Establishing SON in 21q22.11 as a cause a new syndromic form of intellectual disability: Possible contribution to Braddock–Carey syndrome phenotype

Abstract

A recent study of exome analyses in 109 patients with undiagnosed diseases included a 5-year-old girl with intellectual disability and multiple congenital anomalies, who had an apparently de novo frameshift mutation in SON. However, the combination of the truncating mutation in SON and the phenotype has not been reproduced until date, and it remains unclear if this combination represents a distinctive disease entity. Here we report an additional male with intellectual disability, congenital heart disease, distinctive facial features with curly hair and protruding ears, and long slender extremities, and hyperextensible joints. Exome analysis showed that he had the same de novo frameshift mutation in SON in a heterozygous state. Along with the first and original description of the apparently de novo truncating mutation in SON mentioned above, we have established that haploinsufficiency of SON causes a new recognizable syndrome of intellectual disability. SON is located within 21q22.11, a critical region for Braddock-Carey syndrome, which is characterized by congenital thrombocytopenia, intellectual disability, micrognathia, and a distinctive facies. Therefore, we suggest that the intellectual disability observed in Braddock-Carey syndrome could be accounted for by haploinsufficiency of SON. Ó 2016 Wiley Periodicals, Inc.Key words: SON; intellectual disability; 21q22; Braddock-Carey syndrome; thrombocytopenia INTRODUCTIONCausative gene mutations in patients with intellectual disability/ autistic spectrum disorders with or without accompanying malformations are currently being investigated in various exome analyses [de Ligt et al., 2012]. In a recent study of exome analyses in 109 trios with undiagnosed diseases, the supplemental information included a 5-year-old girl with intellectual disability, seizures, minor dysmorphisms, brain white matter abnormalities, intestinal atresia, and ventricular septal defect [Zhu et al., 2015]. This patient had two apparently de novo candidate genetic mutations: a missense mutation in C5AR1 and a frameshift mutation in SON; which is a ubiquitously expressed and phylogenetically conserved gene that encodes a DNA-binding protein [Khan et al., 1994;Wynn et al., 2000]. Because typical newborns acquire at least one new de novo deleterious mutation per generation [Lynch, 2010], it remains unclear if the observation was a chance association or whether either/which of the two mutations was responsible for the phenotype. Documentation of the second, confirmatory patient with the combination of a phenotype similar to the first patient and a frameshift mutation in the same gene, SON, resolved the "n-of-1 2587problem," and our data established an existence of a new human disease entity caused by a mutation in SON. CLINICAL REPORTThe propositus was the first child of healthy unrelated parents. At delivery, the mother was 35 years old and the father was 30 years old. The pregnancy course was uneventful, except for mild maternal anemia. The propositus was born at 40 and 1/7 weeks of gestation by...

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.…”

“…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].…”

“…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.…”

Jacobsen syndrome, Braddock–Carey syndrome, and Beyond: Reflections on intellectual disability accompanied with thrombocytopenia

“…This patient had an apparently de novo frameshift mutation in SON , which is located within the critical region for Braddock–Carey syndrome. Although pinpointing the cause of the intellectual disability is difficult, taking into consideration the prior report of a patient with a similar phenotype and the same frameshift mutation in SON [Zhu et al, ], we suggest that the developmental delay observed in Braddock–Carey syndrome may be attributable to haploinsufficiency of SON [Takenouchi et al, ]. Because Braddock–Carey syndrome is a contiguous gene syndrome in 21q22, genes other than SON could contribute to its overall phenotype.…”

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

“…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 haploinsufficiency.…”