Chromosome 17q12 microdeletions but not intragenic HNF1B mutations link developmental kidney disease and psychiatric disorder
2016; Elsevier BV; Volume: 90; Issue: 1 Linguagem: Inglês
10.1016/j.kint.2016.03.027
ISSN1523-1755
AutoresRhian Clissold, Charles Shaw‐Smith, Peter D. Turnpenny, Benjamin Bunce, Detlef Böckenhauer, Larissa Kerecuk, Simon Waller, Pamela Bowman, Tamsin Ford, Sian Ellard, Andrew T. Hattersley, Coralie Bingham,
Tópico(s)Genomic variations and chromosomal abnormalities
ResumoHeterozygous 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. 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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 (242) Google Scholar, 23Cheroki C. Krepischi-Santos A.C. 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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 suggests that the neuropsychological phenotype is less severe than that previously reported when the 17q12 deletion is identified secondary to renal abnormalities. Comparison of 26 children with HNF1B deletions and 13 with point mutations under the care of pediatric nephrologists showed no significant differences in relation to learning abilities and schooling, although the deletion group tended to have lower intelligence quotients (IQs) and more educational difficulties at school than those with a mutation. However, formal neuropsychological evaluation was only carried out in a small subset of the cohort (11 of 39) and several of the children included in the study were too young to evaluate for schooling difficulties and ASD. The 1.3 Mb deleted region contains 14 genes in addition to HNF1B and it is not clear what genetic mechanism gives rise to this neurodevelopmental phenotype. One hypothesis is haploinsufficiency of 1 of these 15 genes. HNF1B is involved in hindbrain development in both zebra fish and mice and so is a good candidate to be the etiological gene.27Choe S.K. Hirsch N. Zhang X. Sagerstrom C.G. hnf1b genes in zebrafish hindbrain development.Zebrafish. 2008; 5: 179-187Crossref PubMed Scopus (13) Google Scholar, 28Makki N. Capecchi M.R. Identification of novel Hoxa1 downstream targets regulating hindbrain, neural crest and inner ear development.Dev Biol. 2011; 357: 295-304Crossref PubMed Scopus (46) Google Scholar There have been rare reports of learning difficulties and epilepsy in 5 patients with HNF1B gene mutations, which would support this.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, 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, 29Shihara N. Horikawa Y. Onishi T. et al.Identification of a new case of hepatocyte nuclear factor-1beta mutation with highly varied phenotypes.Diabetologia. 2004; 47: 1128-1129Crossref PubMed Google Scholar Another candidate is LHX1, which is also expressed in the brain during early development; a mouse model with a targeted mutation of Lhx1 confirms its role as a key regulator of the vertebrate head organizer.30Avraham O. Hadas Y. Vald L. et al.Transcriptional control of axonal guidance and sorting in dorsal interneurons by the Lim-HD proteins Lhx9 and Lhx1.Neural Dev. 2009; 4: 21Crossref PubMed Scopus (71) Google Scholar, 31Shawlot W. Behringer R.R. Requirement for Lim1 in head-organizer function.Nature. 1995; 374: 425-430Crossref PubMed Scopus (673) Google Scholar A study investigating new hotspots of copy-number variation associated with ASD has implicated ACACA within the 17q12 deletion.32Girirajan S. Dennis M.Y. Baker C. et al.Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.Am J Hum Genet. 2013; 92: 221-237Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar However, no single gene deletions or mutations resulting in haploinsufficiency and neurological disease in humans have been detected in either of these genes to date. An alternative hypothesis would involve more complex interactions between genes within the deleted 17q12 region and other transcription factors giving rise to an increased risk of neurodevelopmental disorders.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 In this study, we systematically 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 aspect of the phenotype. Thirty-eight individuals participated in the study; 18 (47%) had a known intragenic HNF1B mutation and 20 (53%) had a whole-gene deletion. The intragenic mutations included 4 nonsense, 13 insertions/deletions, and 1 missense change (Supplementary Table S1). The presence of the common 1.3 Mb 17q12 deletion was confirmed by dosage analysis of ZNHIT3 and HNF1B, the most 5′ and 3′ of the 15 genes within the interval, by droplet digital polymerase chain reaction (PCR) in the deletion group (data not shown). Both mutation and deletion groups were similar in terms of general characteristics (Table 1). Median age at study inclusion was similar between the groups, as was sex breakdown. Participants were predominantly of White British origin, reflecting the fact that 61% were recruited from South West England. Levels of deprivation were similar in both mutation and deletion groups as measured using the median Index of Multiple Deprivation 2007 score. Cysts or cystic dysplasia were the renal phenotype seen most commonly in both groups, similar to cohorts with HNF1B-associated kidney disease previously described in the literature.