Novel ANKRD11 gene mutation in an individual with a mild phenotype of KBG syndrome associated to a GEFS+ phenotypic spectrum: a case report
Abstract Background KBG syndrome is a very rare autosomal dominant disorder, characterized by macrodontia, distinctive craniofacial findings, skeletal findings, post-natal short stature, and developmental delays, sometimes associated with seizures and EEG abnormalities. So far, there have been over...
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2019-01-01
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Online Access: | http://link.springer.com/article/10.1186/s12881-019-0745-7 |
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Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Rita Maria Alves Paolo Uva Marielza F. Veiga Manuela Oppo Fabiana C. R. Zschaber Giampiero Porcu Henrique P. Porto Ivana Persico Stefano Onano Gianmauro Cuccuru Rossano Atzeni Lauro C. N. Vieira Marcos V. A. Pires Francesco Cucca Maria Betânia P. Toralles Andrea Angius Laura Crisponi |
spellingShingle |
Rita Maria Alves Paolo Uva Marielza F. Veiga Manuela Oppo Fabiana C. R. Zschaber Giampiero Porcu Henrique P. Porto Ivana Persico Stefano Onano Gianmauro Cuccuru Rossano Atzeni Lauro C. N. Vieira Marcos V. A. Pires Francesco Cucca Maria Betânia P. Toralles Andrea Angius Laura Crisponi Novel ANKRD11 gene mutation in an individual with a mild phenotype of KBG syndrome associated to a GEFS+ phenotypic spectrum: a case report BMC Medical Genetics Whole exome sequencing KBG syndrome ANKRD11 gene Generalized epilepsy with febrile seizures (GEFS+) SCN9A gene |
author_facet |
Rita Maria Alves Paolo Uva Marielza F. Veiga Manuela Oppo Fabiana C. R. Zschaber Giampiero Porcu Henrique P. Porto Ivana Persico Stefano Onano Gianmauro Cuccuru Rossano Atzeni Lauro C. N. Vieira Marcos V. A. Pires Francesco Cucca Maria Betânia P. Toralles Andrea Angius Laura Crisponi |
author_sort |
Rita Maria Alves |
title |
Novel ANKRD11 gene mutation in an individual with a mild phenotype of KBG syndrome associated to a GEFS+ phenotypic spectrum: a case report |
title_short |
Novel ANKRD11 gene mutation in an individual with a mild phenotype of KBG syndrome associated to a GEFS+ phenotypic spectrum: a case report |
title_full |
Novel ANKRD11 gene mutation in an individual with a mild phenotype of KBG syndrome associated to a GEFS+ phenotypic spectrum: a case report |
title_fullStr |
Novel ANKRD11 gene mutation in an individual with a mild phenotype of KBG syndrome associated to a GEFS+ phenotypic spectrum: a case report |
title_full_unstemmed |
Novel ANKRD11 gene mutation in an individual with a mild phenotype of KBG syndrome associated to a GEFS+ phenotypic spectrum: a case report |
title_sort |
novel ankrd11 gene mutation in an individual with a mild phenotype of kbg syndrome associated to a gefs+ phenotypic spectrum: a case report |
publisher |
BMC |
series |
BMC Medical Genetics |
issn |
1471-2350 |
publishDate |
2019-01-01 |
description |
Abstract Background KBG syndrome is a very rare autosomal dominant disorder, characterized by macrodontia, distinctive craniofacial findings, skeletal findings, post-natal short stature, and developmental delays, sometimes associated with seizures and EEG abnormalities. So far, there have been over 100 cases of KBG syndrome reported. Case presentation Here, we describe two sisters of a non-consanguineous family, both presenting generalized epilepsy with febrile seizures (GEFS+), and one with a more complex phenotype associated with mild intellectual disability, skeletal and dental anomalies. Whole exome sequencing (WES) analysis in all the family members revealed a heterozygous SCN9A mutation, p.(Lys655Arg), shared among the father and the two probands, and a novel de novo loss of function mutation in the ANKRD11 gene, p.(Tyr1715*), in the proband with the more complex phenotype. The reassessment of the phenotypic features confirmed that the patient fulfilled the proposed diagnostic criteria for KBG syndrome, although complicated by early-onset isolated febrile seizures. EEG abnormalities with or without seizures have been reported previously in some KBG cases. The shared variant, occurring in SCN9A, has been previously found in several individuals with GEFS+ and Dravet syndrome. Conclusions This report describe a novel de novo variant in ANKRD11 causing a mild phenotype of KGB syndrome and further supports the association of monogenic pattern of SCN9A mutations with GEFS+. Our data expand the allelic spectrum of ANKRD11 mutations, providing the first Brazilian case of KBG syndrome. Furthermore, this study offers an example of how WES has been instrumental allowing us to better dissect the clinical phenotype under study, which is a multilocus variation aggregating in one proband, rather than a phenotypic expansion associated with a single genomic locus, underscoring the role of multiple rare variants at different loci in the etiology of clinical phenotypes making problematic the diagnostic path. The successful identification of the causal variant in a gene may not be sufficient, making it necessary to identify other variants that fully explain the clinical picture. The prevalence of blended phenotypes from multiple monogenic disorders is currently unknown and will require a systematic re-analysis of large WES datasets for proper diagnosis in daily practice. |
