, a broader, more comprehensive range of phenotypic manifestations is present in 17q12 duplication. It is mainly characterized by intelligence ranging from normal to severe disability and other different clinical signs such as speech and motor delays, epilepsy, and other neurodevelopmental and psychiatric disorders. Notably, most individuals with 17q12 deletion and duplication were identified by chromosomal microarray analysis (CMA) during the assessment of DD, ID, and/or ASD [1]. Given the complexity and wide variability of phenotypes, ranging from asymptomatic to fatal, it is essential to adequately understand the prenatal ultrasound features of both CNVs and to identify genotype-phenotype correlations.

In this study, we performed the clinical and molecular cytogenetic analysis of prenatal 17q12 deletion and duplication cases. We also conducted a brief literature review to summarize the intrauterine phenotype and pregnancy outcome of all reported prenatal 17q12 deletion and duplication cases to facilitate accurate prenatal diagnosis and comprehensive genetic counseling.

2 Materials and methods

2.1 Subjects

We conducted a retrospective study of 48 fetuses diagnosed with 17q12 microdeletion or microduplication by CMA at Guangzhou Women and Children Medical Center from September 2013 to December 2022. Using our medical records database, we acquired all clinical data of the patients, including maternal age, gestational age, previous reproductive history, family medical history, ultrasound findings, indications for invasive testing, genetic testing results, pregnancy outcomes, and postpartum treatment (if necessary). All pregnancies were offered genetic counseling and signed informed consent before invasive diagnosis. This study was approved by the Ethics Committee of Guangzhou Women and Children's Medical Center. The report follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies.

2.2 Sample preparation and genetic testing tools

First, genomic DNA was extracted using the Qiagen DNA Blood Midi/Mini kit (Qiagen GmbH, Hilden, Germany) according to the manufacturer's protocol. We analyzed fetal samples by quantitative fluorescence polymerase chain reaction (QF-PCR, Guangzhou Darui Biotechnology Co., Ltd, Guangdong, China) to rapidly detect 13, 18, 21, X, and Y aneuploidies and to exclude the possibility of maternal cell contamination. When QF-PCR results were negative, we used CMA or CMA + karyotype analysis as routine tests to exclude other chromosomal abnormalities and genomic imbalances. Karyotype analysis was conducted using standard G-band technology (>400-band resolution). According to the manufacturer's standard operational procedures, genomic DNA digestion, PCR amplification, product purification, fragmentation, labeling, hybridization, washing, and scanning were performed. The Chromosome Analysis Suite (ChAS) V3.2 software (Affymetrix, California, United States) was used for data analysis, and the CMA results were analyzed using relevant databases to determine the properties of chromosome copy number variants. The built reference genome was aligned on GRCh37/hg19. The CytoScan 750 K or CytoScan HD arrays are used to detect whole genome copy number variants, loss of heterozygosity (LOH), isodisomy of uniparental disomy (iso-UPD), and mosaicism at >30 %. The process has been described in detail elsewhere [8].

2.3 Literature review

The terms “17q12 microdeletion”, “17q12 microduplication”, “prenatal diagnosis”, “chromosomal microarray analysis” and their synonyms were used to search the Medical Literature Analysis and Retrieval System Online (MEDLINE), PreMEDLINE, PubMed Central, and Record supplied by Publisher, with 227 articles retrieved. To reduce the chance of missing publications, two authors independently reviewed these documents' titles, abstracts, and full texts, and 20 were finally included. The prenatal ultrasound manifestations, clinical phenotypes, and pregnancy outcomes of the cases described in the literature were summarized and categorized.

3 Results

3.1 Research subjects

From September 2013 to December 2022, we collected 37 fetuses with 17q12 microdeletion and 11 fetuses with 17q12 microduplication diagnosed by CMA. The mean maternal age was 27.5 years (range: 21.0–40.0 years), and the median gestational age was 25.4 weeks (range: 13.7–33.0 weeks). Chorionic villus, amniotic fluid, or cord blood was extracted based on gestational age. Of these, 64.6 % (31/48) underwent amniocentesis, while percutaneous umbilical cord blood sampling and chorionic villus sampling were performed in 33.3 % and 2.1 % of pregnancies, respectively.

3.2 CMA and ultrasound results

3.2.1 17q12 microdeletion

As shown in Table 1, the size of the 17q12 microdeletion ranged from 1.42 Mb to 1.94 Mb in these cases, all of which contained the HNF1B, LHX1, and ACACA genes. A total of 27 fetal parents underwent CMA validation, with 22 (81.5 %) confirmed as de novo variants, and another five were inherited from their parents. Considering the financial factor, other parents refused the offer of parental CMA verification because its price was close to 1000 dollars. Apart from an isolated abdominal cyst or ependymal cyst detected by prenatal ultrasound in Del 36 and Del 37, renal anomalies were found in other 35 fetuses (94.6 %), with HEK (28/37, 75.7 %) and MCDK (17/37, 45.9 %) being the most common findings. In addition, our study has reported 3 MCDK fetuses combined with other first-reported ultrasound findings (e.g., congenital cystic adenomatoid malformation, short limbs, and enlarged cisterna magna), expanding the phenotypic spectrum of this CNV.Table 1 Clinically relevant characteristics of 17q12 deletion fetuses and pathogenic CMA findings.

