Mutation analysis of the NSD1 gene in patients with autism spectrum disorders and macrocephaly (original) (raw)
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Heterogeneity of NSD1 alterations in 116 patients with Sotos syndrome
Human Mutation, 2007
Sotos syndrome is an overgrowth syndrome characterized by distinctive facial features, learning difficulties, and macrocephaly with frequent pre-and postnatal overgrowth with advanced bone age. Here, we report on our experience in the molecular diagnostic of Sotos syndrome on 116 patients. Using direct sequencing and a quantitative multiplex PCR of short fluorescent fragments (QMPSF)-based assay allowing accurate detection of both total and partial NSD1 deletions, we identified NSD1 abnormalities in 104 patients corresponding to 102 Sotos families (90%). NSD1 point mutations were detected in 80% of the index cases, large deletions removing the NSD1 gene entirely in 14%, and intragenic NSD1 rearrangements in 6%. Among the 69 detected distinct point mutations, 48 were novel. The QMPSF assay detected an exonic duplication and a mosaic partial deletion. QMPSF mapping of the 15 large deletions revealed the heterogeneity of the deletions, which vary in size from 1 to 4.5 Mb. Clinical features of NSD1-positive Sotos patients revealed that the phenotype in patients with nontruncating mutations was less severe that in patients with truncating mutations. This study confirms the heterogeneity of NSD1 alterations in Sotos syndrome and therefore the need to complete sequencing analysis by screening for partial deletions and duplications to ensure an accurate molecular diagnosis of this syndrome. Hum Mutat 28(11), 1098-1107. r r 2007 Wiley-Liss, Inc.
The American Journal of Human Genetics, 2005
We identified 266 individuals with intragenic NSD1 mutations or 5q35 microdeletions encompassing NSD1 (referred to as "NSD1-positive individuals"), through analyses of 530 subjects with diverse phenotypes. Truncating NSD1 mutations occurred throughout the gene, but pathogenic missense mutations occurred only in functional domains (). Sotos syndrome was clinically diagnosed in 99% of NSD1-positive individuals, independent of 516 P ! 2 # 10 the molecular analyses, indicating that NSD1 aberrations are essentially specific to this condition. Furthermore, our data suggest that 93% of patients who have been clinically diagnosed with Sotos syndrome have identifiable NSD1 abnormalities, of which 83% are intragenic mutations and 10% are 5q35 microdeletions. We reviewed the clinical phenotypes of 239 NSD1-positive individuals. Facial dysmorphism, learning disability, and childhood overgrowth were present in 90% of the individuals. However, both the height and head circumference of 10% of the individuals were within the normal range, indicating that overgrowth is not obligatory for the diagnosis of Sotos syndrome. A broad spectrum of associated clinical features was also present, the occurrence of which was largely independent of genotype, since individuals with identical mutations had different phenotypes. We compared the phenotypes of patients with intragenic NSD1 mutations with those of patients with 5q35 microdeletions. Patients with microdeletions had less-prominent overgrowth () and more-severe learning disability (P p .0003 P p 3 #) than patients with mutations. However, all features present in patients with microdeletions were also observed 59 10 in patients with mutations, and there was no correlation between deletion size and the clinical phenotype, suggesting that the deletion of additional genes in patients with 5q35 microdeletions has little specific effect on phenotype. We identified only 13 familial cases. The reasons for the low vertical transmission rate are unclear, although familial cases were more likely than nonfamilial cases () to carry missense mutations, suggesting that the underlying P p .005 NSD1 mutational mechanism in Sotos syndrome may influence reproductive fitness.
Journal of Advances in Medicine and Medical Research
Sotos syndrome is a rare genetic disorder with autosomal dominant inheritance, marked by overgrowth with macrocephaly, a distinctive facial appearance, and intellectual impairment. It occurs due to pathogenic variants encompassing the NSD1 gene. In addition, Sotos-like syndromes are also recognized, including Malan syndrome, known as Sotos syndrome type 2, which is caused by variants encompassing the NFIX gene. Herein we present a series of 3 pediatric patients diagnosed with Sotos syndrome type 1 and 1 patient with Sotos syndrome type 2 and discuss their genotypes and phenotypes.
Annals of Human Genetics, 2005
Sotos syndrome belongs to the family of overgrowth syndromes and is characterized by large head circumference, craniofacial anomalies, advanced bone age and mental retardation. The syndrome is due to haploinsufficiency of the NSD1 gene, consisting of 23 exons with an open reading frame of 8088bp, which makes mutation screening by direct sequencing quite a laborious and expensive task. We have developed a dHPLC screening protocol for mutation detection in NSD1 and identified 9 novel mutations among 33 patients, thus achieving a mutation detection efficiency comparable to direct sequencing. A real-time quantitative PCR approach identified two patients with NSD1 deletions. Our mutation screen is compared to other studies and all published mutations and polymorphisms are summarized.
