학술논문
Clinical description, molecular delineation and genotype-phenotype correlation in 340 patients with KBG syndrome: addition of 67 new patients.
Document Type
Academic Journal
Author
Martinez-Cayuelas E; Department of Pediatrics, Hospital Universitario Fundacion Jimenez Diaz, Madrid, Spain.; Blanco-Kelly F; Department of Genetics and Genomics, Hospital Universitario Fundacion Jimenez Diaz (IIS-FJD), Madrid, Spain.; Centro de Investigacion Biomedica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain.; Lopez-Grondona F; Department of Genetics and Genomics, Hospital Universitario Fundacion Jimenez Diaz (IIS-FJD), Madrid, Spain.; Swafiri ST; Department of Genetics and Genomics, Hospital Universitario Fundacion Jimenez Diaz (IIS-FJD), Madrid, Spain.; Centro de Investigacion Biomedica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain.; Lopez-Rodriguez R; Department of Genetics and Genomics, Hospital Universitario Fundacion Jimenez Diaz (IIS-FJD), Madrid, Spain.; School of Pharmacy, Universidad San Pablo CEU. CEU Universities, Madrid, Spain.; Losada-Del Pozo R; Department of Pediatrics, Hospital Universitario Fundacion Jimenez Diaz, Madrid, Spain.; Mahillo-Fernandez I; Department of Statistics, Hospital Universitario Fundacion Jimenez Diaz (IIS-FJD), Madrid, Spain.; Moreno B; Department of Pediatrics, Hospital Universitario Fundacion Jimenez Diaz, Madrid, Spain.; Rodrigo-Moreno M; Department of Pediatrics, Hospital Universitario Fundacion Jimenez Diaz, Madrid, Spain.; Casas-Alba D; Clinical Genetics and Dysmorphology, Department of Genetic and Molecular Medicine, Pediatric Insitute of Rare Diseases (IPER), Hospital Sant Joan de Deu, Barcelona, Spain.; Lopez-Gonzalez A; Clinical Genetics and Dysmorphology, Department of Genetic and Molecular Medicine, Pediatric Insitute of Rare Diseases (IPER), Hospital Sant Joan de Deu, Barcelona, Spain.; García-Miñaúr S; Centro de Investigacion Biomedica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain.; Medical and Molecular Genetics Institute (INGEMM), Hospital Universitario La Paz, Madrid, Spain.; Ángeles Mori M; Centro de Investigacion Biomedica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain.; Medical and Molecular Genetics Institute (INGEMM), Hospital Universitario La Paz, Madrid, Spain.; Pacio-Minguez M; Medical and Molecular Genetics Institute (INGEMM), Hospital Universitario La Paz, Madrid, Spain.; Rikeros-Orozco E; Medical and Molecular Genetics Institute (INGEMM), Hospital Universitario La Paz, Madrid, Spain.; Santos-Simarro F; Centro de Investigacion Biomedica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain.; Medical and Molecular Genetics Institute (INGEMM), Hospital Universitario La Paz, Madrid, Spain.; Cruz-Rojo J; Dysmorphology and Genetics Unit (UDISGEN), Hospital Universitario 12 de Octubre, Madrid, Spain.; Endocrinology Unit, Department of Pediatrics, Hospital Universitario 12 de Octubre, Madrid, Spain.; Quesada-Espinosa JF; Dysmorphology and Genetics Unit (UDISGEN), Hospital Universitario 12 de Octubre, Madrid, Spain.; Department of Genetics, Hospital Universitario 12 de Octubre, Madrid, Spain.; Sanchez-Calvin MT; Dysmorphology and Genetics Unit (UDISGEN), Hospital Universitario 12 de Octubre, Madrid, Spain.; Department of Genetics, Hospital Universitario 12 de Octubre, Madrid, Spain.; Sanchez-Del Pozo J; Dysmorphology and Genetics Unit (UDISGEN), Hospital Universitario 12 de Octubre, Madrid, Spain.; Endocrinology Unit, Department of Pediatrics, Hospital Universitario 12 de Octubre, Madrid, Spain.; Bernado Fonz R; Pediatric Neurology Unit, Department of Pediatrics, Navarrabiomed Pediatric Neurology Research Group, Hospital Universitario de Navarra, Pamplona, Spain.; Isidoro-Garcia M; Department of Biochemistry, Hospital Universitario de Salamanca. IBSAL Universidad de Salamanca, Salamanca, Spain.; Ruiz-Ayucar I; Department of Pediatrics, Hospital Universitario de Salamanca, Salamanca, Spain.; Alvarez-Mora MI; Department of Biochemistry and Molecular Genetics, IDIBAPS (Institut de Investigacions Biomèdiques August Pi I