Sotos Syndrome Research Articles

Genetic Analysis of a Case of Sotos Syndrome with Suspected Germinal Mosaicism in Mother.

This study is to identify the pathogenic mutation of a child with Sots syndrome and provide prenatal diagnosis for his pregnant mother. Chromosome microarray technology was used to detect whether there were minor deletions/duplication in patients' chromosomes. The gene mutation of patients was screened by next-generation sequencing technology, and it was verified by Sanger sequencing. Prenatal diagnosis of the fetus was conducted according to the selected pathogenic sites, and genetic counseling was conducted for her parents. Chromosome microarray results showed that there was no minor deletion in a chromosome 5q35 region, and the second-generation sequencing results showed that there was a c.4138delG heterozygous mutation in the patient's NSD1 gene, and the pathogenic of this mutation was not reported in related databases. Sanger sequencing found that there was a c.4138delG heterozygous mutation in the NSD1 gene of the patient and her parents' genotype at this locus was wild type. The prenatal gene test results indicated that there was heterozygous mutation of NSD1 gene c.4138delG in the fetus, so it was suggested to terminate the pregnancy. Gentling results indicated that the fetus and the patient inherited the same maternal chromosome 5. The heterozygous mutation of NSD1 gene c.4138delG is the pathogenic mutation of this Sots syndrome patient, and the mother may be germinal mosaicism.

Molecular Analysis and Reclassification of NSD1 Gene Variants in a Cohort of Patients with Clinical Suspicion of Sotos Syndrome.

Sotos syndrome is a rare genetic disorder caused by haploinsufficiency of the NSD1 (nuclear receptor binding SET domain containing protein 1) gene. No clinical diagnostic consensus criteria are published yet, and molecular analysis reduces the clinical diagnostic uncertainty. We screened 1530 unrelated patients enrolled from 2003 to 2021 at Galliera Hospital and Gaslini Institute in Genoa. NSD1 variants were identified in 292 patients including nine partial gene deletions, 13 microdeletions of the entire NSD1 gene, and 115 novel intragenic variants never previously described. Thirty-two variants of uncertain significance (VUS) out of 115 identified were re-classified. Twenty-five missense NSD1 VUS (25/32, 78.1%) changed class to likely pathogenic or likely benign, showing a highly significant shift in class (p < 0.01). Apart from NSD1, we identified variants in additional genes (NFIX, PTEN, EZH2, TCF20, BRWD3, PPP2R5D) in nine patients analyzed by the NGS custom panel. We describe the evolution of diagnostic techniques in our laboratory to ascertain molecular diagnosis, the identification of 115 new variants, and the re-classification of 25 VUS in NSD1. We underline the utility of sharing variant classification and the need to improve communication between the laboratory staff and the referring physician.

A case of Sotos syndrome with various oral symptoms

A case of Sotos syndrome with various oral symptoms

Diagnostic tardiv de tulburare de spectru autist şi sindrom Sotos la un pacient cu simptomatologie atipică în copilăria timpurie

Autism spectrum disorder (ASD) is a very complex neurodevelopmental disorder whose symptomatology has been reported in several different genetic syndromes, one of which is Sotos syndrome. This syndrome is a congenital disorder, inherited autosomal dominant, being caused by a heterozygous pathogenic variant in the NSD1 gene or a deletion of this gene, which are present in more than 90% of individuals with this clinical diagnosis. We describe the case of a 13-year-old patient diagnosed with autism and Sotos syndrome. Objective. The description of this patient is intended to emphasize the importance of being aware in case of the co-association of ASD with one of the genetic syndromes, in the presence of clinical features not typical for both of them, in order to avoid delays in diagnosis. Conclusions. The late diagnosis of ASD and Sotos syndrome in our patient also leads us to the conclusion that, in cases of speech and communication delays in children, it is necessary to carry out a careful examination and a detailed assessment of the child’s development, including experts such as pediatricians development, child psychiatrists, geneticists, speech therapists etc. This will help to establish an early diagnosis, which is important for the development of follow-up, coordination of multidisciplinary care, treatment and prognosis.

