Journal Article

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

Blanco-Kelly, Fiona, Lopez-Pison, Javier, Palomares-Bralo, Maria, Moreno, Beatriz, Martinez-Cayuelas, Elena, Casas-Alba, Didac, De Azua, Begoña, Ayuso, Carmen, Madrigal, Irene, Bernado Fonz, Raquel, Martinez-Menendez, Beatriz, Sanchez-del Pozo, Jaime, Alvarez-Mora, Maria Isabel, Gomez-Lado, Carmen, Rodrigo-Moreno, Maria, Ramiro-Leon, Soraya, Cueto-González, Anna, Aguilera-Albesa, Sergio, Arteche-Lopez, Ana, Blanco-Lago, Raquel, Santos-Simarro, Fernando, Gil-Fournier, Belen, Irazabal, Nadia, Ángeles Mori, Maria, Eiris, Jesus, Swafiri, Saoud Tahsin, García-Miñaúr, Sixto, Llano-Rivas, Isabel, Fernández-Jaén, Alberto, Ruiz-Ayucar, Irene, Prieto-Matos, Pablo, Lopez-Gonzalez, Vanessa, Isidoro-Garcia, Maria, Lorda-Sanchez, Isabel, Rikeros-Orozco, Emi, Martinez-Monseny, Antonio, Lopez-Gonzalez, Aitor, Pacio-Minguez, Marta, Sanchez-Calvin, Maria Teresa, Gener-Querol, Blanca, Malaga, Ignacio, Lopez-Rodriguez, Rosario, Garcia-Peñas, Juan Jose, Lopez-Grondona, Fermina, Cruz-Rojo, Jaime, Garcia-Hoyos, Maria, Almoguera, Berta, Quesada-Espinosa, Juan Francisco, Mahillo-Fernandez, Ignacio, Alvarez

2023

Overview

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) involving ANKRD11 cause 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 specific ANKRD11 variants in 340 patients, and propose updated clinical diagnostic criteria based on our findings.

• Publisher: BMJ Publishing Group Ltd,BMJ Publishing Group LTD
• Subject: Abnormalities, Multiple - diagnosis / Attention deficit hyperactivity disorder / Autism / Autism Spectrum Disorder - genetics / Bone Diseases, Developmental - genetics / Chromosome Deletion / Comorbidity / Congenital diseases / Copy number / Cryptorchidism / Diagnosis / DNA Copy Number Variations / Ear diseases / Facies / Genetics / Genetics, Medical / Genomics / Genotype & phenotype / Genotype-phenotype correlations / Genotypes / Hearing loss / Humans / Intellectual disabilities / Intellectual Disability - diagnosis / Intellectual Disability - epidemiology / Intellectual Disability - genetics / Literature reviews / Male / Neurodevelopmental disorders / Otitis media / Patients / Pediatrics / Phenotype / Phenotypes / Questionnaires / Repressor Proteins - genetics / Seizures / Tooth Abnormalities - genetics / Transcription Factors - genetics / Variables