Prenatal diagnosis of HNF1B‐associated renal cysts: Is there a need to differentiate intragenic variants from 17q12 microdeletion syndrome?

17q12 microdeletions containing HNF1B and intragenic variants within this gene are associated with variable developmental, endocrine, and renal anomalies, often already noted prenatally as hyperechogenic/cystic kidneys. Here, we describe prenatal and postnatal phenotypes of seven individuals with HNF1B aberrations and compare their clinical and genetic data to those of previous studies.

These include agenesis or hypoplasia of the pancreas, 8,19 impaired liver function, 23 urogenital anomalies, 24 electrolyte abnormalities, 17,25 and diaphragmatic hernia. 26 HNF1B pathogenic variants include intragenic mutations such as single-nucleotide variants (SNVs), small insertions or deletions of bases (indels), and small copy number variants (CNVs) affecting only parts of the gene as well as larger CNVs encompassing the entire HNF1B. 7 SNVs/indels described to date include nonsense, frameshift, splice-site, and missense variants. The latter are mainly distributed within exons 2 to 4, which code for the DNA-binding domain. 8,19,22,27 All described HNF1B whole gene deletions so far correspond to chromosome 17q12 microdeletions spanning 1.3 to 1.8 Mb on average and including neighboring genes. 10,28,29 Both intragenic variants and genomic rearrangements contribute almost equally to the HNF1Bassociated phenotype. 11 Importantly, numerous studies reported neurodevelopmental disorders (NDDs) in individuals with 17q12 microdeletions (MIM #614527) containing HNF1B. 10,[28][29][30][31][32][33] Although NDDs were considered an exclusive feature of chromosome 17q12 microdeletion syndrome (17q12DS), there are recent reports also in individuals with intragenic HNF1B alterations. 16,[34][35][36] In this study, we report on a series of seven individuals with intragenic HNF1B aberrations or 17q12DS and describe their renal and extra-renal phenotypes prenatally and in childhood or adult life. By comparing our findings of this cohort with reports from current literature, we discuss the potential need to differentiate intragenic variants from 17q12DS in the increasingly common setting of prenatally diagnosed kidney abnormalities.
This question is important not only for prenatal decision making but also for postnatal management in affected individuals.

| 17q12 microdeletions in individuals I2 to I7
Postnatal high-resolution CMA in individuals I2 to I7 revealed 17q12 microdeletions of variable sizes ranging from 1.42 Mb in I5 to 1 80 Mb in I6 ( Figure 2A). De novo occurrence was confirmed in all cases apart from individual I3, where the deletion was excluded in the mother, but paternal DNA was not available (see also Table 1 and Supplementary Note).

| Clinical features of the affected individuals
Prenatal renal anomalies such as hyperechogenic kidneys were only identified in individual I1 with the in-frame deletion in HNF1B

| Reviewed intragenic variants and clustering in protein domains
We retrieved a total of 217 intragenic HNF1B variants from data-  Figure S1).  In this regard, the association of 17q12DS with a wide spectrum of NDDs in 30% to 89% individuals is of particular importance (Table 2). 10,[29][30][31][32][33]43 57 The amino acid (AA) residue Gly239 mutated in individual I1 is shown in sphere representation (red). The neighboring residues Trp238 (cyan) and Lys237 (blue) are annotated as having a "specific DNA base contact [s]" or being involved in "DNA binding," respectively (based on NCBI NP_000449.1). Additionally, the variant c.712T>C, p.(Trp238Arg), has been reported as pathogenic. 9 The typical alpha-helix breaker glycine at position 239 is located at the end of an alpha-helix motif (residues 240-252; purple), and its deletion (I1 described herein) or substitution 40 The frequency of diabetes in individuals with HNF1B-related clinical phenotypes is highly variable, ranging from 9% to 82% with a mean age of diagnosis at 24 years, but neonatal onset is also possible ( In conclusion, similar to previous studies, our study indicated no differences in the prenatal renal phenotypic spectrum between intra- for HNF1B-associated disease ( Table 2). Building on these efforts, future studies using a standardized ascertainment of phenotype/ genotype information will improve our understanding and characterization of HNF1B-associated disorders and enable the optimization of genetic counseling.

A.R. was supported by the German Ministry of Education and
Research (Bundesministerium für Bildung und Forschung, grant numbers 01GS08160 and 01GM1520A [Chromatin-Net]), and the IZKF Erlangen (E16).

CONFLICTS OF INTEREST
None declared. Ra. F.F., and A.Re. reviewed the draft manuscript.

ETHICS APPROVAL
Informed written consent was obtained from all patients or their legal guardians, and the study was approved by the Ethical Review Board of the Friedrich-Alexander-Universität Erlangen-Nürnberg.

DATA AVAILABILITY STATEMENT
The data supporting this article are provided in the supplementary files available from the publisher's website.