Sotos syndrome and haploinsufficiency of <i>NSD1</i>: clinical features of intragenic mutations and submicroscopic deletions

Sotos syndrome (MIM 117550) is a congenital developmental disorder characterised by overgrowth and advanced bone age in infancy to early childhood, mental retardation, and various minor anomalies such as macrocephaly, prominent forehead, hypertelorism, downward slanting palpebral fissures, large ears, high and narrow palate, and large hands and feet.1,2 It is also frequently associated with brain, cardiovascular, and urinary anomalies3–6 and is occasionally accompanied by malignant lesions such as Wilms tumour and hepatocarcinoma.7,8 This condition has been classified as an autosomal dominant disorder, because several familial cases consistent with dominant inheritance have been described previously.9 Thus, sporadic cases accounting for most of the Sotos syndrome patients are assumed to be the result of de novo dominant mutations. We have recently shown that Sotos syndrome is caused by haploinsufficiency of the gene for NSD1 (nuclear receptor binding Su-var, enhancer of zeste, and trithorax domain protein 1).10 NSD1 consists of 23 exons and encodes at least six functional domains possibly related to chromatin regulations (SET, PWWP-I, PWWP-II, PHD-I, PHD-II, and PHD-III), in addition to 10 putative nuclear localisation signals.11 It is expressed in several tissues including fetal/adult brain, kidney, skeletal muscle, spleen, and thymus11 and is likely to interact with nuclear receptors as a bifunctional transcriptional cofactor.12 In this paper, we report on clinical findings in Japanese patients with proven point mutations in NSD1 and those with submicroscopic deletions involving the entire NSD1 gene and discuss genotype-phenotype correlation. This study consisted of five patients with heterozygous NSD1 point mutations and 21 patients with heterozygous submicroscopic deletions involving the entire NSD1 gene. The mutations were identified by direct sequencing of exons 2–23 and their flanking introns covering the whole coding region of NSD1 ,11 using genomic DNA extracted from peripheral leucocytes or …