NSD1 analysis for Sotos syndrome: Insights and perspectives from the clinical laboratory

Abstract

Purpose: Sotos syndrome is a genetic disorder characterized primarily by overgrowth, developmental delay, and a characteristic facial gestalt. Defects in the NSD1 gene are present in approximately 80% of patients with Sotos syndrome. The goal of this study was to determine the incidence of NSD1 abnormalities in patients referred to a clinical laboratory for testing and to identify clinical criteria that distinguish between patients with and without NSD1 abnormalities. Methods: Deletion or mutation analysis of the NSD1 gene was performed on 435 patients referred to our clinical genetics laboratory. Detailed clinical information was obtained on 86 patients with and without NSD1 abnormalities, and a clinical checklist was developed to help distinguish between these two groups of patients. Results: Abnormalities of the NSD1 gene were identified in 55 patients, including 9 deletions and 46 mutations. Thus, in the clinical laboratory setting, deletions were found in 2% and mutations in 21% of samples analyzed, because not all patients had both tests. Thirty-three previously unreported mutations in the NSD1 gene were identified. Clinical features typically associated with Sotos syndrome were not found to be significantly different between individuals with and without NSD1 abnormalities. The clinical checklist developed included poor feeding, increased body mass index, and enlarged cerebral ventricles, in addition to the typical clinical features of Sotos syndrome, and was able to distinguish between the two groups with 80% sensitivity and 70% specificity. Conclusions:The dramatic decrease in the frequency of finding NSD1 abnormalities in the clinical laboratory is likely because of the heterogeneity of the patient population. Our experience from a diagnostic laboratory can help guide clinicians in deciding for whom NSD1 genetic analysis is indicated. Genet Med 2005:7(8):524-533.

Three Novel Mutations in Greek Sotos Patients with Rare Clinical Manifestations

“…NSD1 mutations leading to Sotos syndrome consist of various intragenic mutations and microdeletions encompassing part or the whole of NSD1, suggesting that haploinsufficiency for NSD1 leads to Sotos syndrome [13,18,19,20,21,22,23,24,25,26,27,28,29]. …”

Steric Clash in the SET Domain of Histone Methyltransferase NSD1 as a Cause of Sotos Syndrome and Its Genetic Heterogeneity in a Brazilian Cohort

“…Various mutations abrogating NSD1 function include missense mutations, partial gene deletions, microdeletions and truncating mutations resulting from small nucleotide insertions, deletions or splice-site mutations [3,4,11,12]. More than 80% of patients with Sotos syndrome carry NSD1 mutations, whereas for 20% of phenotypically characterized cases with Sotos syndrome underlying aberrations in the NSD1 gene have not been detected [5,13]. In particular, partial or whole NSD1 gene 5q35 microdeletions are the most common cause of Sotos syndrome in Japanese patients.…”

“…NSD1 also apparently contains five zinc finger-like plant homeodomain (PHD) domains and two proline-tryptophan-tryptophan-proline (PWWP) motifs, both of which are involved in protein–protein interactions [19,20]. However, the number of functional domains in NSD1, especially the PHD domain, has not been clearly defined yet [13,19,21,22]. NSD1 is a member of mammalian histone lysine methyltransferases that play important roles in multiple aspects of development and disease by acting as a transcriptional intermediary factor capable of both negatively and positively influencing transcription of nuclear receptors, such as the estrogen, retinoic acid and thyroid hormone receptors, depending on the cellular context [22,23,24,25].…”

Síndrome de Sotos: pesquisa de microdeleções e mutações intragênicas no gene NSD1

“…Em um deles a paciente era portadora de uma duplicação do exon 4 e no outro caso, a duplicação envolvia o exon 10 (Waggoner et al, 2005;Saugier-Veber et al, 2007).…”

“…O atraso de desenvolvimento (atraso para andar) foi observado em 31% da nossa amostra e não foi mencionado por Tatton- , entretanto, Waggoner, et al (2005) relatou o atraso de desenvolvimento em 100% de sua amostra.…”