Genome-Wide SNP Array Analysis in Patients with Features of Sotos Syndrome

Abstract

Background: Sotos syndrome is characterized by overgrowth, facial dysmorphism and learning impairment. Haploinsufficiency of NSD1 accounts for approximately 60–90% of the patients. Consequently, a considerable number of patients with features of Sotos syndrome remain without a molecular diagnosis. To date, target-gene approaches in these patients have not been successful. Methods: Twenty-six Sotos syndrome-like patients were analyzed with a high-resolution whole-genome SNP array, and segregation was studied in the parents. Results: Four possible pathogenic copy-number variants including deletions of 10p12.32-p12.31, 14q13.1, Xq21.1-q21.31 and a duplication of 15q11.2-q13.1 were detected. They varied in size from 155 kb to 13.36 Mb. The 10p12.32-p12.31 deletion revealed a candidate gene (PLXDC2) for overgrowth. The 14q13.1 deletion affected only the NPAS3 gene and the patient carrying this deletion displayed mental retardation as the main feature. The Xq21.1-q21.31 deletion and the 15q11.2-q13.1 duplication encompassed multiple genes of which several could be associated with phenotypic expression. Conclusion: The high-resolution genome-wide SNP array approach resulted in a detection rate of 15% of novel abnormalities and is therefore a powerful method to attain a molecular diagnosis in Sotos syndrome-like patients. Identified candidate genes provide directions for future screening of larger patient cohorts.

Further delineation of the phenotype of chromosome 14q13 deletions: (positional) involvement ofFOXG1appears the main determinant of phenotype severity, with no evidence for a holoprosencephaly locus

“…This region contains four genes: C14orf128, ARHGAP5, AKAP6 and NPAS3. NPAS3 is partially deleted in patient 58 described by Visser et al ,19 who did not have HPE or ACC (as determined by CT scan) (Dr S Kant, personal communication) and in our patient 6, who has a severe phenotype but no HPE. However, since ACC may be missed on a CT scan NPAS3 remains a candidate gene.…”

“…Most of the deletion of this patient overlaps with deletions from our patients who have a much milder phenotype. The only gene outside the common deleted region is NPAS3, which might be a gene relevant for developmental delay, but is unlikely to be the single cause of the severe phenotype of this patient since the patient presented by Visser et al 19 with a deletion of the first exon of NPAS3 has an IQ of 76. It is likely that this deletion will preclude translation and therefore lead to haploinsufficiency of NPAS3 .…”

Immunohistochemical Analyses of NPAS3 Expression in the Developing Human Fetal Brain

“…Apart from NPAS3 being considered as a candidate for holoprosencephaly (Kamnasaran et al., 2005), mutations or allelic associations in this gene were also identified in patients diagnosed with Schizophrenia (Kamnasaran et al., 2003; Lavedan et al., 2009; Macintyre et al., 2010) and in Sotos syndrome (Visser et al., 2010). We also recently discovered the first neoplastic role of NPAS3 in malignant astrocytomas (Moreira, et al., manuscript in press).…”

19p13.2 microduplication causes a Sotos syndrome‐like phenotype and alters gene expression

“…NSD1 encodes n uclear receptor‐binding S u‐var, enhancer of zeste, and trithorax d omain protein 1 , which functions as a histone methyltransferase that both activates and represses transcription through chromatin modification (4). Some individuals with a Sotos‐like phenotype have an associated de novo genomic copy number variant (CNV) (5).…”