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 We report 25 unpublished individuals from 22 families with molecularly confirmed diagnoses.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.

ANKRD11 (Ankyrin Repeat Domain 11) is a chromatin regulator and a risk gene for KBG syndrome, a rare developmental disorder characterized by multiple organ abnormalities, including cardiac defects. However, the role of ANKRD11 in heart development is unknown. The neural crest plays a leading role in embryonic heart development, and its dysfunction is implicated in many congenital heart defects. Here, we demonstrate that conditional knockout of Ankrd11 in the murine embryonic neural crest leads to a severe congenital cardiac defect termed persistent truncus arteriosus (PTA), ventricular dilation, and impaired ventricular contractility. We further show these defects occur due to aberrant cardiac neural crest cell organization and failure to initiate outflow tract septation. Finally, conditional knockout of Ankrd11 in the neural crest leads to impaired Sema3C (Semaphorin 3C) expression, and reduced mTOR (mammalian target of rapamycin) and BMP (Bone Morphogenetic Protein) signaling in the cardiac neural crest cells within the outflow tract. This study identifies Ankrd11 as a novel regulator of neural crest-mediated heart development and function and suggests a mechanism for aberrant heart development in KBG syndrome patients.

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.

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Cat eye syndrome (CES), a human genetic disorder caused by the inverted duplication of a region on chromosome 22, has been known since the late 1890s. Despite the significant impact this disorder has on affected individuals, models for CES have not been produced due to the difficulty of effectively duplicating the corresponding chromosome region in an animal model. However, the study of phenotypes associated with individual genes in this region such as CECR2 may shed light on the etiology of CES. In this study we have shown that deleterious loss of function mutations in mouse Cecr2 effectively demonstrate many of the abnormal features present in human patients with CES, including coloboma and specific skeletal, kidney and heart defects. Beyond phenotypic analyses we have demonstrated the importance of utilizing multiple genetic backgrounds to study disease models, as we see major differences in penetrance of Cecr2-related abnormal phenotype between mouse strains, reminiscent of the variability in the human syndrome. These findings suggest that Cecr2 is involved in the abnormal features of CES and that Cecr2 mice can be used as a model system to study the wide range of phenotypes present in CES.