Sunyer), Hospital Clinic de Barcelona, Barcelona, Spain.; Blanco-Lago R; Pediatric Neurology Unit, Department of Pediatrics, Hospital Universitario Central de Asturias, Oviedo, Spain.; De Azua B; Department of Pediatrics, Hospital Son Llàtzer, Palma de Mallorca, Spain.; Eiris J; Department of Pediatric Neurology, Hospital Universitario de Santiago de Compostela, Santiago de Compostela, Spain.; Garcia-Peñas JJ; Pediatric Neurology Unit, Department of Pediatrics, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.; Gil-Fournier B; Department of Genetics, Hospital Universitario de Getafe, Madrid, Spain.; Gomez-Lado C; Department of Pediatric Neurology, Hospital Universitario de Santiago de Compostela, Santiago de Compostela, Spain.; Irazabal N; Department of Pediatrics, Hospital Can Misses, Eivissa, Spain.; Lopez-Gonzalez V; Medical Genetics Unit, Department of Genetics, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain.; Madrigal I; Centro de Investigacion Biomedica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain.; Department of Biochemistry and Molecular Genetics, IDIBAPS (Institut de Investigacions Biomèdiques August Pi I Sunyer), Hospital Clinic de Barcelona, Barcelona, Spain.; Malaga I; Pediatric Neurology Unit, Department of Pediatrics, Hospital Universitario Central de Asturias, Oviedo, Spain.; Martinez-Menendez B; Pediatric Neurology Unit, Department of Neurology, Hospital Universitario de Getafe, Madrid, Spain.; Ramiro-Leon S; Department of Genetics, Hospital Universitario de Getafe, Madrid, Spain.; Garcia-Hoyos M; Genetic Diagnosis Service, NIMGenetics Genomics and Medicine, Madrid, Spain.; Prieto-Matos P; Department of Pediatrics, Hospital Universitario de Salamanca, Salamanca, Spain.; Lopez-Pison J; Pediatric Neurology Unit, Department of Pediatrics, Hospital Universitario Miguel Servet, Zaragoza, Spain.; Aguilera-Albesa S; Pediatric Neurology Unit, Department of Pediatrics, Navarrabiomed Pediatric Neurology Research Group, Hospital Universitario de Navarra, Pamplona, Spain.; Alvarez S; Genetic Diagnosis Service, NIMGenetics Genomics and Medicine, Madrid, Spain.; Fernández-Jaén A; Department of Pediatric Neurology, Hospital Universitario Quironsalud Madrid, Madrid, Spain.; Llano-Rivas I; Department of Genetics, Hospital Universitario de Cruces. Biocruces Bizcaia Health Research Institute, Bizcaia, Spain.; Gener-Querol B; Department of Genetics, Hospital Universitario de Cruces. Biocruces Bizcaia Health Research Institute, Bizcaia, Spain.; Ayuso C; Department of Genetics and Genomics, Hospital Universitario Fundacion Jimenez Diaz (IIS-FJD), Madrid, Spain.; Centro de Investigacion Biomedica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain.; Arteche-Lopez A; Dysmorphology and Genetics Unit (UDISGEN), Hospital Universitario 12 de Octubre, Madrid, Spain.; Department of Genetics, Hospital Universitario 12 de Octubre, Madrid, Spain.; Palomares-Bralo M; Centro de Investigacion Biomedica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain.; Medical and Molecular Genetics Institute (INGEMM), Hospital Universitario La Paz, Madrid, Spain.; Cueto-González A; Department of Clinical and Molecular Genetics, Vall d'Hebron Research Institute, Hospital Universitario Vall d'Hebron, Barcelona, Spain.; Valenzuela I; Department of Clinical and Molecular Genetics, Vall d'Hebron Research Institute, Hospital Universitario Vall d'Hebron, Barcelona, Spain.; Martinez-Monseny A; Clinical Genetics and Dysmorphology, Department of Genetic and Molecular Medicine, Pediatric Insitute of Rare Diseases (IPER), Hospital Sant Joan de Deu, Barcelona, Spain.; Lorda-Sanchez I; Department of Genetics and Genomics, Hospital Universitario Fundacion Jimenez Diaz (IIS-FJD), Madrid, Spain.; Centro de Investigacion Biomedica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain.; Almoguera B; Department of Genetics and Genomics, Hospital Universitario Fundacion Jimenez Diaz (IIS-FJD), Madrid, Spain balmoguera@quironsalud.es.; Centro de Investigacion Biomedica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain.
