Intellectual disability in patients with MODY due to hepatocyte nuclear factor 1B (HNF1B) molecular defects

Dubois‐Laforgue, Danièle; Bellanné‐Chantelot, Christine; Charles, Peter C.; Jacquette, Aurélia; Larger, Étienne; Ciangura, C.; Saint‐Martin, Cécile; Rastel, Coralie; Keren, Boris; Timsit, José; Ajzenberg, C.; Azar, Rabih R.; Badet, E.; Baechler-Sadoul, E.; Barrande, Gaëlle; Bertin, Éric; Bony, H.; Gross, Milton; Bouché, C.; Gautier, Jean‐François; Guillausseau, P. J.; Bourcigaux, Nathalie; Jacquesson, L.; Bruzeau, J; Lefort, Gaëlle; Colmar-Montiel, C.; Cordonnier, M.; Couzi, Lionel; Delgrange, Etienne; Pasquier, Laurent; Ronco, Pierre; Dupont, Jean‐Michel; Dusselier, L.; Etr, Martine El; Franchini, A.; Godart, Catherine; Vincent-Dejean, Caroline; Guemazi, F.; Jeanjean, M.E.; Jeanne, Sandrine; Loric, Sylvain; Joubert, Michaël; Reznik, Yves; Kaloustian, E; Kessler, L.; Paris-Bockel, D.; Perrin, P.; Kitzis, Alain; Lemoine, A.; Penher, D. Le; Perlemoine, Caroline; Lesire, V.; Smati, D.; Thai, F Le; Lévy, Dominique; Maury, Eléonore; Moulin, Philippe; Pierre, P.; Plat, F.; Poynard, J.-P.; Raffin-Sanson, Marie Laure; Coz, Sylvie Régnier-Le; Requeda, E.; Roussey-Kesler, G.; Schillo, F.; Subra, Jean‐François; Sonnet, E.; Valéro, René; Vantyghem, M.C.; Wautelet, R.; Wojtusciszyn, Anne

doi:10.1016/j.diabet.2016.10.003

Cited by 19 publications

(20 citation statements)

References 16 publications

(31 reference statements)

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“…Until recently, only single cases of NDDs in carriers of intragenic HNF1B variants had been reported . However, a recent study described NDDs in (6/54) 11% of individuals with MODY harboring HNF1B intragenic alterations; this frequency was significantly higher than in cases who had another cause of diabetes and not significantly different from 17q12DS cases (17.0%; 9/53) . This study only excluded CNVs and fragile X syndrome in individuals with NDDs without further application of exome sequencing.…”

Section: Discussionmentioning

confidence: 99%

“…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 …”

Section: Introductionmentioning

confidence: 99%

“…10,[28][29][30][31][32][33] Although NDDs were considered an exclusive feature of chromosome 17q12 microdeletion syndrome (17q12DS), there are recent reports also in individuals with intragenic HNF1B alterations. 16,[34][35][36] In this study, we report on a series of seven individuals with intragenic HNF1B aberrations or 17q12DS and describe their renal and extra-renal phenotypes prenatally and in childhood or adult life. By comparing our findings of this cohort with reports from current literature, we discuss the potential need to differentiate intragenic variants from 17q12DS in the increasingly common setting of prenatally diagnosed kidney abnormalities.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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Objective 17q12 microdeletions containing HNF1B and intragenic variants within this gene are associated with variable developmental, endocrine, and renal anomalies, often already noted prenatally as hyperechogenic/cystic kidneys. Here, we describe prenatal and postnatal phenotypes of seven individuals with HNF1B aberrations and compare their clinical and genetic data to those of previous studies. Methods Prenatal sequencing and postnatal chromosomal microarray analysis were performed in seven individuals with renal and/or neurodevelopmental phenotypes. We evaluated HNF1B‐related clinical features from 82 studies and reclassified 192 reported intragenic HNF1B variants. Results In a prenatal case, we identified a novel in‐frame deletion p.(Gly239del) within the HNF1B DNA‐binding domain, a mutational hot spot as demonstrated by spatial clustering analysis and high computational prediction scores. The six postnatally diagnosed individuals harbored 17q12 microdeletions. Literature screening revealed variable reporting of HNF1B‐associated clinical traits. Overall, both mutation groups showed a high phenotypic heterogeneity. The reclassification of all previously reported intragenic HNF1B variants provided an up‐to‐date overview of the mutational spectrum. Conclusions We highlight the value of prenatal HNF1B screening in renal developmental diseases. Standardized clinical reporting and systematic classification of HNF1B variants are necessary for a more accurate risk quantification of prenatal and postnatal clinical features, improving genetic counseling and prenatal decision making.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…In 17q12 microdeletion syndrome, the 1.4 Mb deleted region involves 15 genes, including the HNF1B gene, which is associated with MODY5 . Other features of 17q12 microdeletion syndrome are cystic renal disease, liver abnormalities and neurocognitive defects . Studies have reported that 40% to 50% of HNF1B ‐related syndrome is associated with HNF1B mutations, whereas in others, it is associated with a whole HNF1B gene deletion .…”

