Clinical description, molecular delineation and genotype–phenotype correlation in 340 patients with KBG syndrome: addition of 67 new patients
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 , 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 Alberto , Llano-Rivas Isabel , Gener-Querol Blanca , Ayuso Carmen , Arteche-Lopez Ana , Palomares-Bralo Maria , Cueto-González Anna , Valenzuela Irene , Martinez-Monseny Antonio , Lorda-Sanchez Isabel , Almoguera Berta 
Published: November 2022

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) involvingANKRD11cause 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 specificANKRD11variants in 340 patients, and propose updated clinical diagnostic criteria based on our findings.