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.

Knockdown of Son, a mouse homologue of the ZTTK syndrome gene, causes neuronal migration defects and dendritic spine abnormalities.

“…3a). The former is derived from a SON mutation reported by Kim et al [1], and the latter is from the most prevalent mutation found in ZTTK syndrome [1,3,4]. The effective production of hSONr, hSONm1, and hSONm2 in HEK293 cells in the presence of shRNA#1 was con rmed (Fig.…”

“…Instead, other functions, such as transcriptional regulation, are more relevant to neural pathology since SON interacts with more than a thousand of genes via its DNA-binding region and is involved in the transcriptional repression of many target genes [9]. This is supported by the fact that rare non-truncating mutations, i.e., missense mutations [4] and an in-frame deletion [1], identi ed in ZTTK syndrome patients, are located exclusively in and around the genomic region that encodes the DNA-binding region (Table 1). However, there is a possibility that hSONm2 in uences SON-mediated RNA splicing because of its structural similarity to SON E, a physiological isoform of SON.…”

“…Recent genetic studies identi ed 31 individuals exhibiting intellectual disability (ID) and/or developmental delay with de novo heterozygous mutations in SON, which was established as Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome [1][2][3][4][5][6]. ZTTK syndrome was further characterized as a congenital anomaly syndrome of ID, brain malformation, facial dysmorphism, musculoskeletal abnormalities, and less common visceral malformations [1,2,4].…”

“…Recent genetic studies identi ed 31 individuals exhibiting intellectual disability (ID) and/or developmental delay with de novo heterozygous mutations in SON, which was established as Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome [1][2][3][4][5][6]. ZTTK syndrome was further characterized as a congenital anomaly syndrome of ID, brain malformation, facial dysmorphism, musculoskeletal abnormalities, and less common visceral malformations [1,2,4]. The mutations found to be associated with ZTTK syndrome are mostly frameshift mutations and nonsense substitutions generating a premature termination codon [1][2][3][4][5][6], and transcripts of the mutant gene seem to be degraded due to nonsense-mediated mRNA decay (NMD) [1]; this has made ZTTK syndrome to be regarded as an entity caused by SON haploinsu ciency.…”

“…SON is a ubiquitously expressed and evolutionarily conserved gene in vertebrates and is located on the human chromosome region 21q22.11 [4]. It encodes the DNA-and RNA-binding protein SON, which functions in RNA splicing as well as gene repression [7][8][9][10][11][12][13].…”