Supplemental Material for Sensory Processing in Sotos Syndrome and Tatton-Brown–Rahman Syndrome

Supplemental Material for Sensory Processing in Sotos Syndrome and Tatton-Brown–Rahman Syndrome

P354: An apparently new brain MRI finding in Sotos syndrome: Extensively dilated perivascular spaces

P354: An apparently new brain MRI finding in Sotos syndrome: Extensively dilated perivascular spaces

P167: Atypical Sotos syndrome with normal length and late hyperinsulinemic hypoglycemia presentation

P167: Atypical Sotos syndrome with normal length and late hyperinsulinemic hypoglycemia presentation

Humoral immunodeficiency in a patient with Malan syndrome secondary to chromosome 19p13.2 microdeletions

Malan syndrome (Sotos Syndrome 2, OMIM 614753) is a rare autosomal dominant overgrowth disorder caused by either chromosome 19p13.2/19p13.13 microdeletion or Nuclear Factor 1 X-Type (NFIX) gene haploinsufficiency

NSD1 gene evolves under episodic selection within primates and mutations of specific exons in humans cause Sotos syndrome

BackgroundModern human brains and skull shapes differ from other hominids. Brain growth disorders as micro- (ASPM, MCPH1) and macrocephaly (NFIX, GLI3) have been highlighted as relevant for the evolution in humans due to the impact in early brain development. Genes associated with macrocephaly have been reported to cause this change, for example NSD1 which causes Sotos syndrome.ResultsIn this study we performed a systematic literature review, located the reported variants associated to Sotos syndrome along the gene domains, compared the sequences with close primates, calculated their similarity, Ka/Ks ratios, nucleotide diversity and selection, and analyzed the sequence and structural conservation with distant primates. We aimed to understand if NSD1 in humans differs from other primates since the evolution of NSD1 has not been analyzed in primates, nor if the localization of the mutations is limited to humans. Our study found that most variations causing Sotos syndrome are in exon 19, 22 and 10. In the primate comparison we did not detect Ka/Ks ratios > 1, but a high nucleotide diversity with non-synonymous variations in exons 10, 5, 9, 11 and 23, and sites under episodic selection in exon 5 and 23, and human, macaque/colobus/tarsier/galago and tarsier/lemur/colobus. Most of the domains are conserved in distant primates with a particular progressive development from a simple PWWP1 in O. garnetti to a complex structure in Human.ConclusionNSD1 is a chromatin modifier that suggests that the selection could influence brain development during modern human evolution and is not present in other primates; however, nowadays the nucleotide diversity is associated with Sotos syndrome.

Generation of induced pluripotent stem cell lines from a patient with Sotos syndrome carrying 5q35 microdeletion

Sotos syndrome (SoS) is a neurodevelopmental disorder caused by haploinsufficiency of the NSD1 gene located on chromosome 5 region q35.3. In order to understand the pathogenesis of Sotos syndrome and in view of future therapeutic approaches for its efficient treatment, we generated two human induced pluripotent stem cells (iPSCs) lines from one SoS patient carrying a 5q35 microdeletion. The established iPSCs expressed pluripotency markers, showing the capacity to differentiate into the three germ layers.

Genome-Wide DNA Methylation Profiling Solves Uncertainty in Classifying NSD1 Variants.

Inactivating NSD1 mutations causing Sotos syndrome have been previously associated with a specific genome-wide DNA methylation (DNAm) pattern. Sotos syndrome is characterized by phenotypic overlap with other overgrowth syndromes, and a definite diagnosis might not be easily reached due to the high prevalence of variants of unknown significance (VoUS) that are identified in patients with a suggestive phenotype. we performed microarray DNAm profiling in a set of 11 individuals with a clinical suspicion of Sotos syndrome and carrying an NSD1 VoUS or previously unreported variants to solve uncertainty in defining pathogenicity of the observed variants. The impact of the training cohort size on sensitivity and prediction confidence of the classifier was assessed. The Sotos syndrome-specific DNAm signature was validated in six individuals with a clinical diagnosis of Sotos syndrome and carrying bona fide pathogenic NSD1 variants. Applying this approach to the remaining 11 individuals with NSD1 variants, we succeeded in confirming pathogenicity in eight subjects and excluding the diagnosis of Sotos syndrome in three. The sensitivity and prediction confidence of the classifier based on the different sizes of the training sets did not show substantial differences, though the overall performance was improved by using a data balancing strategy. The present approach solved uncertainty in cases with NDS1 VoUS, further demonstrating the clinical utility of DNAm profiling.

