Natural history of adults with KBG syndrome: A physician-reported experience.

PURPOSE: KBG syndrome (KBGS) is a rare neurodevelopmental syndrome caused by haploinsufficiency of ANKRD11. The childhood phenotype is extensively reported but limited for adults. Thus, we aimed to delineate the clinical features of KBGS. METHODS: We collected physician-reported data of adults with molecularly confirmed KBGS through an international collaboration. Moreover, we undertook a systematic literature review to determine the scope of previously reported data. RESULTS: The international collaboration identified 36 adults from 31 unrelated families with KBGS. Symptoms included mild/borderline intellectual disability (n = 22); gross and/or fine motor difficulties (n = 15); psychiatric and behavioral comorbidities including aggression, anxiety, reduced attention span, and autistic features (n = 26); nonverbal (n = 3), seizures with various seizure types and treatment responses (n = 10); ophthalmological comorbidities (n = 20). Cognitive regression during adulthood was reported once. Infrequent features included dilatation of the ascending aorta (n = 2) and autoimmune conditions (n = 4). Education, work, and residence varied, and the diversity of professional and personal roles highlighted the range of abilities seen. The literature review identified 154 adults reported across the literature, and we have summarized the features across both data sets. CONCLUSION: Our study sheds light on the long-term neurodevelopmental outcomes, seizures, behavioral and psychiatric features, and education, work, and living arrangements for adults with KBGS.

Novel congenital disorder of O-linked glycosylation caused by GALNT2 loss of function.

Congenital disorders of glycosylation are a growing group of rare genetic disorders caused by deficient protein and lipid glycosylation. Here, we report the clinical, biochemical, and molecular features of seven patients from four families with GALNT2-congenital disorder of glycosylation (GALNT2-CDG), an O-linked glycosylation disorder. GALNT2 encodes the Golgi-localized polypeptide N-acetyl-d-galactosamine-transferase 2 isoenzyme. GALNT2 is widely expressed in most cell types and directs initiation of mucin-type protein O-glycosylation. All patients showed loss of O-glycosylation of apolipoprotein C-III, a non-redundant substrate for GALNT2. Patients with GALNT2-CDG generally exhibit a syndrome characterized by global developmental delay, intellectual disability with language deficit, autistic features, behavioural abnormalities, epilepsy, chronic insomnia, white matter changes on brain MRI, dysmorphic features, decreased stature, and decreased high density lipoprotein cholesterol levels. Rodent (mouse and rat) models of GALNT2-CDG recapitulated much of the human phenotype, including poor growth and neurodevelopmental abnormalities. In behavioural studies, GALNT2-CDG mice demonstrated cerebellar motor deficits, decreased sociability, and impaired sensory integration and processing. The multisystem nature of phenotypes in patients and rodent models of GALNT2-CDG suggest that there are multiple non-redundant protein substrates of GALNT2 in various tissues, including brain, which are critical to normal growth and development.