topic |
Whole exome sequencing KBG syndrome ANKRD11 gene Generalized epilepsy with febrile seizures (GEFS+) SCN9A gene |
url |
http://link.springer.com/article/10.1186/s12881-019-0745-7 |
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doaj-22adc8b7ac914df3a0cf5814817a5e602021-04-02T05:52:38ZengBMCBMC Medical Genetics1471-23502019-01-012011710.1186/s12881-019-0745-7Novel ANKRD11 gene mutation in an individual with a mild phenotype of KBG syndrome associated to a GEFS+ phenotypic spectrum: a case reportRita Maria Alves0Paolo Uva1Marielza F. Veiga2Manuela Oppo3Fabiana C. R. Zschaber4Giampiero Porcu5Henrique P. Porto6Ivana Persico7Stefano Onano8Gianmauro Cuccuru9Rossano Atzeni10Lauro C. N. Vieira11Marcos V. A. Pires12Francesco Cucca13Maria Betânia P. Toralles14Andrea Angius15Laura Crisponi16Postgraduate Program in Interactive Processes of Organs and Systems - Federal University of BahiaCentre for Advanced Studies, Research and Development in Sardinia (CRS4), Science and Technology Park PolarisPostgraduate Program in Interactive Processes of Organs and Systems - Federal University of BahiaDepartment of Biomedical Science, University of SassariResearch group Epi-GenéticResearch group Epi-GenéticResearch group Epi-GenéticInstitute of Genetic and Biomedical Research, National Research Council (CNR), Cittadella Universitaria di CagliariDepartment of Biomedical Science, University of SassariCentre for Advanced Studies, Research and Development in Sardinia (CRS4), Science and Technology Park PolarisCentre for Advanced Studies, Research and Development in Sardinia (CRS4), Science and Technology Park PolarisClinic Ponto Alto diagnostic by ImageResearch group Epi-GenéticDepartment of Biomedical Science, University of SassariPostgraduate Program in Interactive Processes of Organs and Systems - Federal University of BahiaDepartment of Biomedical Science, University of SassariDepartment of Biomedical Science, University of SassariAbstract Background KBG syndrome is a very rare autosomal dominant disorder, characterized by macrodontia, distinctive craniofacial findings, skeletal findings, post-natal short stature, and developmental delays, sometimes associated with seizures and EEG abnormalities. So far, there have been over 100 cases of KBG syndrome reported. Case presentation Here, we describe two sisters of a non-consanguineous family, both presenting generalized epilepsy with febrile seizures (GEFS+), and one with a more complex phenotype associated with mild intellectual disability, skeletal and dental anomalies. Whole exome sequencing (WES) analysis in all the family members revealed a heterozygous SCN9A mutation, p.(Lys655Arg), shared among the father and the two probands, and a novel de novo loss of function mutation in the ANKRD11 gene, p.(Tyr1715*), in the proband with the more complex phenotype. The reassessment of the phenotypic features confirmed that the patient fulfilled the proposed diagnostic criteria for KBG syndrome, although complicated by early-onset isolated febrile seizures. EEG abnormalities with or without seizures have been reported previously in some KBG cases. The shared variant, occurring in SCN9A, has been previously found in several individuals with GEFS+ and Dravet syndrome. Conclusions This report describe a novel de novo variant in ANKRD11 causing a mild phenotype of KGB syndrome and further supports the association of monogenic pattern of SCN9A mutations with GEFS+. Our data expand the allelic spectrum of ANKRD11 mutations, providing the first Brazilian case of KBG syndrome. Furthermore, this study offers an example of how WES has been instrumental allowing us to better dissect the clinical phenotype under study, which is a multilocus variation aggregating in one proband, rather than a phenotypic expansion associated with a single genomic locus, underscoring the role of multiple rare variants at different loci in the etiology of clinical phenotypes making problematic the diagnostic path. The successful identification of the causal variant in a gene may not be sufficient, making it necessary to identify other variants that fully explain the clinical picture. The prevalence of blended phenotypes from multiple monogenic disorders is currently unknown and will require a systematic re-analysis of large WES datasets for proper diagnosis in daily practice.http://link.springer.com/article/10.1186/s12881-019-0745-7Whole exome sequencingKBG syndromeANKRD11 geneGeneralized epilepsy with febrile seizures (GEFS+)SCN9A gene |