Section: Discussionmentioning

confidence: 99%

Molecular diagnosis of maturity‐onset diabetes of the young in a cohort of Chinese children

Lin

Sheng

et al. 2020

Pediatr Diabetes

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Objective: The purpose of this study was to investigate the molecular basis of maturity-onset diabetes of the young (MODY) by whole-exome sequencing (WES) and estimate the frequency and describe the clinical characteristics of MODY in southern China. Methods: Genetic analysis was performed in 42 patients with MODY aged 1 month to 18 years among a cohort of 759 patients with diabetes, identified with the following four clinical criteria: age of diagnosis ≤18 years; negative pancreatic autoantibodies; family history of diabetes; or persistently detectable C-peptide; or diabetes associated with extrapancreatic features. GCK gene mutations were first screened by Sanger sequencing. GCK mutation-negative patients were further analyzed by WES. Results: Mutations were identified in 24 patients: 20 mutations in GCK, 1 in HNF4A, 1 in INS, 1 in ABCC8, and a 17q12 microdeletion. Four previously unpublished novel GCK mutations: c.1108G>C in exon 9, and c.1339C>T, c.1288_1290delCTG, and c.1340_1343delGGGGinsCTGGTCT in exon 10 were detected. WES identified a novel missense mutation c.311A>G in exon 3 in the INS gene, and copy number variation analysis detected a 1.4 Mb microdeletion in the long arm of the chromosome 17q12 region. Compared with mutation-negative subjects, the mutation-positive subjects had lower hemoglobin A1c and initial blood glucose levels. Conclusions: Most MODY cases in this study were due to GCK mutations, which is in contrast to previous reports in Chinese patients. Diabetes associated with extrapancreatic features should be a clinical criterion for MODY genetic analysis. Mutational analysis by WES provided a precise diagnosis of MODY subtypes. Moreover, WES can be useful for detecting large deletions in coding regions in addition to point mutations. K E Y W O R D S childhood, maturity-onset diabetes of the young, South China, whole-exome sequencing Aijing Xu and Yunting Lin contribute equally to this work.

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“…[16, 34, 36] However, a recent study described NDDs in (6/54) 11% of individuals with MODY harboring HNF1B intragenic alterations; this frequency was significantly higher when compared with cases who had another cause of diabetes and not significantly different from 17q12DS cases (17.0%; 9/53). [35] This study only excluded CNVs and Fragile X syndrome in individuals with NDDs without further application of exome sequencing. This leaves the possibility of a second, independent variant causing a blended phenotype, as has been shown for 4.9% of the cases in a large cohort of individuals receiving exome sequencing for different diseases.…”

Section: Discussionmentioning

confidence: 99%

Prenatal diagnosis of HNF1B-associated renal cysts: Need to differentiate intragenic variants from 17q12 microdeletion syndrome?

Vasileiou

Hoyer

Thiel

et al. 2019

Preprint

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Objective Large deletions of chromosome 17q12 (17q12DS) or intragenic variants in HNF1B are associated with variable developmental, endocrine and renal anomalies, often already noted prenatally as hyperechogenic/cystic kidneys. Here, we describe pre-and postnatal phenotypes of seven individuals with HNF1B aberrations and compare their clinical and genetic data to previous studies. MethodsPrenatal sequencing and postnatal chromosomal microarray analysis was performed in seven individuals with renal and/or neurodevelopmental phenotypes. We evaluated HNF1B-related clinical features from 82 studies and reclassified 192 reported intragenic HNF1B variants. Results In a prenatal case, we identified a novel in-frame deletion p.(Gly239del) within the HNF1B DNA binding domain, a mutational hotspot as demonstrated by spatial clustering analysis and high computational prediction scores. The six postnatally diagnosed individuals harbored 17q12 microdeletions of varying size. Literature screening revealed highly variable reporting of HNF1B-associated clinical traits. Overall, developmental delay was more frequent in 17q12DS carriers, although both mutation groups showed a high phenotypic heterogeneity. The reclassification of all previously reported intragenic HNF1B variants provided an up-to-date overview of the mutational spectrum. Conclusions We highlight the value of prenatal HNF1B screening in renal developmental diseases. Standardized clinical reporting and systematic classification of HNF1B variants is necessary for a more accurate risk quantification of pre-and postnatal clinical features, improving genetic counseling and prenatal decision-making.

show abstract

Intellectual disability in patients with MODY due to hepatocyte nuclear factor 1B (HNF1B) molecular defects

Cited by 19 publications

References 16 publications

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

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

Molecular diagnosis of maturity‐onset diabetes of the young in a cohort of Chinese children

Prenatal diagnosis of HNF1B-associated renal cysts: Need to differentiate intragenic variants from 17q12 microdeletion syndrome?

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