Table 1Cases	GA (weeks)	MA (years)	Prenatal ultrasound findings	CMA findings	Size (Mb)	Inheritance	Outcomes	
1	27.3	26	Isolated HEK	arr17q12(34,822,493–36,243,365) × 1	1.42	ND	TOP	
2	29.6	29	Isolated HEK	arr17q12(34,822,466–36,418,529) × 1	1.60	De novo	TOP	
3	26.2	26	Isolated HEK	arr17q12(34,822,466–36,243,365) × 1	1.42	ND	TOP	
4	24.9	29	Isolated HEK	arr17q12(34,822,466–36,404,136) × 1	1.58	De novo	TOP	
5	26.3	38	Isolated HEK	arr17q12(34,822,465–36,418,529) × 1	1.60	ND	Live birth (Normal)	
6	29.4	23	Isolated HEK	arr17q12(34,822,465–36,307,773) × 1	1.49	Inherited	Lost to follow-up	
7	33.1	27	Isolated HEK	arr17q12(34,822,465–36,307,773) × 1	1.49	Inherited	Live birth (CBD, Hydronephrosis)	
8	26.4	29	Isolated HEK	arr17q12(34,822,465–36,404,555) × 1	1.58	Inherited	Live birth (Normal)	
9	23.1	30	Isolated HEK	arr17q12(34,822,465–36,418,529) × 1	1.60	ND	Live birth (HEK)	
10	23.3	26	Isolated HEK	arr17q12(34,822,465–36,307,773) × 1	1.49	De novo	TOP	
11	25.3	23	Isolated HEK	arr17q12(34,822,465–36,243,365) × 1	1.42	De novo	TOP	
12	21.4	34	HEK, MCDK	arr17q12(34,835,984–36,307,773) × 1	1.47	ND	TOP	
13	24.7	30	HEK, MCDK	arr17q12(34,822,466–36,418,529) × 1	1.60	Inherited	Live birth (MCDK)	
14	22.3	24	HEK, MCDK	arr17q12(34,822,466–36,243,365) × 1	1.42	ND	TOP	
15	26.3	27	HEK, MCDK	arr17q12(34,822,465–36,243,365) × 1	1.42	ND	TOP	
16	24.7	28	HEK, MCDK	arr17q12(34,822,465–36,311,009) × 1	1.49	De novo	TOP	
17	23.4	31	HEK, MCDK	arr17q12(34,822,465–36,404,136) × 1	1.58	De novo	TOP	
18	25.7	28	HEK, MCDK	arr17q12(34,822,465–36,244,332) × 1	1.42	Inherited	TOP	
19	25.6	28	HEK, MCDK	arr17q12(34,822,465–36,307,773) × 1	1.49	De novo	TOP	
20	23.6	24	HEK, MCDK	arr17q12(34,475,679–36,410,720) × 1	1.94	De novo	Live birth (MCDK)	
21	27.9	26	HEK, MCDK	arr17q12(34,822,465–36,404,555) × 1	1.58	De novo	TOP	
22	32.1	25	HEK, MCDK, enlarged kidney, polyhydramnios	arr17q12(34,477,479–36,404,104) × 1	1.93	De novo	TOP	
23	24.7	23	HEK, polyhydramnios	arr17q12(34,822,465–36,243,365) × 1	1.42	De novo	Live birth (HEK)	
24	23.9	34	HEK, renal cysts, polyhydramnios	arr17q12(34,822,466–36,370,997) × 1	1.55	De novo	IUFD	
25	23.9	24	HEK, renal dysplasia	arr17q12(34,822,465–36,418,529) × 1	1.60	De novo	TOP	
26	25.4	33	HEK, enlarged kidney	arr17q12(34,822,465–36,404,555) × 1	1.58	De novo	TOP	
27	25.7	31	HEK, duplex kidney	arr17q12(34,822,466–36,404,555) × 1	1.58	De novo	TOP	
28	30.6	28	HEK, pyelectasis	arr17q12(34,822,492–36,404,104) × 1	1.58	De novo	TOP	
29	24.3	40	Isolated MCDK	arr17q12(34,822,466–36,404,104) × 1	1.58	De novo	TOP	
30	28.1	28	MCDK, hydronephrosis	arr17q12(34,822,465–36,307,773) × 1	1.49	ND	TOP	
31	25.4	22	MCDK, polyhydramnios	arr17q12(34,822,465–36,316,144) × 1	1.49	De novo	TOP	
32	25.6	31	MCDK, CCAM, polyhydramnios	arr17q12(34,822,465–36,418,529) × 1	1.60	De novo	TOP	
33	26.3	37	MCDK, enlarged cisterna magna	arr17q12(34,822,465–36,418,529) × 1	1.60	De novo	TOP	
34	25.9	24	MCDK, short limbs	arr17q12(34,822,465–36,404,104) × 1	1.58	ND	TOP	
35	26.1	35	Hydronephrosis	arr17q12(34,822,465–36,283,612) × 1	1.46	De novo	TOP	
36	26.1	30	Abdominal cyst	arr17q12(34,822,465–36,410,559) × 1	1.59	ND	TOP	
37	31.6	27	Ependymal cyst	arr17q12(34,822,465–36,316,144) × 1	1.49	De novo	TOP	
CMA: chromosome microarray analysis; GA: gestational age; MA: maternal age; HEK: hyperechogenic kidneys; ND: not documented; TOP: termination of pregnancy; CBD: congenital biliary dilation; MCDK: multicystic dysplastic kidney; IUFD: intra-uterine fetal death; CCAM: congenital cystic adenomatoid malformation.

