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

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. 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. Heterozygous mutations in the gene encoding the transcription factor hepatocyte nuclear factor 1β (HNF1B) are the commonest known monogenic cause of developmental kidney disease.1Weber S. Moriniere V. Knuppel T. et al.Prevalence of mutations in renal developmental genes in children with renal hypodysplasia: results of the ESCAPE study.J Am Soc Nephrol. 2006; 17: 2864-2870Crossref PubMed Scopus (284) Google Scholar, 2Thomas R. Sanna-Cherchi S. Warady B.A. et al.HNF1B and PAX2 mutations are a common cause of renal hypodysplasia in the CKiD cohort.Pediatr Nephrol. 2011; 26: 897-903Crossref PubMed Scopus (95) Google Scholar, 3Madariaga L. Moriniere V. Jeanpierre C. et al.Severe prenatal renal anomalies associated with mutations in HNF1B or PAX2 genes.Clin J Am Soc Nephrol. 2013; 8: 1179-1187Crossref PubMed Scopus (71) Google Scholar The phenotype of HNF1B-associated renal disease is very variable despite this single genetic etiology. Abnormalities are often detected on prenatal ultrasonography, where bilateral hyperechogenic kidneys with normal or slightly increased size are commonly found.4Decramer S. Parant O. Beaufils S. et al.Anomalies of the TCF2 gene are the main cause of fetal bilateral hyperechogenic kidneys.J Am Soc Nephrol. 2007; 18: 923-933Crossref PubMed Scopus (167) Google Scholar Cystic disease, including cystic dysplasia, is usually seen in both pediatric and adult populations but other developmental kidney disease has been reported, including single kidneys, hypoplasia, horseshoe kidneys, duplex kidneys, collecting system abnormalities, bilateral hydronephrosis and hyperuricemic nephropathy.1Weber S. Moriniere V. Knuppel T. et al.Prevalence of mutations in renal developmental genes in children with renal hypodysplasia: results of the ESCAPE study.J Am Soc Nephrol. 2006; 17: 2864-2870Crossref PubMed Scopus (284) Google Scholar, 5Heidet L. Decramer S. Pawtowski A. et al.Spectrum of HNF1B mutations in a large cohort of patients who harbor renal diseases.Clin J Am Soc Nephrol. 2010; 5: 1079-1090Crossref PubMed Scopus (204) Google Scholar, 6Faguer S. Decramer S. Chassaing N. et al.Diagnosis, management, and prognosis of HNF1B nephropathy in adulthood.Kidney Int. 2011; 80: 768-776Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 7Ulinski T. Lescure S. Beaufils S. et al.Renal phenotypes related to hepatocyte nuclear factor-1beta (TCF2) mutations in a pediatric cohort.J Am Soc Nephrol. 2006; 17: 497-503Crossref PubMed Scopus (203) Google Scholar, 8Edghill E.L. Oram R.A. 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Johnstone K.A. et al.HNF1B mutations associate with hypomagnesemia and renal magnesium wasting.J Am Soc Nephrol. 2009; 20: 1123-1131Crossref PubMed Scopus (197) Google Scholar, 11Bingham C. Ellard S. van't Hoff W.G. et al.Atypical familial juvenile hyperuricemic nephropathy associated with a hepatocyte nuclear factor-1beta gene mutation.Kidney Int. 2003; 63: 1645-1651Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar HNF1B-associated disease is a multisystem disorder; extrarenal phenotypic features include early onset diabetes mellitus, pancreatic hypoplasia, genital tract malformations, and abnormal liver function tests.12Bingham C. Bulman M.P. Ellard S. et al.Mutations in the hepatocyte nuclear factor-1beta gene are associated with familial hypoplastic glomerulocystic kidney disease.Am J Hum Genet. 2001; 68: 219-224Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar, 13Bellanne-Chantelot C. Chauveau D. 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Massa O. et al.Renal cysts and diabetes syndrome linked to mutations of the hepatocyte nuclear factor-1 beta gene: description of a new family with associated liver involvement.Am J Kidney Dis. 2002; 40: 397-402Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar Genetic changes in the HNF1B gene comprise either whole-gene deletions (approximately one-half of patients) or intragenic mutations (base substitutions or small insertions/deletions within the HNF1B gene).8Edghill E.L. Oram R.A. Owens M. et al.Hepatocyte nuclear factor-1beta gene deletions—a common cause of renal disease.Nephrol Dial Transplant. 2008; 23: 627-635Crossref PubMed Scopus (84) Google Scholar, 18Bellanne-Chantelot C. Clauin S. Chauveau D. et al.Large genomic rearrangements in the hepatocyte nuclear factor-1beta (TCF2) gene are the most frequent cause of maturity-onset diabetes of the young type 5.Diabetes. 