KBG Syndrome: Prospective Videoconferencing and Use of AI-driven Facial Phenotyping in 25 New Patients

Abstract

Genetic variants in the gene Ankyrin Repeat Domain 11 (ANKRD11) and deletions in 16q24.3 are known to cause KBG syndrome, a rare syndrome associated with craniofacial, intellectual, and neurobehavioral anomalies. We report 25 unpublished individuals from 22 families, all with molecularly confirmed diagnoses of KBG syndrome. Twenty-one individuals have de novo variants, three have inherited variants, and one is inherited from a parent exhibiting low-level mosaicism. Of these variants, 20 are truncating (frameshift or nonsense), and five are missense. We created a novel protocol for collection and reporting of data, including prospectively interviewing these individuals and their families throughout eight countries via videoconferencing by a single clinician. Participants’ medical records, including imaging, were reviewed, and data was uploaded to the Human Disease Gene website using Human Phenotype Ontology (HPO) terms. Photos of the participants were submitted to GestaltMatcher and Face2Gene (FDNA Inc, USA) for facial analysis, and we found similar facial phenotypes among the participants. Within our cohort, common traits included short stature, macrodontia, anteverted nares, wide nasal bridge, wide nasal base, thick eyebrows, synophrys and hypertelorism. Seventy-two percent of participants had gastrointestinal complaints and 80% had hearing loss. Three participants were started on growth hormone with positive results. Behavioral issues and global developmental delays were found in most participants. Neurologic abnormalities including seizures and/or EEG abnormalities were also very common (44%), suggesting that early detection and seizure prophylaxis could be an important point of intervention. Twenty-four percent were diagnosed with attention deficit hyperactivity disorder (ADHD) and 28% were diagnosed with autism spectrum disorder (ASD). Additionally, we have identified minimally reported symptoms, including recurrent sinus infections (16%) and previously unreported migraines (20%). Based on the videoconferencing and these data, we provide a set of recommendations regarding diagnostic and treatment approaches for KBG syndrome.

Expanding the Phenotypic spectrum ofNAA10-related neurodevelopmental syndrome andNAA15-related neurodevelopmental syndrome

“…A separate written informed consent was obtained for publication of photographs; these photos were loaded onto Face2Gene (version 20.1.4; FDNA Inc, USA) (Gurovich et al 2019) and GestaltMatcher (version 1.0) through Bonn University (Hsieh et al 2022). Future work will focus on detailed analysis of the many photographs with these programs that use deep convolutional neural networks to build syndrome and patient classifiers, respectively, as we recently accomplished for a different syndrome, KBG Syndrome (Guo et al 2021).…”

KBG syndrome: Clinical features and molecular findings in seven unrelated Korean families with a review of the literature

“…Although there were differences in the degree of delay among the patients included in this study, developmental delay or intellectual disability was observed in all eight patients, consistent with previous findings. The reported co‐occurrence rate of ADHD and KBG syndrome is generally10–15% (Goldenberg et al, 2016 ; Low et al, 2016 ), while one paper proposed a rate of approximately 28% (Guo et al, 2021 ). Of the eight patients in this study, two were diagnosed with ADHD, representing 25% comorbidity; however, continued follow‐up is required, as this study included infants who are not yet of an age at which ADHD can be tested.…”

Documentation and prevalence of prenatal and neonatal outcomes in a cohort of individuals with KBG syndrome

“…Data collected from 25 of these individuals has already been published. 12 The individuals interviewed reside in 11 different countries and were recruited via a private Facebook group created by the KBG Foundation or by self-referral. Inclusion criteria included a molecular diagnosis of KBG syndrome, which was confirmed by review of medical records by G.J.L.…”