3.2.2 17q12 microduplication

The common duplication in 11 cases of 17q12 microduplication fetuses encompasses a genomic region of about 1.41 Mb (chr17: 34,822,466–36,236,609, GRCh37/hg19), and all of the duplicated regions include the HNF1B, LHX1, and ACACA genes. We obtained seven cases with parental CMA validation results, of which four (4/7, 57.1 %) were parentally inherited, lower than previously reported in the literature [1]. Clinical information of all cases is summarized in Table 2. The “double bubble sign” was observed in 4 cases (Dup 1-4), including Dup 3 and Dup 4 combined with polyhydramnios, strongly indicating the occurrence of duodenal obstruction (DO). In addition, cardiac structural abnormalities (ventricular septal defect (VSD), pentalogy of Cantrell, and echogenic intracardiac focus) were identified as new prenatal phenotypes of 17q12 duplication.Table 2 Clinically relevant characteristics of 17q12 duplication fetuses and pathogenic CMA findings.

Table 2Cases	GA (weeks)	MA (years)	Prenatal ultrasound findings	CMA findings (hg19)	Size (Mb)	Inheritance	Outcomes	
1	24.3	28	Duodenal obstruction	arr17q12(34,822,466–36,378,678) × 3	1.56	Inherited	TOP	
2	22.7	24	Duodenal obstruction	arr17q12(34,440,082–36,283,612) × 3	1.84	ND	TOP	
3	30.1	25	Duodenal obstruction, polyhydramnios	arr17q12(34,822,465–36,410,559) × 3	1.59	Inherited	TOP	
4	25.9	34	Duodenal obstruction, polyhydramnios	arr17q12(34,822,466–36,397,279) × 3	1.57	ND	TOP	
5	26.1	33	VSD	arr17q12(34,822,466–36,283,612) × 3	1.46	ND	TOP	
6	13.7	19	Pentalogy of Cantrell	arr17q12(34,449,165–36,243,365) × 3	1.79	De novo	TOP	
7	26.1	21	Echogenic intracardiac focus	arr17q12(34,822,466–36,307,773) × 3	1.49	ND	TOP	
8	18.7	26	Cystic hygroma	arr17q12(34,440,082–36,375,201) × 3	1.94	Inherited	TOP	
9	28.3	26	Microcephaly, agenesis of the corpus callosum	arr17q12(34,822,465–36,378,678) × 3	1.56	De novo	TOP	
10	18.8	40	Normal (Age = 40 years)	arr17q12(34,440,089–36,236,609) × 3	1.80	Inherited	TOP	
11	17.9	38	Normal (Autism in the last pregnancy)	arr17q12(34,822,465–36,350,028) × 3	1.53	De novo	TOP	
CMA: chromosome microarray analysis; GA: gestational age; MA: maternal age; TOP: termination of pregnancy; ND: not documented; VSD: ventricular septal defect.

3.3 Pregnancy outcomes

For 37 pregnancies with 17q12 deletion, pregnancy outcomes were obtained in 36 cases (97.3 %). Twenty-eight families (75.7 %) chose to terminate the pregnancy, and seven cases (18.9 %) were live births, including four isolated HEK fetuses and the other three HEK fetuses combined with MCDK or polyhydramnios. All children underwent postnatal ultrasound, except for Del7, in which biliary dilation and hydronephrosis were found; the remaining six cases showed no abnormalities or were consistent with prenatal ultrasound findings. Moreover, Del 24 was intra-uterine fetal death, and Del 6 was lost to follow-up. While 11 cases of 17q12 duplication were chosen to terminate the pregnancy, none agreed to a further autopsy.

