Identification of eight novel <i>NSD1</i> mutations in Sotos syndrome

otos 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 19 NSD1 encodes 2696 amino acids (GenBank accession no.AF395588), and the gene has several putative functional domains, such as NID 2L , 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][20][21][22][23][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.

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