Expanding the KBG syndrome phenotype through 2D facial morphometry, clinical and molecular characterization

Abstract

KBG syndrome (KBGS) is a neurodevelopmental disorder caused by ANKRD11 (ankyrin repeat domain-containing protein 11) haploinsufficiency. Its broad phenotypic variability and overlap with other types of chromatinopathies frequently hinder clinical recognition, and genotype-phenotype associations remain limited. The present study aimed to characterize the clinical and molecular features of individuals with KBGS and expand the craniofacial phenotype using two-dimensional (2D) facial morphometry. The present retrospective study involved patients with molecularly confirmed KBGS evaluated between January 2017 and February 2025 at Fundación Valle del Lili (Cali, Colombia). Detailed developmental, craniofacial, skeletal, neurological and behavioral features were documented. Molecular diagnoses were established using clinical exome sequencing. Craniofacial differences were quantified using 2D morphometric analysis. A systematic review of the literature was performed to compare the prevalence of clinical manifestations observed in the present cohort with previously reported cohorts. All 10 individuals carried pathogenic or likely pathogenic ANKRD11 variants, including multiple novel frameshift mutations. Developmental delay and intellectual disability were universal. Recurrent clinical findings included facial asymmetry, low hair implantation, bulbous nasal tip, synophrys, scoliosis, seizures, behavioral disturbance and hearing impairment. Morphometric analysis identified distinctive craniofacial patterns differentiating patients from controls, mainly involving facial asymmetry, increased forehead height, nasal prominence, increased lower lip thickness and reduced chin prominence. The literature review confirmed shared chromatinopathy-related features, including developmental delay, intellectual disability, craniofacial dysmorphism, skeletal anomalies and behavioral disturbances, as well as under-recognized findings such as facial asymmetry, low anterior hairline, hypotonia and hearing impairment. The present study broadens the phenotypic and genotypic landscape of KBGS, providing quantitative craniofacial characterization, and refines genotype-phenotype associations to support improved diagnostic accuracy.