title: 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.
authors.affiliation: University of Exeter Medical School, Exeter, UK; National Institute for Health Research Exeter Clinical Research Facility, Royal Devon and Exeter National Health Service Foundation Trust, Exeter, UK.
authors.forename: Rhian L
authors.initials: RL
authors.lastname: Clissold
authors.affiliation: Clinical Genetics Department, Royal Devon and Exeter National Health Service Foundation Trust, Exeter, UK.
authors.forename: Charles
authors.initials: C
authors.lastname: Shaw-Smith
authors.affiliation: Clinical Genetics Department, Royal Devon and Exeter National Health Service Foundation Trust, Exeter, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Turnpenny
authors.affiliation: Department of Molecular Genetics, Royal Devon and Exeter National Health Service Foundation Trust, Exeter, UK.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bunce
authors.affiliation: Department of Nephrology, Great Ormond Street Hospital for Children National Health Service Foundation Trust, London, UK; University College of London Centre for Nephrology, London, UK.
authors.forename: Detlef
authors.initials: D
authors.lastname: Bockenhauer
authors.affiliation: Department of Nephrology, Birmingham Children's Hospital, Birmingham, UK.
authors.forename: Larissa
authors.initials: L
authors.lastname: Kerecuk
authors.affiliation: Department of Nephrology, Evelina London Children's Hospital, St. Thomas' Hospital, London, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Waller
authors.affiliation: University of Exeter Medical School, Exeter, UK.
authors.forename: Pamela
authors.initials: P
authors.lastname: Bowman
authors.affiliation: University of Exeter Medical School, Exeter, UK.
authors.forename: Tamsin
authors.initials: T
authors.lastname: Ford
authors.affiliation: University of Exeter Medical School, Exeter, UK; Department of Molecular Genetics, Royal Devon and Exeter National Health Service Foundation Trust, Exeter, UK.
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.affiliation: University of Exeter Medical School, Exeter, UK; National Institute for Health Research Exeter Clinical Research Facility, Royal Devon and Exeter National Health Service Foundation Trust, Exeter, UK; Macleod Diabetes and Endocrine Centre, Royal Devon and Exeter National Health Service Foundation Trust, Exeter, UK.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
authors.affiliation: University of Exeter Medical School, Exeter, UK; Exeter Kidney Unit, Royal Devon and Exeter National Health Service Foundation Trust, Exeter, UK. Electronic address: c.bingham@exeter.ac.uk.
authors.forename: Coralie
authors.initials: C
authors.lastname: Bingham
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence / Q000235:genetics; D002648:Child; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D005260:Female; D057895:Haploinsufficiency; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D065886:Neurodevelopmental Disorders / Q000235:genetics*; D010641:Phenotype; D012017:Referral and Consultation; D017384:Sequence Deletion / Q000235:genetics*; D055815:Young Adult
chemical_list: C496495:HNF1B protein, human; D051539:Hepatocyte Nuclear Factor 1-beta
keywords: 17q12 deletion; HNF1B; cystic kidneys; developmental kidney disease; neurodevelopmental disorders