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Ayuso Garcia, Maria Del Carmen TomasaAuthorMartinez-Cayuelas, EAuthor

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Clinical description, molecular delineation and genotype-phenotype correlation in 340 patients with KBG syndrome: addition of 67 new patients

Publicated to:JOURNAL OF MEDICAL GENETICS. 60 (7): 644-654 - 2023-01-01 60(7), DOI: 10.1136/jmg-2022-108632

Authors: Martinez-Cayuelas, Elena; Blanco-Kelly, Fiona; Lopez-Grondona, Fermina; Swafiri, Saoud Tahsin; Lopez-Rodriguez, Rosario; Losada-Del Pozo, Rebeca; Mahillo-Fernandez, Ignacio; Moreno, Beatriz; Rodrigo-Moreno, Maria; Casas-Alba, Didac; Lopez-Gonzalez, Aitor; Garcia-Minaur, Sixto; Mori, Maria Angeles; Pacio-Minguez, Marta; Rikeros-Orozco, Emi; Santos-Simarro, Fernando; Cruz-Rojo, Jaime; Quesada-Espinosa, Juan Francisco; Sanchez-Calvin, Maria Teresa; Sanchez-Del Pozo, Jaime; Fonz, Raquel Bernado; Isidoro-Garcia, Maria; Ruiz-Ayucar, Irene; Alvarez-Mora, Maria Isabel; Blanco-Lago, Raquel; De Azua, Begona; Eiris, Jesus; Garcia-Penas, 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; Fernandez-Jaen, Alberto; Llano-Rivas, Isabel; Gener-Querol, Blanca; Ayuso, Carmen; Arteche-Lopez, Ana; Palomares-Bralo, Maria; Cueto-Gonzalez, Anna; Valenzuela, Irene; Martinez-Monseny, Antonio; Lorda-Sanchez, Isabel; Almoguera, Berta

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Abstract

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.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.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.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.© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.

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