The 17q12 microdeletion syndrome is a recurrent copy number variant (CNV) characterized by a 1.06–2.46 Mb deletion that encompasses the hepatocyte nuclear factor 1 homeobox B (HNF1B) [OMIM 189907] gene (Moreno-De-Luca et al., 2010; Wu et al., 2021). The reported prevalence of this microdeletion syndrome is between 1:14,000 and 1:50,000, with high penetrance and variable expressivity (Rosenfeld et al., 2013; Martin et al., 2020). Unlike most genomic disorders, the 17q12 deletion was once thought to be one of the rare genetic abnormalities devoid of any developmental delay or intellectual disabilities (Mefford et al., 2007). However, more recent studies have described patients with this pathogenic CNV who were referred for genetic testing because of neurodevelopmental abnormalities, including autism spectrum disorders (ASD) and schizophrenia, rather than renal abnormalities (Moreno-De-Luca et al., 2010; Palumbo et al., 2014; Laffargue et al., 2015). Congenital diaphragmatic hernia, hypotonia, seizures, and genitourinary defects, including Mayer-Rokitansky-Kuster-Hauser syndrome, duodenal atresia, and newborn cholestasis were also reported seldom in patients with 17q12 microdeletions (Bernardini et al., 2009; Yap et al., 2015; Su et al., 2022).

Due to the limitations of prenatal ultrasound, only obvious structural abnormalities can be detected prenatally, most commonly with renal involvement. Bilateral hyperechogenic kidneys with normal or slightly increased size can be detected by prenatal ultrasonography. Otherwise, neuropsychiatric disorders can be observed only after birth (Decramer et al., 2007). It is estimated that 20% of birth abnormalities are identifiable by ultrasound as fetal renal anomalies (FRA) (Dias et al., 2014), and congenital anomalies of the kidney and urinary tract (CAKUTs) are common birth defects in newborns. Due to the differences in sociodemographic background, malformation inclusion criteria, study population, diagnostic technology, and surveillance quality, the prevalence of CAKUTs varies greatly, ranging from 4.2 per 10,000 births in China to 4.0 per 1,000 births in European countries (Andrés-Jensen et al., 2016; Laurichesse Delmas et al., 2017). The large difference may be due to the differential inclusion criteria applied by the studies. While the former was restricted to only cases found in the first 7 days following delivery, the latter covered cases up to 22 weeks of gestation as well as infants up to 8 years old. Although fetal anomalies, such as renal pelvis dilatation and hyperechogenicity can occasionally resolve spontaneously with fetal maturation, a genetic condition such as 17q12 microdeletion syndrome may be an underlying genomic cause of these conditions (Verbitsky et al., 2019). Chromosomal microarray analysis (CMA) has been proven to be an efficient first-line diagnostic technique for fetal kidney anomalies, while trio whole-exome sequencing (Trio-WES) is a first-line test in patients exhibiting congenital anomalies (CA), developmental delay (DD), and intellectual disability (ID) (Groopman et al., 2018; Manickam et al., 2021).

With increased knowledge about prenatal diagnosis and advancements in molecular detection techniques, the prenatal diagnosis of 17q12 deletion syndrome has become more common. In this study, we retrospectively analyzed the clinical indications, ultrasonic manifestations, and molecular detection results of three fetuses with confirmed 17q12 deletion as well as their parents to expand the knowledge about the prenatal diagnosis of this syndrome.

A total of 46 singleton pregnancies with anomalies in the urinary system underwent amniocentesis from Feb 2022 to October 2023 in the Prenatal Diagnosis Center of Lianyungang Maternal and Child Health Hospital. These fetuses were subjected to CMA and/or Trio-WES. These families were all unrelated, healthy, non-consanguineous, and had no family history of genetic disease or congenital malformations. Information of three cases with confirmed 17q12 deletion was retrospectively collected, including the clinical characteristics, diagnostic procedures, diagnosis outcomes, and pregnancy outcomes and their family analysis.

Of 46 fetuses, 33 (71.7%) had isolated urinary system anomalies, and 13 (28.3%) had non-isolated system anomalies. The whole frequency of chromosomal aberrations in fetuses with urinary system anomalies was 15.2% (7/46), including one case (2.2%) with trisomy 13, three cases (6.5%) with 17q12 deletion, and three cases (6.5%) with other likely pathogenic CNVs. 17q12 recurrent deletion syndrome was the most frequently detected microdeletion syndrome in our study (3/46, 6.5%). The general characteristics regarding prenatal sonographic findings, molecular analyses, and pregnancy outcomes of three cases with 17q12 deletion are presented in Table 1.

In the present study, we identified three fetuses with 17q12 microdeletion prenatally. The region of chromosome 17 is highly susceptible to genomic rearrangement as it is flanked by non-allelic homologous recombination between flanking segmental duplications (Mefford et al., 2007). As a result, all patients with this microdeletion exhibit almost the same unique genetic variation of 1.4 Mb deletion, encompassing HNF1B plus 14 additional genes (Roehlen et al., 2018). Patients with 17q12 deletions experience a wide range of renal and extra-renal manifestations due to this disease’s heterogeneity, and its clinical manifestations mainly involve congenital abnormalities and dysfunctions in the urinary and genital systems, maturity-onset diabetes of the young type 5, and neurodevelopmental issues (Verscaj et al., 2024).

