EP104: Two patients with autism secondary to ZBTB18 loss-of-function pathogenic variants

Abstract

Neurodevelopmental disorders and intellectual disability remain a diagnostic challenge due to heterogeneity and the long diagnostic odyssey experienced by many patients and families. Advancements in molecular technology and the increasing use of exome sequencing have led to the emergence of a growing list of causative genes. The ZBTB18 gene was found to function as a transcriptional repressor influencing neuronal growth, migration, differentiation, and maturation. Point variants in ZBTB18 have been identified in patients with neurodevelopmental disorders with significant variability in the phenotypic spectrum, with the most consistent features being anomalies of the corpus callosum, developmental delay, dysmorphic facial features, and hypotonia. Autism has been previously reported in only 2/30 patients with ZBTB18-related disorder. We present two additional patients with ZBTB18-related disorder who presents with autism in addition to previously described phenotypes. Our first case is an 8-year-old boy who presented with mild to moderate speech and developmental delay, hypotonia, autism spectrum disorder, and attention deficit hyperactivity disorder (ADHD). He said his first word at 18 months of age and at 8 years old he said 50-100 words and could speak in 3 word sentences. He could use utensils by 6 years old, but typically ate with his fingers. He can dress himself, but needs assistance for bathing. He began walking at 2 ½ years of age and climbed stairs alone at 4 years of age. He continues to have low tone and significant ataxia. OFC is 25%, height is 80%, and weight is 50%. His brain MRI at 3 years of age showed a prominent cisterna magna versus retrocerebellar arachnoid cyst, but there was no agenesis of the corpus callosum. He had brachycephaly with coarse facial features, mild mid-face retrusion, a cupid-bow upper lip, wide nasal tip, and hirsutism. He additionally had joint hypermobility with a Beighton score of 6/9. Chromosomal microarray and fragile X testing were normal. Exome sequencing analysis identified a likely pathogenic de novo c.583C>T, p.Arg195Ter variant in ZBTB18. Our second case is a 7-year-old boy, born at 30-weeks gestation, who presented with mild to moderate speech and developmental delays, hypotonia, autism spectrum disorder, and ADHD. He did not say his first word until around 3 years of age and is now able to combine only 2-3 words. He can dress himself and can scribble. He walked at 2 years of age and was able to jump at 3 years of age. OFC is 30%, height is 20%, and weight is 70%. He has a bulbous nasal tip with a high nasal bridge, mild hypotelorism, mild synophrys, unilateral preauricular skin tags with ear symmetry, and broad hands. He had an EEG done due to concerns of possible seizure activity, but this study was normal. He has not had a brain MRI. Chromosomal microarray and fragile X testing were normal. Exome sequencing analysis identified a pathogenic de novo c.881C>T, p.Gln271Ter variant in ZBTB18. We report two new unrelated patients with ZBTB18-related disorder, adding to the 30 patients reported previously. Both our patients also have autism in addition to significant behavioral issues and hypotonia with ataxia. These findings broaden the current phenotype of ZBTB18-related disorder to include autism. ZBTB18-related disorder is a chromatinopathy, as ZBTB18 is active in chromatin assembly, organization and transcriptional repression. Although autism has not been consistently reported in other patients with ZBTB18-related disorder, autism in these patients is not unexpected, as autism is a common feature of many chromatinopathies.