3.4 Literature review

The flowchart of literature retrieval and review progression is illustrated in Fig. 1. The search strategy identified 227 studies, of which 194 were excluded, and another 33 were reviewed in full text, with 20 articles eventually enrolled, containing 56 fetuses with 17q12 deletion and 17 fetuses with 17q12 duplication [[9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28]]. We summarized and categorized the prenatal and postnatal ultrasound phenotypes, CMA findings, and pregnancy outcomes of the cases reported in the included articles (Table 3, Table 4). In addition, we counted the ultrasound abnormalities found in the available literature (including our study, Fig. 2, Fig. 3), and we identified HEK and DO as the most common prenatal ultrasound phenotypes for 17q12 microdeletion and microduplication, respectively.Fig. 1 Flowchart of literature retrieval and review progression.

Fig. 1

Table 3 Clinically relevant features and pathogenic CMA findings in fetuses with 17q12 deletion syndrome in published cases.

Table 3Reference	Number of cases	GA (weeks)	Prenatal ultrasound findings	CMA findings (hg19)	Size (Mb)	Inheritance	Outcomes	
Tutulan et al., 2022	2	24	Unilateral MCDK	arr17q12(34,817,422–36,168,104) × 1	1.35	ND	TOP	
17	Megabladder, SUA, CPCs	arr17q12(34,851,537–36,168,104) × 1	1.31	ND	TOP	
Deng et al., 2022	6	26.1	Isolated HEK	arr17q12(34,475,679–36,423,183) × 1	1.95	ND	Live birth (Normal)	
24.1	Isolated HEK	arr17q12(34,823,295–36,404,104) × 1	1.58	ND	TOP	
ND	HEK, SUA	arr17q12(34,822,465–36,316,144) × 1	1.49	ND	TOP	
21.9	HEK, unilateral MCDK	arr17q12(34,822,466–36,418,529) × 1	1.60	ND	TOP	
30.7	HEK, polyhydramnios	arr17q12(34,822,465–36,307,773) × 1	1.49	ND	Live birth (HEK)	
26.4	HEK, polyhydramnios	arr17q12(34,822,465–36,418,529) × 1	1.60	ND	TOP	
Wang et al., 2022	2	23	HEK, polyhydramnios	arr17q12(36,486,626–37,930,498) × 1	1.44	De novo	TOP	
20	HEK, bilateral MCDK	arr17q12(34,822,466–36,300,630) × 1	1.48	De novo	TOP	
Qiao et al., 2022	1	22.6	Isolated HEK	arr17q12(34,460,443–36,316,144) × 1	1.90	ND	TOP	
Zhang et al., 2021	2	23.4	Hydronephrosis, polyhydramnios	arr17q12(34,822,465–36,243,365) × 1	1.40	Inherited	TOP	
26.2	HEK, polyhydramnios	arr17q12(34,822,465–36,243,365) × 1	1.40	Inherited	TOP	
Zhou et al., 2021	10	23	HEK, polyhydramnios	arr17q12(34,477,479–36,243,365) × 1	1.76	Inherited	TOP	
32	Isolated HEK	arr17q12(34,822,465–36,378,678) × 1	1.55	ND	ND	
26	HEK, enlarged kidney	arr17q12(34,822,492–36,216,603) × 1	1.39	De novo	TOP	
20	Unilateral MCDK	arr17q12(34,822,465–36,300,466) × 1	1.47	De novo	TOP	
18	17q12 deletion in the last pregnancy	arr17q12(34,822,465–36,311,009) × 1	1.48	Inherited	TOP	
23	Isolated HEK	arr17q12(34,822,465–36,243,365) × 1	1.42	De novo	Live birth (Bilateral polycystic kidneys)	
25	Isolated HEK	arr17q12(34,822,465–36,404,555) × 1	1.58	Inherited	TOP	
25	Isolated HEK	arr17q12(34,822,465–36,387,880) × 1	1.56	De novo	TOP	
29	Hydronephrosis, polyhydramnios	arr17q12(34,476,877–36,425,336) × 1	1.94	De novo	TOP	
26	Isolated HEK	arr17q12(34,822,492–36,397,279) × 1	1.57	De novo	ND	