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 Renal function was worse in the mutation group with a median estimated glomerular filtration rate (GFR) of 42.6 ml/min/1.73 m2 (interquartile range [IQR]: 31, 60) compared with 81.4 (IQR: 56, 91) in the deletion group, P = 0.002. Serum magnesium levels were lower in the deletion group, whereas hyperuricemia was more common in the mutation group; both of these findings may be explained by the greater degree of renal impairment seen in the mutation group. Diabetes was present in approximately 40% of patients in both groups. Other extrarenal phenotypes were also similar between mutation and deletion groups.Table 1Characteristics of study patients with either an HNF1B intragenic mutation or 17q12 microdeletionHNF1B mutation(n = 18)17q12 microdeletion(n = 20)PAge, yr19 (13, 45)15.5 (11, 35)0.3SexM 8 (44%), F 10 (56%)M 8 (40%), F 12 (60%)1EthnicityWhite 18 (100%)White 19 (95%), mixed 1 (5%)1Indices of Deprivation 2007 score25 (16, 46)21 (12, 30)0.4Renal phenotypeRenal abnormality Cysts/cystic dysplasia12 (67%)17 (85%)0.3 OtheraOther renal structural abnormalities included single kidney, collecting system abnormalities, and bilateral hydronephrosis.4 (22%)3 (15%) Unknown2 (11%)0Age at diagnosis of renal disease, yr0 (0, 20)0 (0, 24)0.7Renal replacement therapy3 (17%)1 (5%)0.3GFR, ml/min/1.73 m242.6 (31, 60)81.4 (56, 91)0.002ProteinuriabProteinuria defined as albumin-creatinine ratio >30 mg/mmol or protein-creatinine ratio >50 mg/mmol.,cOnly assessed in individuals with native renal function.2 (13%)2 (11%)1Serum magnesium,cOnly assessed in individuals with native renal function. mmol/l0.7 (0.67, 0.75)0.58 (0.53, 0.69)0.01HypomagnesemiacOnly assessed in individuals with native renal function.,dHypomagnesemia defined as serum magnesium 30 mg/mmol or protein-creatinine ratio >50 mg/mmol.c Only assessed in individuals with native renal function.d Hypomagnesemia defined as serum magnesium <0.7 mmol/l.e Hyperuricemia defined as serum urate level above upper limit of normal reference range for age and sex from analyzing laboratory.f Hypoplasia of body and/or tail of pancreas.g Not systematically assessed for.h Genital tract malformations included (i) unilateral undescended testicle and blind-ending epididymis, (ii) bilateral undescended testicles, and (iii) bicornuate uterus. Open table in a new tab Values are median (IQR) or n (%). Bold P-values are statistically significant. F, female; GFR, glomerular filtration rate; IQR, interquartile range; M, male. The 38 patients included in this study represented 45% of those with HNF1B-associated disease who were eligible to take part from the 4 different sites. Supplementary Table S2 compares the general characteristics of participants and nonparticipants. Briefly, the 2 groups were similar in terms of genetic abnormality, age, sex, levels of deprivation, and renal phenotype. The only difference was in ethnicity, with other ethnic groups besides White British being more commonly represented among nonparticipants. However, the data available for nonparticipants was incomplete with 13 of 47 (28%) having no information on ethnicity recorded. Use of the parent-reported Strengths and Difficulties Questionnaire (SDQ) revealed more patient difficulties in the deletion group with a median total difficulties score of 15.5 (IQR: 10, 20) compared with 7 in the mutation group (IQR: 3.5, 7.5; P = 0.048) (Figure 1). This is also higher than the mean total difficulties score of 8 ± 5.8 (SD) obtained in a normative sample of 10,438 British school-aged children.33Meltzer H. Gatward R. Goodman R. Ford T. The Mental Health of Children and Adolescents in Great Britain. The Stationery Office, London1999Google Scholar When analyzing the 4 subsections of the total difficulties score, conduct problems and peer relationship problems were more common in the deletion group as follows: median scores were 2.5 (IQR: 2, 5) and 4.5 (IQR: 1, 6), respectively, versus 0.5 (IQR: 0, 1) and 0 (IQR: 0, 0.5) in the mutation group, P = 0.04 and 0.02, respectively (Supplementary Figure S1). Five of the 10 children with a deletion scored above the suggested clinical cut-point of 15; all of these children apart from 1 had already been referred for further psychological evaluation. Parental scores for the impact of these difficulties on the child's life were similarly high in the deletion group with a median score of 5 (IQR: 2, 8). This was compared with a median score of 0 in the mutation group (IQR: 0, 0; P = 0.02) and a mean score of 0.4 ± 1.1 in the large normative sample mentioned previously.33Meltzer H. Gatward R. Goodman R. Ford T. The Mental Health of Children and Adolescents in Great Britain. The Stationery Office, London1999Google Scholar Eight of 20 participants (40%) with a deletion had a clinical diagnosis of either an ASD, attention deficit hyperactivity disorder (ADHD), and/or learning difficulties requiring a Statement of Special Educational Needs or current attendance at a special school compared with 0 of 18 with a mutation, P = 0.004 (Figure 2a). Of these 8 patients, 4 had comorbidity with learning difficulties accompanying a diagnosis of ASD and/or ADHD (Figure 2b, Supplementary Table S3). According to the second national survey of children's mental health and well-being carried out in 2004, the prevalence of ASD in British children was 0.9% and hyperkinetic disorder/ADHD was 1.5%.34Green H. McGinnity A. Meltzer H. et al.Mental Health of Children and Young People in Great Britain, 