KBG syndrome: videoconferencing and use of artificial intelligence driven facial phenotyping in 25 new patients

Abstract

Genetic variants in 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 We report 25 unpublished individuals from 22 families with molecularly confirmed diagnoses. Twelve individuals have de novo variants, three have inherited variants, and one is inherited from a parent with low-level mosaicism. The mode of inheritance was unknown for nine individuals. Twenty are truncating variants, and the remaining five are missense (three of which are found in one family). We present a protocol emphasizing the use of videoconference and artificial intelligence (AI) in collecting and analyzing data for this rare syndrome. A single clinician interviewed 25 individuals throughout eight countries. Participants’ medical records were reviewed, and data was uploaded to the Human Disease Gene website using Human Phenotype Ontology (HPO) terms. Photos of the participants were analyzed by the GestaltMatcher and DeepGestalt, Face2Gene platform (FDNA Inc, USA) algorithms. Within our cohort, common traits included short stature, macrodontia, anteverted nares, wide nasal bridge, wide nasal base, thick eyebrows, synophrys and hypertelorism. Behavioral issues and global developmental delays were widely present. Neurologic abnormalities including seizures and/or EEG abnormalities were common (44%), suggesting that early detection and seizure prophylaxis could be an important point of intervention. Almost a quarter (24%) were diagnosed with attention deficit hyperactivity disorder and 28% were diagnosed with autism spectrum disorder. Based on the data, we provide a set of recommendations regarding diagnostic and treatment approaches for KBG syndrome.

Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes

“…While not directly linked to epilepsy, ANKRD11 is a known causal gene for the KBG syndrome, 18 a rare genetic disorder characterized by a range of developmental and neurological abnormalities including epilepsy. 19-21…”

“…While not directly linked to epilepsy, ANKRD11 is a known causal gene for the KBG syndrome, 18 a rare genetic disorder characterized by a range of developmental and neurological abnormalities including epilepsy. [19][20][21] Analysis of protein-truncating URVs in NAFE revealed as the most significant gene, DEPDC5 ([MIM: 614191], log[OR]=2.6, P<2.2×10 -16 ; Fig. 1a), which encodes part of the GATOR1 complex, a repressor of the mTORC1 pathway that has been prominently associated with focal epilepsies.…”

Ankrd11, a chromatin regulator and a KBG syndrome risk gene, is a critical regulator of cardiac neural crest cell biology and heart development

“…From a clinical perspective, cardiac defects are detected in up to 40% of KBG syndrome patients (Digilio et al, 2021;Guo et al, 2022;Kierzkowska et al, 2023). Moreover, ANKRD11 variants are reported in large-scale exome and genome sequencing studies of gene-disease associations in CHD, including conotruncal defects (Chui et al, 2023;Jin et al, 2017;Reuter et al, 2020).…”

“…Moreover, ANKRD11 variants are reported in large-scale exome and genome sequencing studies of gene-disease associations in CHD, including conotruncal defects (Chui et al, 2023;Jin et al, 2017;Reuter et al, 2020). The reported defects include aortic coarctation, patent ductus arteriosus, valve stenosis, Tetralogy of Fallot, and atrial and ventricular septal defects (Digilio et al, 2021;Guo et al, 2022;Kierzkowska et al, 2023). Such defects are also found in many other neural crestmediated developmental disorders, including DiGeorge and Noonan syndromes (Vega-Lopez et al, 2018).…”

“…Patients with KBG syndrome display global developmental delay, short stature, craniofacial defects, and intellectual disability (Digilio et al, 2021;Gnazzo et al, 2020;Goldenberg et al, 2016;Handrigan et al, 2013;Low et al, 2016;Murray et al, 2017;Ockeloen et al, 2015;Sirmaci et al, 2011;Willemsen et al, 2010). About 40% of patients show cardiovascular defects, which include aortic coarctation, patent ductus arteriosus, valve stenosis, and ventricular septal defects (VSD) (Digilio et al, 2021;Guo et al, 2022;Kierzkowska et al, 2023). Notably, these cardiovascular defects indicate a potential dysregulation of CNCC function (Neeb et al, 2013;Vega-Lopez et al, 2018).…”