2005; 54: 3126-3132Crossref PubMed Scopus (213) Google Scholar Both may arise spontaneously; 50% of whole-gene deletions are de novo.4Decramer S. Parant O. Beaufils S. et al.Anomalies of the TCF2 gene are the main cause of fetal bilateral hyperechogenic kidneys.J Am Soc Nephrol. 2007; 18: 923-933Crossref PubMed Scopus (167) Google Scholar, 7Ulinski T. Lescure S. Beaufils S. et al.Renal phenotypes related to hepatocyte nuclear factor-1beta (TCF2) mutations in a pediatric cohort.J Am Soc Nephrol. 2006; 17: 497-503Crossref PubMed Scopus (203) Google Scholar, 19Edghill E.L. Bingham C. Ellard S. Hattersley A.T. Mutations in hepatocyte nuclear factor-1beta and their related phenotypes.J Med Genet. 2006; 43: 84-90Crossref PubMed Scopus (264) Google Scholar This means there is frequently no family history of renal disease or diabetes. The majority of patients with a whole-gene deletion have an approximate 1.3 Mb deletion at chromosome 17q12, which includes the entire HNF1B gene.20Laffargue F. Bourthoumieu S. Llanas B. et al.Towards a new point of view on the phenotype of patients with a 17q12 microdeletion syndrome.Arch Dis Child. 2015; 100: 259-264Crossref PubMed Scopus (25) Google Scholar These recurrent microdeletions of 17q12 are mediated by flanking segmental duplications via nonallelic homologous recombination.21Mefford H.C. Clauin S. Sharp A.J. et al.Recurrent reciprocal genomic rearrangements of 17q12 are associated with renal disease, diabetes, and epilepsy.Am J Hum Genet. 2007; 81: 1057-1069Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar Unlike most genomic disorders, the 17q12 deletion was not initially thought to be associated with developmental delay or intellectual disability. More recent work has shown that neurodevelopmental disorders, including autism spectrum disorders (ASD), are part of the phenotype in patients referred for testing via clinical genetics rather than renal services.22Moreno-De-Luca D. Mulle J.G. Kaminsky E.B. et al.for the SGENE ConsortiumDeletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia.Am J Hum Genet. 2010; 87: 618-630Abstract Full Text Full Text PDF PubMed Scopus Google Scholar, C. et associated with Med Genet. 2008; PubMed Scopus Google Scholar, B. of a 17q12 microdeletion and a variable clinical Google Scholar, V. O. et phenotype in 17q12 clinical and of a new PubMed Scopus Google Scholar, M. et al.Clinical of a 17q12 microdeletion with clinical Genet. Google Scholar by et F. Bourthoumieu S. Llanas B. et al.Towards a new point of view on the phenotype of patients with a 17q12 microdeletion syndrome.Arch Dis Child. 2015; 100: 259-264Crossref PubMed Scopus (25) Google Scholar that the phenotype is than that when the 17q12 deletion is to renal of children with HNF1B deletions and with point mutations the of pediatric showed no in to and the deletion to have and more at than with a mutation. was in a small of the cohort of and of the children in the were young to for and The 1.3 Mb 14 genes in to HNF1B and is not genetic to this neurodevelopmental phenotype. is haploinsufficiency of of these genes. HNF1B is involved in in both and and is a to be the N. genes in 2008; 5: PubMed Scopus Google Scholar, N. of novel and 2011; PubMed Scopus Google Scholar have been of and in patients with HNF1B gene which S. Decramer S. Chassaing N. et al.Diagnosis, management, and prognosis of HNF1B nephropathy in adulthood.Kidney Int. 2011; 80: 768-776Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, C. Bulman M.P. Ellard S. et al.Mutations in the hepatocyte nuclear factor-1beta gene are associated with familial hypoplastic glomerulocystic kidney disease.Am J Hum Genet. 2001; 68: 219-224Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar, N. Horikawa Y. T. et of a new of hepatocyte nuclear factor-1beta mutation with 2004; PubMed Google Scholar is which is also in the early a with a mutation of its as a of the O. Y. L. et of and in by the and 2009; PubMed Scopus (71) Google Scholar, for in PubMed Scopus Google Scholar new of associated with has within the 17q12 S. C. et and of new of associated with autism spectrum J Hum Genet. 2013; Full Text Full Text PDF PubMed Scopus Google Scholar no single gene deletions or mutations in haploinsufficiency and disease in have been detected in either of these genes to more genes within the 17q12 and other transcription to an increased risk of neurodevelopmental F. Bourthoumieu S. Llanas B. et al.Towards a new point of view on the phenotype of patients with a 17q12 microdeletion syndrome.Arch Dis Child. 