Cleper et al., 2021	1	32	Cystic kidneys	arr17q12(34,822,465–36,410,720) × 1	1.50	Inherited	TOP	
Wu et al., 2020	2	18	Enlarged kidney, oligohydramnios	arr17q12(34,820,000–36,220,000) × 1	1.40	De novo	TOP	
22	HEK, smaller kidneys	arr17q12(34,822,465–36,307,773) × 1	1.48	De novo	TOP	
Shang et al., 2020	5	29	Isolated HEK	arr17q12(34,822,465–36,351,919) × 1	1.53	ND	TOP	
31	Isolated HEK	arr17q12(34,817,422–36,168,104) × 1	1.35	De novo	TOP	
30	HEK, polyhydramnios	arr17q12(34,822,465–36,307,773) × 1	1.49	De novo	TOP	
26	HEK, smaller kidneys	arr17q12(34,817,422–36,168,104) × 1	1.35	De novo	TOP	
28	HEK, polyhydramnios	arr17q12(34,880,000–36,060,000) × 1	1.18	ND	Lost to follow-up	
Wan et al., 2019	5	ND	MCDK	arr17q12(34,822,465–36,404,555) × 1	1.58	De novo	Live birth (Developmental Delay, MCDK)	
ND	Pyelectasis	arr17q12(34,822,465–36,307,773) × 1	1.48	De novo	Live birth (Normal)	
ND	Isolated HEK	arr17q12(34,822,465–36,404,555) × 1	1.58	De novo	Neonatal death (Abdominal distension)	
ND	Hydronephrosis	arr17q12(34,822,465–36,243,365) × 1	1.42	De novo	TOP	
ND	Bilateral dysplastic kidneys	arr17q12(34,822,465–36,404,104) × 1	1.58	De novo	TOP	
Hu et al., 2019	8	ND	Hydronephrosis	arr17q12(34,476,877–36,243,365) × 1	1.77	ND	TOP	
ND	Isolated HEK	arr17q12(34,822,465–36,418,529) × 1	1.60	De novo	TOP	
ND	Isolated HEK	arr17q12(34,476,877–36,243,365) × 1	1.77	De novo	TOP	
ND	Isolated HEK	arr17q12(34,822,465–36,404,555) × 1	1.58	De novo	TOP	
ND	Isolated HEK	arr17q12(34,822,465–36,418,529) × 1	1.60	De novo	TOP	
ND	Isolated HEK	arr17q12(34,835,983–36,378,678) × 1	1.54	De novo	TOP	
ND	Isolated HEK	arr17q12(34,822,465–36,307,773) × 1	1.49	De novo	TOP	
ND	Isolated HEK	arr17q12(34,822,465–36,243,365) × 1	1.42	De novo	TOP	
Pan et al., 2019	2	26	Unilateral MCDK	arr17q12(34,817,422–36,168,104) × 1	1.35	De novo	TOP	
26	Isolated HEK	arr17q12(34,817,422–36,168,104) × 1	1.35	De novo	TOP	
Jiang et al., 2017	3	25.2	Bilateral MCDK	arr17q12(34,822,465–36,404,555) × 1	1.50	De novo	TOP	
32.9	Isolated HEK	arr17q12(34,822,465–36,425,336) × 1	1.60	De novo	TOP	
18	Isolated HEK	arr17q12(34,822,465–36,243,365) × 1	1.40	Inherited	TOP	
Xi et al., 2016	2	ND	Unilateral MCDK	arr17q12(34,823,294–36,316,144) × 1	1.49	Inherited	ND	
ND	Unilateral MCDK	arr17q12(34,822,465–36,404,104) × 1	1.58	Inherited	ND	
Yap et al., 2015	3	27	HEK, CDH, pyelectasis, polyhydramnios	arr17q12(34,822,465–36,418,529) × 1	1.60	Inherited	Live birth (CDH, HEK, cystic kidneys, abnormal kidney function)	
27	HEK, pyelectasis	arr17q12(34,822,465–36,418,529) × 1	1.60	Inherited	Live birth (HEK, cystic kidneys)	
21	HEK, CDH	arr17q12(34,822,465–36,311,009) × 1	1.49	De novo	Live birth (CDH, Normal kidneys)	
Chen et al., 2013	1	20	Hydronephrosis	arr17q12(34,653,178–36,402,867) × 1	1.75	Inherited	TOP	
Hendrix et al., 2012	1	20	Isolated CDH	arr17q12(31,890,483–33,281,801) × 1	1.40	ND	Neonatal death	
CMA: chromosomal microarray analysis; GA: gestational age; MCDK: multicystic dysplastic kidney; ND: not documented; TOP: termination of pregnancy; SUA: single umbilical artery; CPCs: choroid plexus cyst; HEK: hyperechogenic kidneys; CDH: congenital diaphragmatic hernia.