Atypical Sotos syndrome caused by a novel splice site variant

Sotos syndrome is usually caused by haploinsufficiency of NSD1; it is characterized by overgrowth, craniofacial features, and learning disabilities. We describe a boy with Sotos syndrome caused by a splicing variant (c.4378+5G>A). The clinical manifestations included severe connective tissue involvement, including joint hypermobility, progressive scoliosis, pectus deformity, and skin hyperextensibility; no overgrowth was observed.

Identification of alternative transcripts of NSD1 gene in Sotos Syndrome patients and healthy subjects

NSD1 gene (Nuclear Receptor Binding SET Domain Protein 1) encodes a methyltransferase that plays an important role in embryonic development. NSD1 is implicated in the transcription and methylation of histone H3 at lysine 36 (H3-K36), but the molecular mechanisms involved in these processes remain largely unknown. Pathogenic variants of NSD1 gene lead to Sotos syndrome, and have also been detected in some type of cancers, such as acute myeloid leukemia.In this study we have investigated NSD1 mRNA expression in fibroblast cell lines obtained from 14 Sotos patients and from 8 healthy controls. In addition to the expected NSD1 canonical transcript (isoform 1), we identified two additional, not yet reported, short NSD1 mRNA isoforms: NSD1 Δ5Δ7 (isoform 2) and NSD1 Δ19-23 (isoform 3), both in healthy subjects and in Sotos patients. We also show that NSD1 mutations in patients can be associated with a decreased level of NSD1 mRNA, as expected. Moreover, one patient, bearing the NSD1 variant c.6010-10G > A, expressed an additional shorter transcript derived from an aberrant splicing event.These results may provide a basis to elucidate the impact of different NSD1 pathogenic variants on the heterogeneity of phenotype associated with Sotos syndrome.

Sotos syndrome: A study of antenatal presentation

ObjectiveTo determine the fetal ultrasound findings associated with Sotos syndrome caused by deletions at 5q35 including the NSD1 and a point mutation in this gene. Study designThis was a retrospective study of eight pregnancies with fetal Sotos syndrome identified by chromosomal microarray (CMA)/whole exome sequencing (WES). Clinical and laboratory data were collected and reviewed for these cases. ResultsTwo cases had no significant fetal abnormalities, and were only diagnosed after birth. One case presented in the first trimester with increased nuchal translucency. The remaining five fetuses were identified at late gestation. One of the five fetuses presented in the second trimester with mild ventriculomegaly, and four in the third trimester with mild ventriculomegaly, macrocephaly and polyhydramnios. CMA was done on all cases and revealed 5q35 deletions in seven cases, and WES detected a maternally inherited NSD1 variant in one case. ConclusionThe fetal ultrasound findings in cases with Sotos syndrome, associated with deletions at 5q35 and a point mutation in the NSD1 are not specific with the most common finding being mild ventriculomegaly.

Lysine Methyltransferase NSD1 and Cancers: Any Role in Melanoma?

Simple SummaryEpigenetic events, which comprise post-translational modifications of histone tails or DNA methylation, control gene expression by altering chromatin structure without change in the DNA sequence. Histone tails modifications are driven by specific cellular enzymes such as histone methyltransferases or histone acetylases, which play a key role in regulating diverse biological processes. Their alteration may have consequences on growth and tumorigenesis.Epigenetic regulations, that comprise histone modifications and DNA methylation, are essential to processes as diverse as development and cancer. Among the histone post-translational modifications, lysine methylation represents one of the most important dynamic marks. Here, we focused on methyltransferases of the nuclear binding SET domain 1 (NSD) family, that catalyze the mono- and di-methylation of histone H3 lysine 36. We review the loss of function mutations of NSD1 in humans that are the main cause of SOTOS syndrome, a disease associated with an increased risk of developing cancer. We then report the role of NSD1 in triggering tumor suppressive or promoter functions according to the tissue context and we discuss the role of NSD1 in melanoma. Finally, we examine the ongoing efforts to target NSD1 signaling in cancers.

