• NSD1
• Sotos syndrome
• mutation

• SoS, Sotos syndrome

Sotos syndrome or cerebral gigantism (SoS, OMIM #117550) is a well-known disorder characterised by overgrowth with advanced bone age, craniofacial anomalies, developmental delay, and occasional seizures.^1,2 A typical face has a large head circumference, frontal bossing with high anterior hairline, down slanting of palpebral fissures, flat nasal bridge, and prominent jaw.³ The hands and feet are usually large. Height and weight tends to normalise in adulthood.⁴ EEG abnormalities, hypotonia, strabismus, congenital heart defects, kyphoscoliosis, and cancer have also been noted.^3,5–10 Since the original report in 1964,¹ more than 300 affected cases have been reported. Most cases are sporadic, while several familial cases have been described, suggesting that SoS is an autosomal dominant disorder.^8,11–17

We have previously isolated the nuclear receptor SET domain containing gene 1 (NSD1) from the 5q35 translocation breakpoint in a Japanese SoS patient with t(5;8)(q35; q24.1).^18,19NSD1 encodes 2696 amino acids (GenBank accession no. AF395588), and the gene has several putative functional domains, such as NID^−L, NID^+L, SET, SAC, PWWP-I, PWWWP-II, PHD-I, PHD-II, and PHD-III, suggesting that the NSD1 protein may be associated with chromatin mediated transcriptional regulation.^19–24 In 42 Japanese sporadic cases of SoS, we identified 20 submicroscopic deletions including the entire NSD1 gene and four point mutations, the data indicating that SoS is caused by haploinsufficiency of NSD1.²⁵ Recently, a UK group reported 29 novel NSD1 point mutations and only three microdeletions in 37 typical SoS and 13 SoS-like patients, and suggested that NSD1 intragenic mutations instead of microdeletions were the major cause of SoS.²⁶

In this study, we validated the spectrum of NSD1 intragenic mutations among 30 newly collected SoS patients.