Further delineation of the clinical spectrum of White-Sutton syndrome: 12 new individuals and a review of the literature

Abstract

White-Sutton syndrome (WHSUS) is a neurodevelopmental disorder caused by heterozygous loss-of-function variants in POGZ. Through the Deciphering Developmental Disorders study and clinical testing, we identified 12 individuals from 10 families with pathogenic or likely pathogenic variants in POGZ (eight de novo and two inherited). Most individuals had delayed development and/or intellectual disability. We analyzed the clinical findings in our series and combined it with data from 89 previously reported individuals. The results demonstrate WHSUS is associated with variable developmental delay or intellectual disability, increased risk of obesity, visual defects, craniofacial dysmorphism, sensorineural hearing loss, feeding problems, seizures, and structural brain malformations. Our series includes further individuals with rod-cone dystrophy, cleft lip and palate, congenital diaphragmatic hernia, and duplicated renal drainage system, suggesting these are rare complications of WHSUS. In addition, we describe an individual with a novel, de novo missense variant in POGZ and features of WHSUS. Our work further delineates the phenotypic spectrum of WHSUS highlighting the variable severity of this disorder and the observation of familial pathogenic POGZ variants.

Fig. 1. Exon and protein models of POGZ showing location of the variants.

On top is an exonic model of POGZ (the first exon is non-coding). Below is the POGZ protein which contains a series of zinc finger domains (Z), a chromobox 5 binding region which contains a further zinc finger domain (CZ), proline-rich domain (PRO), helix-turn-helix centromere protein-B-like DNA-binding domain (HTH), a DDE superfamily endonuclease domain (DDE) and a coiled coil domain (CC). Below the protein model are variants reported in this series. Novel variants are bold. Above the protein model are lines indicating previously reported PTVs (except splice spite), circles representing missense variants in individuals reported to have WHSUS and triangles for variants predicted to affect splicing.

Fig. 2. Photographs of three individuals with POGZ variants.

Individual 1 (A, D) at 9 years of age, individual 12 (B, E) at 4 years of age and individual 13 (C, F) at 7 years of age. Individual 1 and 12 have POGZ PTVs and individual 13 has a de novo missense variant in POGZ c.2096 C > T p.(Thr699Ile). The three individuals demonstrate the variable facial features of WHSUS, with 12 and 13 showing more typical features, including downslanting palpebral fissures, midface hypoplasia, smooth philtrum and a thin upper lip.