Table 4 Clinically relevant features and pathogenic CMA findings in fetuses with 17q12 duplication syndrome in published cases.

Table 4Reference	Number of cases	GA (weeks)	Prenatal ultrasound findings	CMA findings (hg19)	Size (Mb)	Inheritance	Outcomes	
Zhang et al., 2022	6	33.3	Duodenal obstruction, polyhydramnios	arr17q12(34,449,165–36,236,086) × 3	1.78	Inherited	Live birth (Duodenal obstruction)	
25.1	Duplex kidney	arr17q12(34,822,465–36,351,919) × 3	1.50	Inherited	TOP	
19	IUGR, increased NT	arr17q12(34,440,088–36,243,365) × 3	1.80	ND	Lost to follow-up	
24	Duodenal obstruction, polyhydramnios	arr17q12(34,424,710–36,307,773) × 3	1.88	De novo	TOP	
30.7	Duodenal obstruction, polyhydramnios	arr17q12(34,822,466–36,243,365) × 3	1.42	Inherited	Live birth (Duodenal obstruction)	
34.6	Duodenal obstruction	arr17q12(34,822,465–36,404,104) × 3	1.58	Inherited	Live birth (Duodenal obstruction)	
Cai et al., 2022	5	18.3	Strong echo in left ventricle	arr17q12(34,440,088–36,351,919) × 3	1.90	Inherited	Live birth (Normal)	
26.3	ACC, ventriculomegaly, dysplasia of the septum pellucidum	arr17q12(34,822,465–36,378,678) × 3	1.50	Inherited	Live birth (Normal)	
19	Normal (High-risk for Down's screening)	arr17q12(34,440,088–36,243,365) × 3	1.80	ND	TOP	
23.9	Duodenal obstruction	arr17q12(34,440,088–36,243,365) × 3	1.80	ND	TOP	
28.6	Duodenal obstruction	arr17q12(34,426,244–36,300,630) × 3	1.80	ND	Live birth (Duodenal obstruction)	
Zhou et al., 2021	4	29	TOF, FL, and HL < 5 centile	arr17q12(34,822,465–36,307,773) × 3	1.48	Inherited	TOP	
30	BPD and HC < 5 centile	arr17q12(34,822,465–36,300,630) × 3	1.47	Inherited	ND	
25	Duodenal obstruction, polyhydramnios	arr17q12(34,822,465–36,243,365) × 3	1.42	Inherited	TOP	
22	Pulmonary artery stenosis, tricuspid regurgitation	arr17q12(34,822,465–36,300,630) × 3	1.47	De novo	TOP	
Wan et al., 2019	1	ND	Polyhydramnios	arr17q12(34,822,465–36,404,104) × 3	1.58	De novo	Live birth (Normal)	
Chen et al., 2016	1	17	Normal (Age = 36 years)	arr17q12(34,611,377–36,248,889) × 3	1.64	Inherited	Live birth (Normal)	
CMA: chromosome microarray analysis; GA: gestational age; TOP: termination of pregnancy; IUGR: intrauterine growth retardation; NT: nuchal translucency; ND: not documented; ACC: agenesis of the corpus callosum; TOF: tetralogy of Fallot; FL: femur length; HL: humerus length; BPD: biparietal diameter; HC: head circumference.

Fig. 2 Associated malformations identified by ultrasound in fetuses with 17q12 microdeletion syndrome in the available literature (including our study) (Image produced at https://www.chiplot.online/).

Fig. 2

Fig. 3 Associated malformations identified by ultrasound in fetuses with 17q12 microduplication syndrome in the available literature (including our study) (Image produced at https://www.chiplot.online/).

Fig. 3

4 Discussion

With the development and widespread use of CMA technology in the last decade, 17q12 microdeletion is considered the second most common CNV in fetuses with abnormal ultrasound findings and normal karyotype after 22q11.2 deletion syndrome (OMIM #188400) [29]. Whereas 17q12 microduplication was first described by Sharp et al. [30] in 2006, at least 50 individuals have been reported, and these individuals were often further tested for CMA because of ID and/or DD. Increased numbers of postpartum cases are being reported, accompanied by a better description of their postpartum phenotype. However, there are few large prenatal cohort studies to elucidate further the genetic and clinical value of CMA in fetuses with 17q12 CNVs. Therefore, this study aims to investigate the intrauterine phenotype of fetuses with 17q12 CNVs, thus providing a useful reference for prenatal diagnosis and genetic counseling.

The 17q12 microdeletion is closely associated with renal abnormalities, especially HEK. In our study, the rate of kidney abnormalities in 17q12 deletion fetuses was as high as 94.6 %, higher than the rate of 80%–85 % reported in the previous literature [13]. Although the association of 17q12 deletion with renal abnormalities has been initially described, the mechanism leading to developmental anomalies is still under investigation. Mutations in HNF1B, the gene encoding hepatocyte nuclear factor 1β, are the most common genetic cause of kidney malformations [31,32]. Furthermore, the most common mutation in about 50 % of cases is a deletion of the entire gene occurring in the context of 17q12 microdeletion [32,33]. Compared to intragenic HNF1B pathogenic variants, 17q12 deletion fetuses were born with better renal function and a lower risk of progression to end-stage renal disease [34,35]. Clissold et al. [34] revealed that significant DNA methylation changes were observed in cases with a 17q12 heterozygous deletion. They speculated that this might be a regulatory mechanism in response to haploinsufficiency across the entire deleted region. In a large retrospective study illustrating the correlation between fetal kidney abnormalities and CNVs, Su et al. [36] indicated that HEK had a CMA diagnostic yield of up to 39.58 %. In comparison, approximately 31.3 % of HEK cases were associated with 17q12 deletion. As shown in Fig. 2, HEK is the most common prenatal phenotype among the cases reported in the available literature (64/93, 68.8 %), while it may result from various renal abnormalities. Of these, 34.4 % (32/93) of 17q12 deletion fetuses were found with isolated HEK, which signals that without CMA testing, these cases may be ignored without predicting their prognosis, providing sufficient evidence for the necessity of CMA testing for HEK fetuses.

