Abstract
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. Prenatal sequencing and postnatal chromosomal microarray analysis were 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. In a prenatal case, we identified a novel in-frame deletion p.(Gly239del) within the HNF1B DNA-binding domain, a mutational hot spot as demonstrated by spatial clustering analysis and high computational prediction scores. The six postnatally diagnosed individuals harbored 17q12 microdeletions. Literature screening revealed variable reporting of HNF1B-associated clinical traits. Overall, 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. We highlight the value of prenatal HNF1B screening in renal developmental diseases. Standardized clinical reporting and systematic classification of HNF1B variants are necessary for a more accurate risk quantification of prenatal and postnatal clinical features, improving genetic counseling and prenatal decision making.
Highlights
The HNF1B protein is a transcription factor that, together with its dimerization partner HNF1A, belongs to the homeodomain-containing superfamily.[1]
The reclassification of all previously reported intragenic HNF1B variants provided an up-to-date overview of the mutational spectrum
We highlight the value of prenatal HNF1B screening in renal developmental diseases
Summary
The HNF1B (hepatocyte nuclear factor-1-beta, MIM *189907; known as transcription factor-2 [TCF2]) protein is a transcription factor that, together with its dimerization partner HNF1A, belongs to the homeodomain-containing superfamily.[1]. Genetic variants affecting HNF1B are associated with multiple phenotypes.[7,8,9,10,11] Aberrations of HNF1B were initially described as causative for maturity-onset diabetes of the young type 5 (MODY5; MIM #137920).[1,8,11,12,13] HNF1B variants have been shown to be causal for the renal cysts and diabetes syndrome (RCAD; MIM #137920),[14] renal hypodysplasia (RHD),[15] familial glomerulocystic kidney disease (GCKD),[16] autosomal dominant tubulointerstitial kidney disease (ADTKD, “medullary cystic kidney disease” [MCKD] or “juvenile hyperuricemic nephropathy” [FJHN]),[17,18] and congenital anomalies of kidney and urinary tract (CAKUT).[8,11,15,16,19] The latter is a frequent cause of severe fetal renal anomalies often leading to termination of pregnancy (TOP), neonatal death, and chronic renal disease in children.[19,20,21]
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