De Novo Truncating Variants in SON Cause Intellectual Disability, Congenital Malformations, and Failure to Thrive

Abstract

SON is a key component of the spliceosomal complex and a critical mediator of constitutive and alternative splicing. Additionally, SON has been shown to influence cell-cycle progression, genomic integrity, and maintenance of pluripotency in stem cell populations. The clear functional relevance of SON in coordinating essential cellular processes and its presence in diverse human tissues suggests that intact SON might be crucial for normal growth and development. However, the phenotypic effects of deleterious germline variants in SON have not been clearly defined. Herein, we describe seven unrelated individuals with de novo variants in SON and propose that deleterious variants in SON are associated with a severe multisystem disorder characterized by developmental delay, persistent feeding difficulties, and congenital malformations, including brain anomalies.

Figure 1

Photographs and Pedigrees of Subjects with SON Variants Photographs show subjects reported in this article, and pedigrees illustrate the de novo status of all detected SON variants. Shaded symbols represent affected individuals.

Figure 2

Intragenic Location of SON Variants and Key Protein Functional Domains (A) All but one of the SON variants in the described individuals localize to exon 3 of SON (GenBank: NM_138927.2). (B) Approximate location of amino acid changes in relation to SON’s key functional domains, which include a unique central highly repetitive region, an RS-rich domain, a G-patch domain, and a double-stranded RNA-binding motif (DSRM). Data were extracted from GenBank: NP_620305.2. This panel was adapted from Hickey et al.