17q12 duplication fetuses exhibit a broad phenotypic spectrum, and DO appears to be closely associated with this CNV. Besides neurological and psychiatric symptoms, congenital heart disease, duodenal atresia, and microcephaly have been reported in some 17q12 duplication adults [37,38]. In contrast, the ultrasound phenotype of 17q12 duplication fetuses has rarely been reported, with several studies indicating that DO may be closely associated with this CNV [9,26,28]. Our study identified four (4/11, 36.4 %) fetuses suspected of DO, two combined with polyhydramnios. Although the correlation between HNF1B and the phenotype related to 17q12 duplication has not been clearly elucidated, the HNF1B gene is widely and early expressed in several organs, such as the gut, genitourinary tract, bile duct, and thymus [39]. For the gut, several studies showed that HNF1B might function in intestinal differentiation. It has been shown, for example, in animal models, that HNF1B is required for regional gut specification [40,41]. In mice, the expression of Hnf1b is essential for endoderm differentiation of the viscera and morphogenesis of the intestine, liver, and biliary tract [42,43]. In zebrafish, it is expressed in the foregut and hindgut endoderm [44]. Moreover, 17q12 duplication does not seem to be significantly relevant to renal anomalies but may be a genetic cause of cardiovascular abnormalities. Zhou et al. [28] first reported two fetuses with combined cardiac structural abnormalities (tetralogy of Fallot, tricuspid regurgitation) in 2021. In this study, we have reported three cases of 17q12 duplication fetuses combined with isolated cardiac structural abnormalities such as VSD, pentalogy of Cantrell, and echogenic intracardiac focus, further complicating the associated cardiac phenotype of this CNV.

Neurodevelopmental disorder or neuropsychiatric impairment is one of the most concerning extrarenal features of 17q12 deletion or duplication. For 17q12 deletion, several studies have indicated an increased risk of neurodevelopmental/neuropsychiatric disorders [32,37,45,46]. In a case-control study, Moreno-De-Luca et al. [45] indicated that 17q12 deletion patients are exposed to an increased risk of ASD and schizophrenia. They speculated that one or more of these 15 genes within the deletion interval are dose-sensitive and critical for normal brain development and function. Moreover, compared to the general population, Laliève et al. [47] found that HNF1B gene deletion increased the risk of developing neuropsychiatric disorders. However, when considering 17q12 deletion patients secondary to renal abnormalities, the neurological outcome was not as severe as in patients diagnosed for neurological reasons. Therefore, there is a need for more studies to ascertain the role of HNF1B in the human brain. Besides, LHX1 is another candidate gene for neurodevelopmental anomalies. Lhx1 was demonstrated to function in the transcriptional control of axonal guidance and the differentiation of neuronal cells and was shown to regulate head formation in early mouse embryos [[48], [49], [50]]. Therefore, we speculate that LHX1 may also help explain the neurodevelopmental manifestations resulting from this deletion. As for 17q12 duplication patients, the main clinical presentations are intelligence ranging from normal to severe disability, cerebral dysplasia, epilepsy, behavioral abnormalities, and DD [1]. However, due to its incomplete penetrance and extreme phenotypic variability, it is difficult to establish its gene-phenotype correlation, and overexpression of genes in this region does not explain the different phenotypic expressions of 17q12 duplication patients. Therefore, it poses a challenge for prenatal counseling; we need to inform the pregnancies and families about the penetrance and possible phenotypes of this CNV. If the parents intend to continue the pregnancy, then further detailed ultrasound and genetic testing must be performed during the pregnancy to determine if the fetus is normal. Furthermore, prompt neuropsychiatric evaluation and monitoring should be conducted after birth to allow for early intervention.

