Chromosome 17q12 microdeletions but not intragenic HNF1B mutations link developmental kidney disease and psychiatric disorder

Abstract

Heterozygous mutations of the HNF1B gene are the commonest known monogenic cause of developmental kidney disease. Half of patients have a deletion (approximately 1.3 Mb) of chromosome 17q12, encompassing HNF1B plus 14 additional genes. This 17q12 deletion has been linked with an increased risk of neurodevelopmental disorders, such as autism. Here we compared the neurodevelopmental phenotype of 38 patients with HNF1B-associated renal disease due to an intragenic mutation in 18 patients or due to 17q12 deletion in 20 patients to determine whether haploinsufficiency of HNF1B is responsible for the neurodevelopmental phenotype. Significantly, brief behavioral screening in children with the deletion showed high levels of psychopathology and its impact. Eight individuals (40%) with a deletion had a clinical diagnosis of a neurodevelopmental disorder compared to none with an intragenic mutation. The 17q12 deletions were also associated with more autistic traits. Two independent clinical geneticists were able to predict the presence of a deletion with a sensitivity of 83% and specificity of 79% when assessing facial dysmorphic features as a whole. Thus, the 17q12 deletions but not HNF1B intragenic mutations are associated with neurodevelopmental disorders. Hence, the HNF1B gene is not involved in the neurodevelopmental phenotype of these patients. Nephrologists need to be aware of this association to ensure appropriate referral to psychiatric services.

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

“…Although very young, individual I1 with the intragenic HNF1B variant did not show any signs of developmental delay. Clissold and colleagues provided evidence for association of NDDs exclusively with 17q12 microdeletions but not with HNF1B intragenic variants . The predominant hypothesis for the neurodevelopmental phenotypes was haploinsufficiency of other genes encompassed by the deletion .…”

“…Importantly, numerous studies reported neurodevelopmental disorders (NDDs) in individuals with 17q12 microdeletions (MIM #614527) containing HNF1B . Although NDDs were considered an exclusive feature of chromosome 17q12 microdeletion syndrome (17q12DS), there are recent reports also in individuals with intragenic HNF1B alterations …”

Loss of transcriptional activation of the potassium channel Kir5.1 by HNF1β drives autosomal dominant tubulointerstitial kidney disease

“…35, 36 However, more recent data revealed that patients with an intragenic HNF1β mutation suffer from significantly increased renal impairment and have a reduced glomerular filtration rate (GFR) compared to patients with a whole-gene deletion. 37, 38 This indicates that in the case of intragenic HNF1β mutations, there might be an additional interfering effect of the mutant on the function of the HNF1β WT allele. The physiological effect of HNF1β binding to the Kir5.1 promoter was further investigated and confirmed in a HNF1β knockdown experiment.…”

Prenatal diagnosis of 17q12 deletion syndrome: from fetal hyperechogenic kidneys to high risk for autism

“…In cases in which the unique aforementioned sonographic findings are accompanied by a normal CMA result, targeted sequencing of the TCF2 gene should be performed. This approach may aid in the prenatal nephrology counseling, as mutations of TCF2 lead to isolated kidney disease without adverse neurodevelopmental outcomes …”