Phenotypic delineation of SET-related neurodevelopmental disorder: two case reports and literature review

Abstract

The SET nuclear proto-oncogene (SET; MIM# 600960) is a recently identified cause of autosomal dominant mental retardation-58 (MRD58), characterized by intellectual disability (ID), developmental delay, and variable additional clinical features. This report details two novel cases of MRD58 caused by de novo mutations in the SET gene (one in-frame deletion and one frameshift mutation), broadening the known phenotypic spectrum. Patient 1, a 3-year-old girl, presented with global developmental delay (GDD), seizures, right thumb polydactyly, pes planus and strabismus. Patient 2, a boy aged 1 year and 10 months, exhibited severe GDD, hypotonia, squared skull, and pes planus without seizures. Trio whole-exome sequencing identified novel likely pathogenic SET variants: c.292_294del (p.Thr98del) in Patient 1 and c.491_494del (p.Pro164LeufsTer15) in Patient 2. A review of 14 previously reported cases highlights ID and speech delay as universal features, with motor delay, facial dysmorphism, and skeletal anomalies being common; seizures appear less frequent. These cases underscore MRD58's variable expressivity and emphasize speech/language impairment as a core, persistent deficit. The report aims to enhance clinical recognition and understanding of this rare neurodevelopmental disorder.

Keywords

SET gene / MRD58 / intellectual disability / developmental delay / novel mutation / phenotypic spectrum

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