Congenital heart defects in molecularly confirmed <scp>KBG</scp> syndrome patients

Digilio, María Cristina; Calcagni, Giulio; Gnazzo, Maria; Versacci, Paolo; Dentici, Maria Lisa; Capolino, Rossella; Sinibaldi, Lorenzo; Baban, Anwar; Putotto, Carolina; Alfieri, Paolo; Unolt, Marta; Lepri, Francesca; Alesi, Viola; Genovese, Silvia; Novelli, Antonio; Marino, Bruno; Dallapiccola, Bruno

doi:10.1002/ajmg.a.62632

Cited by 11 publications

(14 citation statements)

References 28 publications

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“…The increased rates of perinatal complications in a cohort of individuals with KBG syndrome suggests that there may be an association between ANKRD11 mutations and adverse outcomes in fetuses and newborns. The cardiac deficits and small gestational age findings are consistent with past reports; 11,29 however, the other findings presented here have not been previously documented.…”

Section: Discussionsupporting

confidence: 92%

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

Kierzkowska

Sarino

Carter

et al. 2023

Preprint

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Mutations in the Ankyrin Repeat Domain 11 (ANKRD11) gene are associated with KBG syndrome, a developmental disability that affects multiple organ systems and presents with a variety of skeletal, cardiac, gastrointestinal, and neuropsychiatric manifestations. The function of ANKRD11 in human growth and development is not well understood, but its importance is established by the fact that total gene knockout is lethal in mice embryos and by its role in chromatin regulation, transcription, and development. Individuals with KBG syndrome are often misdiagnosed or undiagnosed until later in life, due to a combination of varying phenotypes, lack of targeted prenatal screening, and lack of documentation of prenatal and neonatal symptoms. The present study aims to report perinatal outcomes in individuals with KBG syndrome and their families and compare them to the prevalence in the overall population. We obtained data from 42 individuals through videoconferences, notes, and emails. Our results show that 45.2% of our cohort was born by C-section, 33.3% had a congenital heart defect, 23.8% were born before 37-weeks' gestation, 23.8% were admitted to the NICU, 14.3% were small for gestational age, and 14.3% of the families in our cohort had a history of miscarriage. The prevalence of birth by C-section, premature birth, NICU admission, and small for gestational age was higher in our cohort compared to the overall population, including non-Hispanic and Hispanic populations. Other reports included feeding difficulties (21.4%), neonatal jaundice (14.3%), decreased fetal movement (7.14%), and pleural effusions in utero (4.67%). These findings suggest that there may be an association between ANKRD11 mutations and perinatal complications, and further research is needed to better assess the mechanisms behind this relationship. Comprehensive perinatal studies about KBG syndrome and updated documentation of its phenotypes can facilitate earlier detection, diagnosis, and treatment.

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Section: Discussionsupporting

confidence: 92%

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

Kierzkowska

Sarino

Carter

et al. 2023

Preprint

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“…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).…”

Section: Discussionmentioning

confidence: 99%

“…Heterozygous variants in ANKRD11 or 16q24.3 microdeletions containing ANKRD11 cause KBG syndrome (OMIM #148050), an autosomal dominant multisystem developmental disorder. 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).…”

Section: Neural Crest Development Requires Intricate Spatiotemporal R...mentioning

confidence: 99%

“…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).…”

Section: Neural Crest Development Requires Intricate Spatiotemporal R...mentioning

confidence: 99%

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

Kibalnyk

Noble

Alexiou

et al. 2023

Preprint

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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.

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“…KBG syndrome is associated with cardiac anomalies [ 5 – 7 ] and diagnoses have been made on their detection. Individual B had a persistent left superior vena cava detected at 20 weeks on fetal ultrasound, which prompted karyotyping.…”

Section: Discussionmentioning

confidence: 99%

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

Guo

Park

et al. 2022

Eur J Hum Genet

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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.

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Congenital heart defects in molecularly confirmed KBG syndrome patients

Cited by 11 publications

References 28 publications

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

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

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

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

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