Either 17q12 deletion or duplication, the short-term prognosis seems to be positive. The follow-up period was approximately three months to three years and seven months after birth. There were seven cases of 17q12 deletion in our study who chose to continue the pregnancy. Del7 suggested an isolated HEK on prenatal ultrasound, but on postnatal ultrasound, the infant showed biliary dilation and hydronephrosis, and the remaining six cases had no additional findings. Furthermore, Del 5, Del 8, and Del 23 underwent renal function and urinalysis in infancy without any abnormality, and the remaining four cases have not been tested. As shown in Table 3, for eight live birth cases, six (75 %) had no additional findings on postpartum follow-up ultrasound or normal renal function tests. Wan et al. [21] described a fetus with MCDK detected by prenatal ultrasound, and the diagnosis was confirmed by postnatal ultrasound. The child had DD and poor physical characteristics one year after birth. At two years old, the child still had poor language expression, could not walk, and was admitted to regular rehabilitation training. Yap et al. [25] reported a case of identical twins in which prenatal ultrasound showed bilateral HEK and mild renal pelvic dilatation in both twins. In addition, in twin 1, a left-sided diaphragmatic hernia that was surgically repaired after delivery. Postnatal ultrasound showed bilateral HEK and cortical cysts in both twins, but renal function scan (MAG-3) demonstrated left-sided renal absence and normal right-sided renal function in twin 1. For 17q12 duplication, 11 cases in our study chose to terminate the pregnancy due to ultrasound and CMA findings. As shown in Table 4, a total of eight of the 17 included cases chose to continue the pregnancy, and four underwent surgery after birth due to DO; the remaining four cases had no significant abnormalities on postnatal follow-up, which undoubtedly increases the confidence of other families to opt to continue the pregnancy. Although some children are currently normal in terms of growth and psychomotor development, detailed renal function monitoring and neuropsychiatric evaluation should be assured in the future for timely intervention, which is one of the significances of our prenatal diagnosis in the prenatal setting.

We acknowledge important limitations when reviewing these findings. First, this is a retrospective study and may have recall bias. Second, some families do not choose to do the parent CMA verification because it costs close to $1000, and we could consider using the MLPA testing for 17q11.2 CNV later as a cheaper option for family member testing. Finally, neurodevelopmental disorders may not manifest until a later age, so further long-term follow-up of these cases must be established to discuss prenatal-postnatal phenotypic correlations for better prenatal genetic counseling and management.

5 Conclusion

To our knowledge, this is the most extensive prenatal study using CMA for genetic analysis of fetuses with 17q12 CNVs. Our study shows that HEK and DO are the most predominant prenatal ultrasound presentations of 17q12 deletion and duplication, respectively, and cardiac structural abnormalities may be associated with the latter. Although 17q12 CNVs have incomplete penetrance and variable expressivity and may be mainly involved in neurodevelopmental disorders, their short-term prognosis appears positive.

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Guangzhou Women and Children's Medical Center (Approval number: 2021-356B01). This study was performed in line with the principles of the Declaration of Helsinki and its later amendments. Informed consent was obtained from all individual participants included in the study.

Funding

This research was funded by the sub-project of the 10.13039/501100012166 National Key R&D Program (2021YFC2701002 ), the 10.13039/501100001809 National Natural Science Foundation of China (82101796 , 82201884 ), the 10.13039/501100021171 Guangdong Basic and Applied Basic Research Foundation (2023A1515010115 ), Guangzhou Science and Technology Project (202201020643 , 202201010879 , 20221A011029 , 202201020604 , 202102020061 ).

Data availability statement

The data that support the findings of this study are not publicly available as the information contained could compromise the privacy of research participants. Further inquiries can be directed to the corresponding author.

CRediT authorship contribution statement

Ruibin Huang: Writing – original draft, Conceptualization. Chunling Ma: Visualization, Resources, Investigation, Data curation. Huanyi Chen: Writing – original draft, Conceptualization. Fang Fu: Validation, Supervision, Funding acquisition. Jin Han: Methodology, Investigation, Data curation. Liyuan Liu: Writing – original draft, Conceptualization. Lushan Li: Validation, Investigation, Data curation. Shujuan Yan: Visualization, Methodology, Investigation. Jianqin Lu: Visualization, Investigation, Formal analysis, Data curation. Hang Zhou: Visualization, Investigation, Formal analysis, Data curation. You Wang: Investigation, Data curation. Fei Guo: Visualization, Investigation, Data curation. Xiangyi Jing: Software, Project administration, Methodology, Data curation. Fucheng Li: Software, Methodology, Investigation, Data curation. Li Zhen: Visualization, Resources, Data curation. Dongzhi Li: Validation, Supervision, Project administration, Data curation. Ru Li: Writing – review & editing, Validation, Supervision. Can Liao: Writing – review & editing, Validation, Supervision, Funding acquisition.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

List of abbreviations

CNVs Copy number variants

Mb Megabase

NAHR nonallelic homologous recombination

OMIM Online Mendelian Inheritance in Man

RCAD renal cysts and diabetes syndrome

MRKHS Mayer-Rokitansky-Kuster-Hauser syndrome

HEK hyperechogenic kidneys

MCDK multicystic dysplastic kidney

MODY5 maturity-onset diabetes of the young type 5

DD developmental delay

ID intellectual disability

ASD autism spectrum disorder

CMA chromosomal microarray analysis

QF-PCR quantitative fluorescence polymerase chain reaction

ChAS Chromosome Analysis Suite;

LOH loss of heterozygosity

iso-UPD isodisomy of uniparental disomy

MEDLINE Medical Literature Analysis and Retrieval System Online;

Del deletion

Dup duplication

DO duodenal obstruction

VSD ventricular septal defect

MAG-3 mercaptoacetyltriglycine.
==== Refs
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