Expanding the SIAH1-Associated Phenotypic Spectrum: Insights From Loss-of-Function Variants

Abstract

Exome sequencing; Loss‐of‐function; Phenotypic expansion

Secuenciación del exoma; Pérdida de función; Expansión fenotípica

Seqüenciació de l'exoma; Pèrdua de funció; Expansió fenotípica

SIAH1 encodes for a RING-type E3 ubiquitin ligase involved in protein ubiquitination. More specifically, it positively regulates Wnt signaling through promoting the accumulation of β-catenin and mediates ubiquitination and degradation of Akt3 in neural development. Heterozygous de novo missense pathogenic variants in SIAH1 have been described in five unrelated individuals and are associated with developmental delay, hypotonia, and dysmorphic features. In this report, we present additional individuals from eight unrelated families and their clinical and genetic findings. We identified two missense and six predicted loss-of-function variants. Motor and speech delay and intellectual disabilities of varying severity were observed in all individuals. Neurodevelopmental issues, as well as infantile hypotonia and facial dysmorphism, were observed in the majority of individuals. Hearing loss, gastroesophageal reflux disease or other gastrointestinal issues, endocrinology abnormalities, and recurrent infections were observed in over 50% of individuals. This study expands the phenotypic spectrum of this syndrome and emphasizes the diverse impact of SIAH1 variation on multi-system clinical manifestations.