Source
Publisher: British Medical Association Country of Publication: England NLM ID: 2985087R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1468-6244 (Electronic) Linking ISSN: 00222593 NLM ISO Abbreviation: J Med Genet Subsets: MEDLINE
Subject
Language
English
Abstract
Background: KBG syndrome is a highly variable neurodevelopmental disorder and clinical diagnostic criteria have changed as new patients have been reported. Both loss-of-function sequence variants and large deletions (copy number variations, CNVs) involving ANKRD11 cause KBG syndrome, but no genotype-phenotype correlation has been reported.
Methods: 67 patients with KBG syndrome were assessed using a custom phenotypical questionnaire. Manifestations present in >50% of the patients and a 'phenotypical score' were used to perform a genotype-phenotype correlation in 340 patients from our cohort and the literature.
Results: Neurodevelopmental delay, macrodontia, triangular face, characteristic ears, nose and eyebrows were the most prevalentf (eatures. 82.8% of the patients had at least one of seven main comorbidities: hearing loss and/or otitis media, visual problems, cryptorchidism, cardiopathy, feeding difficulties and/or seizures. Associations found included a higher phenotypical score in patients with sequence variants compared with CNVs and a higher frequency of triangular face (71.1% vs 42.5% in CNVs). Short stature was more frequent in patients with exon 9 variants (62.5% inside vs 27.8% outside exon 9), and the prevalence of intellectual disability/attention deficit hyperactivity disorder/autism spectrum disorder was lower in patients with the c.1903_1907del variant (70.4% vs 89.4% other variants). Presence of macrodontia and comorbidities were associated with larger deletion sizes and hand anomalies with smaller deletions.
Conclusion: We present a detailed phenotypical description of KBG syndrome in the largest series reported to date of 67 patients, provide evidence of a genotype-phenotype correlation between some KBG features and specific ANKRD11 variants in 340 patients, and propose updated clinical diagnostic criteria based on our findings.
Competing Interests: Competing interests: None declared.
(© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)
Methods: 67 patients with KBG syndrome were assessed using a custom phenotypical questionnaire. Manifestations present in >50% of the patients and a 'phenotypical score' were used to perform a genotype-phenotype correlation in 340 patients from our cohort and the literature.
Results: Neurodevelopmental delay, macrodontia, triangular face, characteristic ears, nose and eyebrows were the most prevalentf (eatures. 82.8% of the patients had at least one of seven main comorbidities: hearing loss and/or otitis media, visual problems, cryptorchidism, cardiopathy, feeding difficulties and/or seizures. Associations found included a higher phenotypical score in patients with sequence variants compared with CNVs and a higher frequency of triangular face (71.1% vs 42.5% in CNVs). Short stature was more frequent in patients with exon 9 variants (62.5% inside vs 27.8% outside exon 9), and the prevalence of intellectual disability/attention deficit hyperactivity disorder/autism spectrum disorder was lower in patients with the c.1903_1907del variant (70.4% vs 89.4% other variants). Presence of macrodontia and comorbidities were associated with larger deletion sizes and hand anomalies with smaller deletions.
Conclusion: We present a detailed phenotypical description of KBG syndrome in the largest series reported to date of 67 patients, provide evidence of a genotype-phenotype correlation between some KBG features and specific ANKRD11 variants in 340 patients, and propose updated clinical diagnostic criteria based on our findings.
Competing Interests: Competing interests: None declared.
(© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)