The American Journal of Human Genetics, 2003
Sotos syndrome is a childhood overgrowth syndrome characterized by a distinctive facial appearance, height and head circumference 197th percentile, advanced bone age, and developmental delay. Weaver syndrome is characterized by the same criteria but has its own distinctive facial gestalt. Recently, a 2.2-Mb chromosome 5q35 microdeletion, encompassing NSD1, was reported as the major cause of Sotos syndrome, with intragenic NSD1 mutations identified in a minority of cases. We evaluated 75 patients with childhood overgrowth, for intragenic mutations and large deletions of NSD1. The series was phenotypically scored into four groups, prior to the molecular analyses: the phenotype in group 1 () was typical of Sotos syndrome; the phenotype in group 2 () was Sotos-like n p 37 n p 13 but with some atypical features; patients in group 3 () had Weaver syndrome, and patients in group 4 n p 7 () had an overgrowth condition that was neither Sotos nor Weaver syndrome. We detected three deletions n p 18 and 32 mutations (13 frameshift, 8 nonsense, 2 splice-site, and 9 missense) that are likely to impair NSD1 functions. The truncating mutations were spread throughout NSD1, but there was evidence of clustering of missense mutations in highly conserved functional domains between exons 13 and 23. There was a strong correlation between presence of an NSD1 alteration and clinical phenotype, in that 28 of 37 (76%) patients in group 1 had NSD1 mutations or deletions, whereas none of the patients in group 4 had abnormalities of NSD1. Three patients with Weaver syndrome had NSD1 mutations, all between amino acids 2142 and 2184. We conclude that intragenic mutations of NSD1 are the major cause of Sotos syndrome and account for some Weaver syndrome cases but rarely occur in other childhood overgrowth phenotypes.
Clinical and molecular heterogeneity in brazilian patients with sotos syndrome
Molecular syndromology, 2015
Sotos syndrome (SoS) is a multiple anomaly, congenital disorder characterized by overgrowth, macrocephaly, distinctive facial features and variable degree of intellectual disability. Haploinsufficiency of the NSD1 gene at 5q35.3, arising from 5q35 microdeletions, point mutations, and partial gene deletions, accounts for a majority of patients with SoS. Recently, mutations and possible pathogenetic rare CNVs, both affecting a few candidate genes for overgrowth, have been reported in patients with Sotos-like overgrowth features. To estimate the frequency of NSD1 defects in the Brazilian SoS population and possibly reveal other genes implicated in the etiopathogenesis of this syndrome, we collected a cohort of 21 Brazilian patients, who fulfilled the diagnostic criteria for SoS, and analyzed the NSD1 and PTEN genes by means of multiplex ligation-dependent probe amplification and mutational screening analyses. We identified a classical NSD1 microdeletion, a novel missense mutation (p.C1...
The first Japanese familial sotos syndrome with a novel mutation of the NSD1 gene
Sotos syndrome is caused by the haploinsufficiency of the NSD1 gene located in 5q35. More than 70% of the Japanese cases carry microdeletions encompassing of this gene, while point mutations are common in Caucasians. Only 15 familial cases of Sotos syndrome have been reported and all cases shown to have not microdeletions but point mutations. We identified the first Japanese familial case (mother and 3 children). They carry the same mutation at splice donor site of intron 13 (IVS13+1G>A), which results in the in-frame skipping of exon 13. This is also the first familial case caused by the mutation of the splice donor site. Each member of this family showed variable phenotypes and mental development. The present report will contribute to further understanding of genotype-phenotype correlation in Sotos syndrome. Sotos syndrome (OMIM 117550) is characterized by pre-and post-natal overgrowth, advanced bone age, distinctive craniofacial features (macrocephaly, frontal bossing with high hairline, high palate, prominent jaw), and variable degrees of mental retardation (7,17). Additional features include neonatal hypotonia, neonatal jaundice, seizures, congenital heart defects, scoliosis, brain anomalies, and malignant lesions (1,6,7,10). Recent reports showed that Sotos syndrome is caused by haploinsufficiency of the gene for NSD1 (the nuclear-receptor-binding SET-domain-containing protein 1) at 5q35 (13). Up to 90% of individuals with Sotos syndrome have a demonstrable mutation or deletion of NSD1. Chromosomal microdeletions encompassing the entire NSD1 gene are the major cause of Japanese patients with Sotos syndrome, whereas point mutations have been identified in the great majority of European patients (8,14,16,19,20). To our knowledge, more than 250 cases with mutation of NSD1 have been reported and identified mutations scattered over the coding region without any hotspots (19). Genotype-phenotype correlation is not fully elucidated in Sotos syndrome. Some studies have suggested that chromosomal microdeletions are associated with less prominent overgrowth and with severer mental retardation than intragenic mutations (8,15,19). Most cases of Sotos syndrome are sporadic, while several familial cases have been described, most of which exhibit autosomal dominant manner of inheritance (21). Only 15 familial cases with proven intragenic mutations in NSD1 have been identified. Among them only 4 familial cases (two of German, and one each of Turkish, Finnish) have been described concisely with clinical phenotypes (3,11,20). In this report, we describe clinical features and molecular genetic findings in the first Japanese familial Sotos syndrome. The mother and her 3 children carry the same mutation resulting in the skipping of exon 13, though each case showed somewhat different
Genome-Wide SNP Array Analysis in Patients with Features of Sotos Syndrome
Hormone Research in Paediatrics, 2010
Background: Sotos syndrome is characterized by overgrowth, facial dysmorphism and learning impairment. Haploinsufficiency of NSD1 accounts for approximately 60–90% of the patients. Consequently, a considerable number of patients with features of Sotos syndrome remain without a molecular diagnosis. To date, target-gene approaches in these patients have not been successful. Methods: Twenty-six Sotos syndrome-like patients were analyzed with a high-resolution whole-genome SNP array, and segregation was studied in the parents. Results: Four possible pathogenic copy-number variants including deletions of 10p12.32-p12.31, 14q13.1, Xq21.1-q21.31 and a duplication of 15q11.2-q13.1 were detected. They varied in size from 155 kb to 13.36 Mb. The 10p12.32-p12.31 deletion revealed a candidate gene (PLXDC2) for overgrowth. The 14q13.1 deletion affected only the NPAS3 gene and the patient carrying this deletion displayed mental retardation as the main feature. The Xq21.1-q21.31 deletion and the 1...