2015; 100: 259-264Crossref PubMed Scopus (25) Google Scholar this we compared the neurodevelopmental phenotype of patients with either an HNF1B intragenic mutation or 17q12 deletion to determine whether haploinsufficiency of the HNF1B gene is responsible for this of the phenotype. individuals in the 18 had a known intragenic HNF1B mutation and 20 had a whole-gene The intragenic mutations and The presence of the common 1.3 Mb 17q12 deletion was by of and the most and of the genes within the by in the deletion not Both mutation and deletion were in of at was the as was were of the that were of were in both mutation and deletion as the of or cystic were the renal phenotype seen most commonly in both to with HNF1B-associated kidney disease in the L. Decramer S. Pawtowski A. et al.Spectrum of HNF1B mutations in a large cohort of patients who harbor renal diseases.Clin J Am Soc Nephrol. 2010; 5: 1079-1090Crossref PubMed Scopus (204) Google Scholar function was in the mutation with a of compared with in the deletion magnesium levels were in the deletion was more common in the mutation both of these may be by the of renal seen in the mutation was in of patients in both extrarenal phenotypes were also mutation and deletion of patients with either an HNF1B intragenic mutation or 17q12 18 of renal single collecting system abnormalities, and bilateral at diagnosis of renal disease, as or in individuals with renal in individuals with renal in individuals with renal as magnesium in individuals with renal as of normal for and at diagnosis of of body tail of tract tract tract and bilateral and liver function are or are renal single collecting system abnormalities, and bilateral as or in individuals with renal as magnesium as of normal for and of body tail of tract and bilateral and in a new are or are The 38 patients in this of with HNF1B-associated disease who were to part the the of and the were in of genetic levels of and renal phenotype. 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Bourthoumieu S. Llanas B. et al.Towards a new point of view on the phenotype of patients with a 17q12 microdeletion syndrome.Arch Dis Child. 2015; 100: 259-264Crossref PubMed Scopus (25) Google Scholar this of patients with an HNF1B whole-gene deletion were with autism as compared to of in the mutation the of children with normal no was in the deletion is that the of the in of and may be by the at both a number of and had HNF1B-associated disease to renal disease or diabetes, the at was compared with in be in the very young and the features of neurodevelopmental disease may be more as children the at diagnosis of and in cohort was work cohort of children with hyperechogenic or cystic kidneys and a 17q12 deletion autism in a than the of in the pediatric C. C. et in patients with cystic or hyperechogenic kidneys and chromosome 17q12 Dial Transplant. 2010; 25: PubMed Scopus Google Scholar This is in with the increased of in deletion patients we in in none of the facial dysmorphic features in association with a 17q12 deletion was more common in the deletion in this This with by et F. Bourthoumieu S. Llanas B. et al.Towards a new point of view on the phenotype of patients with a 17q12 microdeletion syndrome.Arch Dis Child. 2015; 100: 259-264Crossref PubMed Scopus (25) Google Scholar who that a high and were more frequently seen in the presence of a deletion rather than a F. Bourthoumieu S. Llanas B. et al.Towards a new point of view on the phenotype of patients with a 17q12 microdeletion syndrome.Arch Dis Child. 2015; 100: 259-264Crossref PubMed Scopus (25) Google Scholar when the in were as a independent clinical geneticists were able to predict the presence of a deletion with a sensitivity of 83% and specificity of This the that the 17q12 deletion is associated with a but facial D. Mulle J.G. Kaminsky E.B. et al.for the SGENE ConsortiumDeletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia.Am J Hum Genet. 2010; 87: 618-630Abstract Full Text Full Text PDF PubMed Scopus Google Scholar and that genetic HNF1B haploinsufficiency is we that patients with an intragenic HNF1B mutation had a than patients with a this is to be related to the neurodevelopmental the et T. Lescure S. Beaufils S. et al.Renal phenotypes related to hepatocyte nuclear factor-1beta (TCF2) mutations in a pediatric cohort.J Am Soc Nephrol. 2006; 17: 497-503Crossref PubMed Scopus (203) Google Scholar the phenotype of children with HNF1B-associated renal disease and no in renal function individuals with an HNF1B whole-gene deletion and with point that patients with HNF1B-associated renal disease showed that the of individuals with renal was in with a mutation or than in with a deletion L. Decramer S. Pawtowski A. et al.Spectrum of HNF1B mutations in a large cohort of patients who harbor renal diseases.Clin J Am Soc Nephrol. 