C-terminal truncated SPOP, a Janus-faced variant, causing a mixed type 1 and type 2 Nabais Sa-de Vries syndrome

Nabais Sa-de Vries syndrome (NSDVS) is an autosomal dominant neurodevelopmental disorder first described in 2020 and is classified into type 1 (NSDVS1) and type 2 (NSDVS2) which encompassed of spectrum of distinct clinical features due to gain-of-function (GOF) and loss-of-function (LOF) variants respectively. So far only 6 cases of 5 different missense pathogenic variants had been reported which impact on the SPOP substrate binding affinity for the downstream ubiquitylation. Here, we report a novel and de novo heterozygous nonsense pathogenic variant, p.Tyr353Term at the BACK domain in a patient with neurodevelopmental delay plus mixed phenotypes of NSDVS type 1 and 2 using trio exome analysis. The BACK domain is functionally critical for the SPOP higher-order oligomerization and is shown to increase substrate binding avidity with enhanced ubiquitylation efficiency in vitro. Experimentally, a missense variant p.Tyr353Glu is proven to attenuate the tandem SPOP oligomer formation and we envisage the current truncated variant at the same residue would attenuate the oligomerization process. This is the first report providing in vivo clue about the clinical significance of SPOP oligomerization in human neurodevelopmental disorders with new understanding on the expanding spectrum of NSDVS. We conclude the p.Tyr353Term is a Janus-faced variant which explains the dual NSDVS type 1 and 2 phenotypes in this case.