The detection rates of pathogenic CNVs in fetuses with urinary system anomalies in our study was 8.7% (4/46), which is a slightly higher rate than two Chinese studies of small cohort sizes (6.31% and 7.6%, respectively) (Hu et al., 2019; Lin et al., 2019) and a previous Chinese study with a large cohort size (8.32%, 73/877) (Su et al., 2022). Consistent with previous studies, the only phenotype detected prenatally in the current study of 17q12 deletion is renal, all coupled with HNF1B whole-gene deletion detected by CMA and/or Trio-WES (Moreno-De-Luca et al., 2010; Su et al., 2022). Although the most common phenotype detected prenatally for the 17q12 deletion involves renal abnormalities, its renal clinical characteristics are varied, ranging from fetal structural abnormalities like renal agenesis to ultrasonographic soft markers like fetal pyelectasis (Su et al., 2022). The HNF1B gene is located on chromosome 17q12, and its haploinsufficiency, including intragenic mutations and whole gene deletion, is presumably responsible for renal abnormalities in human disorders and related mouse models (Bellanné-Chantelot et al., 2004; Warren et al., 2022). About half of the affected human individuals have HNF1B whole-gene deletions, with point mutations found in the remaining cases (Bellanné-Chantelot et al., 2005). Human kidney development begins around the fifth week of gestation and HNF1B is recruited to regulate important kidney factors during urogenital development, including factors expressed in the ureteric bud and Wolffian duct epithelium to start nephrogenesis and gonad genesis (Hiesberger et al., 2004; Lokmane et al., 2010).

It is reported that approximately 70% of 17q12 deletions occur de novo and about 30% are inherited from parents (Mitchel et al., 2016). In the present study, the clinical phenotypes of the affected parents differed greatly in the two inherent cases (case 2 and case 3). In case 2, the affected father had only bilateral multiple renal cysts. In case 3, the mother manifested classic symptoms of 17q12 deletion syndrome as previously described (Mitchel et al., 2016), including mild to moderate neurocognitive impairment, language development delay, maturity-onset diabetes of the young (MODY), and abnormalities of the kidneys. Previous animal studies have shown that HNF1B is involved in hindbrain development in both zebrafish (Choe et al., 2008) and vertebrates (Pouilhe et al., 2007). Clissold et al. reported that patients with HNFIB deletion had higher levels of impact on psychopathology than those with intragenic mutations of HNF1B (Clissold et al., 2016). There are also limited reports of learning difficulties and epilepsy in patients with HNF1B mutations (Bingham et al., 2001; Bellanné-Chantelot et al., 2005). Besides, almost half of MODY patients have the HNF1B whole gene deletion (Laffargue et al., 2015). Recently, the LHX1 gene, also known as Lim1, was also found to be a major and dependent regulator of renal and urogenital development and is required for epithelial tubular genesis and podocyte development in the kidney (Dormoy et al., 2011). Moreover, because LHX1 may control the development of the anterior mesendoderm, node, and midline cells, which are in charge of establishing the left-right body axis and head formation, LHX1 mutations are also believed to be linked to psychological issues and learning challenges (Costello et al., 2015). For the unreported very high myopia phenotype of the mother in case 3, no gene has been identified, although linkage has been reported to regions on the long arm of chromosomes 17 (Paluru et al., 2003; Farbrother et al., 2004).

Our study further demonstrates the wide heterogeneity of both phenotype and genotype among prenatal and adult patients related to the 17q12 deletion syndrome. The reasons for the heterogenous phenotype remain unclear. A study by Clissold et al. identified several genes that are differentially methylated in HNF1B-associated disease, some of which are specific to 17q12 deletion, and this may partially explain the heterogeneity (Clissold et al., 2018). Recent studies demonstrated that there may be additional gene and/or environmental modifiers that influence the HNF1B function (Dinneen et al., 2022). Further study is needed to explore the precise mechanism.

Notably, these fetuses in our study were all aborted although the counselors did not recommend it as this disease is not a life-threatening condition. However, due to the limitations of prenatal examinations as well as the wide heterogeneity and incomplete penetrance of 17q12 deletion syndrome, fetal phenotypes are often only partially detectable, and structural compromise is prioritized over functional compromise. These fetuses after birth may develop neurodevelopmental disorders or other extra-renal abnormalities. Due to the high sensitivity to genetic diseases by many parents in some countries including China, many families would choose to avoid the birth of an unhealthy baby through termination of the pregnancy. Reasonable and scientific evidence-based genetic counseling and a better understanding of genetic abnormalities will lead to proper management of prenatal diagnosed genetic conditions.

The current study has several limitations. First, it is based on a small sample size and the entire spectrum of neurological abnormalities related to 17q12 microdeletion remains to be fully explored in large-scale studies. Second, these fetuses all underwent induced abortions, and we were unable to assess the neurological development and the presence of other extra-renal abnormalities in their later life.

In conclusion, our findings further expand the prenatal and adult manifestations of 17q12 deletion syndrome. Additionally, genetic testing for 17q12/HNF1B microdeletion should be offered for a wide range of prenatally detected renal anomalies, including structural abnormality and ultrasonographic soft markers of the kidney. More importantly, our findings may allow timely supportive genetic counseling and guidance for the next pregnancy to potentially reduce the number of affected live births.