Clinical description, molecular delineation and genotype–phenotype correlation in 340 patients with KBG syndrome: addition of 67 new patients
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Published:2022-11-29
Issue:
Volume:
Page:jmedgenet-2022-108632
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ISSN:0022-2593
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Container-title:Journal of Medical Genetics
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language:en
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Short-container-title:J Med Genet
Author:
Martinez-Cayuelas ElenaORCID, Blanco-Kelly Fiona, Lopez-Grondona Fermina, Swafiri Saoud TahsinORCID, Lopez-Rodriguez Rosario, Losada-Del Pozo Rebeca, Mahillo-Fernandez Ignacio, Moreno Beatriz, Rodrigo-Moreno Maria, Casas-Alba Didac, Lopez-Gonzalez Aitor, García-Miñaúr Sixto, Ángeles Mori Maria, Pacio-Minguez Marta, Rikeros-Orozco Emi, Santos-Simarro Fernando, Cruz-Rojo Jaime, Quesada-Espinosa Juan Francisco, Sanchez-Calvin Maria Teresa, Sanchez-del Pozo Jaime, Bernado Fonz Raquel, Isidoro-Garcia Maria, Ruiz-Ayucar Irene, Alvarez-Mora Maria Isabel, Blanco-Lago Raquel, De Azua Begoña, Eiris Jesus, Garcia-Peñas Juan Jose, Gil-Fournier Belen, Gomez-Lado Carmen, Irazabal Nadia, Lopez-Gonzalez Vanessa, Madrigal Irene, Malaga Ignacio, Martinez-Menendez Beatriz, Ramiro-Leon Soraya, Garcia-Hoyos Maria, Prieto-Matos Pablo, Lopez-Pison Javier, Aguilera-Albesa Sergio, Alvarez Sara, Fernández-Jaén AlbertoORCID, Llano-Rivas Isabel, Gener-Querol Blanca, Ayuso CarmenORCID, Arteche-Lopez Ana, Palomares-Bralo Maria, Cueto-González Anna, Valenzuela Irene, Martinez-Monseny AntonioORCID, Lorda-Sanchez Isabel, Almoguera BertaORCID
Abstract
BackgroundKBG 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) involvingANKRD11cause KBG syndrome, but no genotype–phenotype correlation has been reported.Methods67 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.ResultsNeurodevelopmental 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.ConclusionWe 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 specificANKRD11variants in 340 patients, and propose updated clinical diagnostic criteria based on our findings.
Funder
Instituto de Salud Carlos III
Subject
Genetics (clinical),Genetics
Cited by
3 articles.
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