Prenatal diagnosis of HNF1B-associated renal cysts: Need to differentiate intragenic variants from 17q12 microdeletion syndrome?

Abstract

Objective Large deletions of chromosome 17q12 (17q12DS) or intragenic variants in HNF1B are associated with variable developmental, endocrine and renal anomalies, often already noted prenatally as hyperechogenic/cystic kidneys. Here, we describe pre-and postnatal phenotypes of seven individuals with HNF1B aberrations and compare their clinical and genetic data to previous studies. MethodsPrenatal sequencing and postnatal chromosomal microarray analysis was performed in seven individuals with renal and/or neurodevelopmental phenotypes. We evaluated HNF1B-related clinical features from 82 studies and reclassified 192 reported intragenic HNF1B variants. Results In a prenatal case, we identified a novel in-frame deletion p.(Gly239del) within the HNF1B DNA binding domain, a mutational hotspot as demonstrated by spatial clustering analysis and high computational prediction scores. The six postnatally diagnosed individuals harbored 17q12 microdeletions of varying size. Literature screening revealed highly variable reporting of HNF1B-associated clinical traits. Overall, developmental delay was more frequent in 17q12DS carriers, although both mutation groups showed a high phenotypic heterogeneity. The reclassification of all previously reported intragenic HNF1B variants provided an up-to-date overview of the mutational spectrum. Conclusions We highlight the value of prenatal HNF1B screening in renal developmental diseases. Standardized clinical reporting and systematic classification of HNF1B variants is necessary for a more accurate risk quantification of pre-and postnatal clinical features, improving genetic counseling and prenatal decision-making.

Phenotypic Variability of 17q12 Microdeletion Syndrome – Three Cases and Review of Literature

“…Differences in deletion size (or other genetic modifiers) may also account for part of the observed phenotypic variation, although almost identical deletions (including in twins) may lead to variable phenotypes.The third patient had ASD as a main feature, in association with mild developmental delay, dysmorphic features and prenatal hydronephrosis. ASD has been previously reported in patients with 17q12 deletion, e.g.,Vasileiou et al [2019] [27] described 2 cases and Loirat et al (2010)[23] reported 3 unrelated boys with de novo 17q12 deletion, with ASD and kidney problems, hypothesizing that autistic behavior may be due to HNF1B deletion. Yet,Clissold et al (2016)…”