MLPA analysis in 30 Sotos syndrome patients revealed one total NSD1 deletion and two partial deletions not previously reported

Abstract

Sotos syndrome (MIM #117550) is an autosomal dominant condition characterized by pre and postnatal overgrowth, macrocephaly and typical facial gestalt with frontal bossing, hypertelorism, antimongoloid slant of the palpebral fissures, prominent jaw and high and narrow palate. This syndrome is also frequently associated with brain, cardiovascular, and urinary anomalies and is occasionally accompanied by malignant lesions such as Wilms tumour and hepatocarcinoma. The syndrome is known to be caused by mutations or deletions of the NSD1 gene. To detect both 5q35 microdeletions and partial NSD1 gene deletions we screened 30 Brazilian patients with clinical diagnosis of Sotos syndrome by multiplex ligation dependent probe amplification. We identified one patient with a total deletion of NSD1 and neighbouring FGFR4, other with missing NSD1 exons 13-14 and another with a deletion involving FGFR4 and spanning up to NSD1 exon 17. All deletions were de novo. The two NSD1 partial deletions have not been previously reported. The clinical features of the three patients included a typical facial gestalt with frontal bossing, prominent jaw and high anterior hairline; macrocephaly, dolichocephaly, large hands; neonatal hypotonia and jaundice. All presented normal growth at birth but postnatal overgrowth. Two patients with NSD1 and FGFR4 gene deletions presented congenital heart anomalies.

Multiplex Ligation-Dependent Probe Amplification Improves the Detection Rate of <b><i>NKX2.1</i></b> Mutations in Patients Affected by Brain-Lung-Thyroid Syndrome

“…MLPA is easy and fast to perform, and can distinguish sequences differing in only a single nucleotide [9,10]. This molecular tool had already proved its efficiency by improving diagnosis in familial hypercholesterolemia or Sotos syndrome [11,12]. …”

Clinical and Molecular Heterogeneity in Brazilian Patients with Sotos Syndrome

“…It is critical to note the detection of NSD1 molecular defects in our cohort of Brazilian SoS patients, namely 19%, and 10% in a study by Fagali et al [2009] is very low compared with findings in the European/American co- horts (70-93%). Only the Japanese population, to date, shows such a low rate of mutations but with an elevated rate of NSD1 deletions.…”

“…Only the Japanese population, to date, shows such a low rate of mutations but with an elevated rate of NSD1 deletions. Although the number of patients included in our study (n = 21) and in the study reported by Fagali et al [2009] As evident, genetic heterogeneity is not an uncommon observation in patients with SoS. In addition, the large clinical overlap among overgrowth syndromes makes it difficult to give a precise diagnosis to several patients and to suggest which genes should be analyzed.…”

“…Microdeletions involving the complete NSD1 gene are frequently observed in Japanese patients (50 vs. 15% in non-Japanese patients), whereas intragenic mutations have been found to be more frequent in non-Japanese patients (27-97 vs. 12% in Japanese patients). Multiplex ligation-dependent probe amplification (MLPA) analysis in 30 Brazilian patients with clinical diagnosis of SoS revealed 3 patients (10%) with NSD1 partial gene deletions [Fagali et al, 2009]. Recently, a novel mosaic NSD1 intragenic deletion has been reported in a patient with an atypical presentation of SoS [Castronovo et al, 2013].…”

Deletion of NSD1 exon 14 in Sotos syndrome: first description

“…Partial deletions or duplications were confirmed by using MLPA analysis. Recently, Fagali et al (2009) described total/partial NSD1 deletions in three patients with clinical diagnosis of Sotos syndrome using MLPA analysis. In one patient, deletion involved the entire NSD1 gene and neighbouring FGFR4.…”