UBTF Haploinsufficiency‐Related Disorder: Report of a New Case Series and Definition of the Facial Gestalt

UBTF codes for a nucleolar transcription factor required for transcription of rDNA genes. UBTF gain-of-function (GoF) has been identified as the cause of CONDBA syndrome, with a recurrent missense change, p.Glu210Lys occurring in most affected individuals. More recently, eight subjects with truncating variants or microdeletions involving UBTF have been associated with a distinct neurodevelopmental disorder in which developmental delay (DD) and intellectual disability (ID) co-occur with behavioral anomalies in the absence of signs of neuroregression. Here, we report on four affected individuals, including one adult subject, from a single family carrying a heterozygous UBTF splice-site variant affecting transcript processing. All subjects presented with a clinical phenotype characterized by DD/ID with behavioral problems, without signs of neuroregression. By systematically examining the clinical features in both current and previously reported cases, we identify a characteristic facial gestalt as a hallmark of the disorder, and recognize increased BMI and a hyper-nasal voice as previously underappreciated features. These data provide further evidence that UBTF haploinsufficiency causes a non-regressive form of DD/ID clinically distinct from CONDBA syndrome.