2004. Department of Health and Scottish Executive, United Kingdom2005Crossref Google Scholar Therefore, the frequency of ASD and ADHD found in participants with a deletion in this study far exceeds the baseline population rates. Patients with a deletion had a higher median Autism Spectrum Quotient (AQ) (43% [IQR: 28, 68] vs. 29% [IQR: 16, 42] in the mutation group, P = 0.02), indicating a greater number of autistic traits (Figure 3a). Although the AQ is not a diagnostic tool, cutoffs have been described for identifying individuals who may have clinically significant levels of autistic traits. However, referral for a full diagnostic assessment is only warranted if the individual is also suffering a degree of distress as a result of these traits.35Auyeung B. Baron-Cohen S. Wheelwright S. Allison C. The Autism Spectrum Quotient: Children's Version (AQ-Child).J Autism Dev Disord. 2008; 38: 1230-1240Crossref PubMed Scopus (358) Google Scholar, 36Baron-Cohen S. Hoekstra R.A. Knickmeyer R. Wheelwright S. The Autism-Spectrum Quotient (AQ)—adolescent version.J Autism Dev Disord. 2006; 36: 343-350Crossref PubMed Scopus (318) Google Scholar, 37Baron-Cohen S. Wheelwright S. Skinner R. et al.The autism-spectrum quotient (AQ): evidence from Asperger syndrome/high-functioning autism, males and females, scientists and mathematicians.J Autism Dev Disord. 2001; 31: 5-17Crossref PubMed Scopus (3911) Google Scholar Six of 38 participants (16%) scored above the suggested cutoff; of these, all had a deletion and 3 of 6 had a confirmed diagnosis of ASD. To see whether the AQ results were being skewed by a small number of individuals with a high number of autistic traits, the analysis was repeated after excluding those with a known ASD. Although there was a trend toward a higher AQ in the deletion group (median AQ: 36% [IQR: 28, 52] vs. 29% [IQR: 16, 42] in the mutation group), this did not reach statistical significance (P= 0.08) (Figure 3b) but may have done so in a larger sample (n = 64). The median IQ composite was similar in both mutation and deletion groups (97 [IQR: 83, 104] vs. 91 [IQR: 76, 107]; P = 0.6) (Figure 4). Two participants with a deletion scored in the lower extreme category with IQ < 70. Facial photographs were analyzed in 33 participants (18 with an intragenic HNF1B mutation, 15 with a deletion). None of the facial dysmorphic features previously described in association with the 17q12 deletion differed in frequency between the mutation and deletion groups (Supplementary Table S4). Variation in results between the 2 assessors was seen although overall interrater agreement was fair with a kappa coefficient of 0.4 (95% confidence interval: 0.3–0.5). When facial dysmorphic features were considered as a whole by both assessors to predict whether an individual had a deletion, sensitivity was 83% and specificity was 79% (Figure 5). Nine of 37 patients (24%) had a head circumference >90th percentile, but there was no difference in macrocephaly between the 2 groups (5 of 19 [26%] in deletion group vs. 4 of 18 [22%] in mutation group, P = 1). The results of this study demonstrate that a neurodevelopmental phenotype is only seen in individuals with a 17q12 deletion. Compared with patients with an intragenic mutation, patients with a deletion had a greater number of autistic traits using the AQ and children displayed higher levels of psychopathology and impact on brief behavioral screening using the parent-reported SDQ. Indeed, 40% of participants with a deletion had been clinically diagnosed with a neurodevelopmental disorder; ASD and ADHD were seen much more commonly in the deletion group than were predicted from population prevalence rates. Most (17 of 18) of the patients with intragenic mutations had a nonsense or insertion/deletion loss of function mutation, predicted to result in reduced protein expression. The discrepancy in neurodevelopmental phenotype between the intragenic mutation and deletion groups suggests it is not simply haploinsufficiency of the HNF1B gene that is responsible for this aspect of the phenotype in individuals with a 17q12 deletion. Our findings highlight the importance for nephrologists to be aware of this association between 17q12 microdeletion and neurodevelopmental disease to ensure referral to psychiatric services where appropriate. The features of conditions such as ASD can range from mild to severe and can also fluctuate over time and in response to different life events; this variable expression adds to the diagnostic challenges posed by these disorders.38National Institute for Health and Clinical ExcellenceAutism: Recognition, Referral, Diagnosis and Management of Adults on the Autism Spectrum. National Institute for Health and Clinical Excellence, London, UK2012Google Scholar Individuals with a deletion and their families should be informed of the increased risk of a neurodevelopmental disorder so they can report any concerning symptoms if they arise to allow prompt investigation. The results of this study contrast with recent work concluding that when children are diagnosed with a 17q12 deletion secondary to renal abnormalities, the neurodevelopmental phenotype is less severe than previously suggested in the literature.20Laffargue F. Bourthoumieu S. Llanas B. et al.Towards a new point of view on the phenotype of patients with a 17q12 microdelet
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