2010; 5: 1079-1090Crossref PubMed Scopus (204) Google Scholar The that the of the patients with mutations may the in renal function the the mutation and deletion in were in of of 18 intragenic mutations in were The results this the description of the neurodevelopmental phenotype of both children and with HNF1B-associated disease. Both mutation and deletion were in of and were for neurodevelopmental features screening were associated with this patients the to the cohort of the due to either to individuals despite or a to the and spectrum of neurodevelopmental disorders in HNF1B-associated renal disease and diabetes individuals were a of screening and review of screening and for and were not This means disease may have been genetic screening for other known of neurodevelopmental disease other copy number was not of the patients with an intragenic HNF1B mutation in had a diagnosis of or individuals with HNF1B-associated disease to gene mutation and either have been other genetic were not S. Decramer S. Chassaing N. et al.Diagnosis, management, and prognosis of HNF1B nephropathy in adulthood.Kidney Int. 2011; 80: 768-776Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, C. Bulman M.P. Ellard S. et al.Mutations in the hepatocyte nuclear factor-1beta gene are associated with familial hypoplastic glomerulocystic kidney disease.Am J Hum Genet. 2001; 68: 219-224Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar, N. Horikawa Y. T. et of a new of hepatocyte nuclear factor-1beta mutation with 2004; PubMed Google Scholar there have been no of HNF1B intragenic mutation and either or in the This that is not haploinsufficiency of the HNF1B gene that is responsible for this of the phenotype in individuals with a 17q12 also that work is in this to determine the cause of the phenotypic seen in these patients. 17q12 microdeletions but not intragenic mutations are associated with a neurodevelopmental phenotype. be of this risk and referred for appropriate psychiatric were to in the renal and diabetes at the and pediatric renal at for and the presence of either an HNF1B intragenic mutation or whole-gene deletion on genetic testing due to renal or diabetes and patients were to was adult and of with The was in with the of and by a of 38 patients with HNF1B-associated disease to mutation screening was by of and with gene by as E.L. Oram R.A. Owens M. et al.Hepatocyte nuclear factor-1beta gene deletions—a common cause of renal disease.Nephrol Dial Transplant. 2008; 23: 627-635Crossref PubMed Scopus (84) Google Scholar, 19Edghill E.L. Bingham C. Ellard S. Hattersley A.T. Mutations in hepatocyte nuclear factor-1beta and their related phenotypes.J Med Genet. 2006; 43: 84-90Crossref PubMed Scopus (264) Google Scholar was to the presence of an approximate 1.3 Mb deletion at chromosome 17q12 in the 20 patients with an HNF1B whole-gene This gene for and the most and genes within the recurrent 1.3 Mb 17q12 was the and a genomic and was to the to to the a was by the and of was by including is on and in including neurodevelopmental disorders, was a of and in plus where of was for their and was as an of results ultrasonography, or were to for and genital tract was the in A. et to in children with Am Soc Nephrol. 2009; 20: PubMed Scopus Google Scholar for children with renal in pediatric renal where and of in in A.S. et al.for the of in more to a new Intern Med. 1999; PubMed Scopus Google Scholar was at for patients on renal was as or was as magnesium and as a the of the normal for and the was either to or on the of with liver function were as or levels the of the normal for and the behavioral screening was in to the R. 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PubMed Scopus Google Scholar was as were with and with and HNF1B gene mutation and deletion were the for and the for of was to be The was to for when dysmorphic features and the independent was the were and the no is by a number is a of the for and a for and are by a with of intragenic HNF1B with of and who were to part in the had either an HNF1B point mutation or whole-gene deletion on genetic testing and renal single collecting system and bilateral in the results were not with of patients with HNF1B-associated disease and a neurodevelopmental disorder; autism spectrum disorder; and with of facial dysmorphic features in patients with either HNF1B mutation or 17q12 microdeletion by independent clinical geneticists and presence of a clinical was the results of or both the was the was to for was at