Clinical delineation of SETBP1 haploinsufficiency disorder

Abstract

SETBP1 haploinsufficiency disorder (MIM#616078) is caused by haploinsufficiency of SETBP1 on chromosome 18q12.3, but there has not yet been any systematic evaluation of the major features of this monogenic syndrome, assessing penetrance and expressivity. We describe the first comprehensive study to delineate the associated clinical phenotype, with findings from 34 individuals, including 24 novel cases, all of whom have a SETBP1 loss-of-function variant or single (coding) gene deletion, confirmed by molecular diagnostics. The most commonly reported clinical features included mild motor developmental delay, speech impairment, intellectual disability, hypotonia, vision impairment, attention/concentration deficits, and hyperactivity. Although there is a mild overlap in certain facial features, the disorder does not lead to a distinctive recognizable facial gestalt. As well as providing insight into the clinical spectrum of SETBP1 haploinsufficiency disorder, this reports puts forward care recommendations for patient management.

Fig. 1. Schematic representation of the SETBP1 protein including its domains, indicating the LoF variants found in novel (yellow) and literature (blue) cases.

For cDNA annotation of the variants see supplementary table 1.

Fig. 2. An overview of milestones and growth parameters.

A Motor developmental milestones, with green lines highlighting the normal range of the milestone in the general population. B Speech milestones of the verbal individuals. C Growth parameters at birth and at last examination. The mean of each variable is marked with a bold line. OFC occipital frontal circumference.

Fig. 3. Clinical photographs of SETBP1 haploinsufficiency disorder patients. Numbers refer to the number of the individual in supplementary file 1.

Clinical data of these individuals are presented in supplementary file 1.