SP030HNF1B WHOLE-GENE DELETIONS ARE ASSOCIATED WITH AUTISTIC TRAITS

Abstract

Introduction and Aims: Heterozygous mutations and deletions of the HNF1B gene result in a multi‐system disorder and are the commonest monogenic cause of developmental kidney disease. Increasing interest has focused on whether HNF1B gene anomalies are associated with neuropsychiatric conditions. A 1.4 Mb deletion at chromosome 17q12, which includes HNF1B, confers an increased risk of autism and cognitive impairment. The deleted stretch of DNA contains 15 genes and it is not clear what genetic mechanism gives rise to this neuropsychological phenotype. We aimed to assess neuropsychological disorders in patients with both HNF1B mutations or whole‐gene deletions under follow‐up with nephrology or diabetes services. Methods: 21 patients (age range 8‐65 years) with known HNF1B coding region/splice site mutations (n=12) or whole‐gene deletions (n=9) from 3 UK centres were compared. Cognitive ability was assessed using the Kaufman Brief Intelligence Test, Second Edition. Autistic traits were assessed using the Autism‐Spectrum Quotient (AQ). Results were analysed using the unpaired t‐test and Fisher's exact test. Results: Patients with an HNF1B whole‐gene deletion had a higher mean AQ (60.0% versus 30.9% in the mutation group, P<0.0001), indicating a greater number of autistic traits. The mean IQ composite was not statistically different between the two groups (95.3 in mutation group versus 92.4 in deletion group, P=0.7). 3/9 patients with a whole‐gene deletion had a clinically diagnosed neuropsychological disorder (versus 0/ 12 patients with a mutation, P=0.2). Both groups were similar in terms of mean age (33.1 years in mutation group versus 33.3 years in deletion group, P=1), gender (50% male in mutation group versus 33.3% in deletion group, P=0.7) and mean Indices of Deprivation 2007 score (36.4 in mutation group versus 29.3 in deletion group, P=0.4). Conclusions: Patients with a whole‐gene deletion of HNF1B displayed a greater number of autistic traits than those with HNF1B mutations. IQ composite scores were similar between the 2 groups but the number of patients in each group was small. As the HNF1B gene deletion usually occurs as part of a larger deletion of chromosome 17q12, this suggests it is not haploinsufficiency of the HNF1B gene that is responsible for this neuropsychological phenotype but another genetic mechanism that is yet to be determined. Nephrologists should be aware of this association between 17q12 deletions involving HNF1B and neuropsychological disorders to ensure that referral to appropriate psychiatric services can be made where applicable.