Efficacy of congenital heart disease transition clinics in improving patient education

Abstract Background Less than one third of adolescents with congenital heart disease (CHD) successfully complete a structured transition to adult care. Patient education is at the centre of the transition process, however, data on the impact of transition visits are limited. Purpose To assess the efficacy of our transition clinic in educating adolescents with CHD about their cardiac condition in preparation for adult CHD care. Methods All patients seen in our transition clinic between April 2015 and January 2022 were included. Integrated care pathways designed by the Pan London Transition Consortium guided us in the assessment and education during each of the 3 pre-planned transition visits (“ready, steady and go” model). Data collected included demographic and clinical characteristics, and qualitative assessment of the following categories: understanding, naming and describing their cardiac condition, adherence to and involvement in medication management, self-reported anxiety and awareness of the importance of dental hygiene. Results A total of 611 patients were included in the study (age 15.1±2.3 years at the first visit, 48.1% female). 51.1% of patients attended 2 and 19.3% 3 transition consultations. Most adolescents (52.5%) had CHD of moderate complexity, whereas 28.5% had simple defects and 19% severe complexity. Learning disability (LD) was present in 19% of cases, of which 35.3% were genetic syndromes (21.6% Down Syndrome, 8.6% DiGeorge Syndrome, 2.6% Noonan Syndrome, 1.9% Sotos Syndrome, 0.9% Asperger Syndrome, 0.9% Cornelia De Lange Syndrome). The overall comprehension of their condition increased significantly in patients without LD at the second (good or excellent understanding: from 20.9% to 60.2%, p&amp;lt;0.0001; naming: from 19.8% to 50.2%, p&amp;lt;0.0001; describing: from 13.9% to 40.2%, p&amp;lt;0.0001) and third visit (understanding: 66.7%, p=0.043; naming: 60.4%, p=0.004, describing: 56.3%, p=0.002; Table 1). Patients with LD did not improve their knowledge over time in understanding, naming, and describing their condition between the first and second and second and third visits (all p&amp;gt;0.05). Adherence to and the involvement in medication management, the self-reported anxiety and awareness of the importance of dental care did not change over time (Figure 1). Conclusions A structured transition program is an important tool in educating and supporting the delivery of care for CHD adolescents and their families prior their transition into the adult care. Our transition programme had a positive impact on comprehension in the majority of children. Adolescents with learning difficulties are a group who may benefit from more intensive or individually tailored education during transition to ensure that they are supported to understand their health needs and empowered to make their own choices where possible. Funding Acknowledgement Type of funding sources: None.

Neonatal Sotos Syndrome: A Novel Frameshift Mutation of the NSD1 Gene Associated with Neonatal Encephalopathy Presenting without Overgrowth

AbstractSotos syndrome type I is one of the more common genetic overgrowth disorders. It presents classically with macrocephaly, distinctive facial gestalt, and acromegalic features, along with neonatal complications including hypotonia, feeding difficulties, and hypoglycemia with other minor feature inconstancies. The phenotypical overlap of features of this syndrome, more so in neonatal age, thwarts an easy diagnosis. In this case report, a neonate of a nonconsanguineous marriage to a multigravida mother with insignificant obstetric history, presented primarily with respiratory difficulty, central hypotonia, and hypoglycemia. Sparse hair, tall forehead, pointed chin, and lax skin were accompanied by persistent encephalopathy and refractory myoclonic jerks. However, the quintessential features of pre- and postnatal overgrowth were lacking, making the line of diagnosis difficult. On neuroimaging, atypical diffuse pachygyria was found. Clinical exome sequencing revealed heterozygous single base pair deletion in exon 21 of the NSD1 gene on chromosome 5q35, resulting in an unreported frameshift and premature truncation of the protein 19 amino acids downstream to codon 2065, confirming the genetic diagnosis of autosomal dominant Sotos syndrome 1. The neonate later succumbed to death after withdrawal of ventilatory support.

Survey on experiences and attitudes of parents toward disclosing information to children with genetic syndromes and their siblings in Japan

Many parents face the dilemma of when, how, and what to disclose to their children regarding their genetic conditions. The purpose of this study was to learn about the experiences of parents regarding disclosing information to their children with genetic conditions. A questionnaire was sent to 378 parents of children and adolescents with the following genetic syndromes: 22q11.2 deletion syndrome, Beckwith–Wiedemann syndrome, Noonan syndrome, Russell–Silver syndrome, Kabuki syndrome, Williams syndrome, Prader–Willi syndrome, and Sotos syndrome. Findings were analyzed using descriptive statistics for multiple-choice questions. Of the parents surveyed, 158 (41.8%) responded to the questionnaires. The average age of children with genetic syndromes was 12 years. Sixty-seven parents had disclosed relevant information to their children, whereas 91 had not. Among them (who had disclosed information), out of 53 respondents who answered that their affected child had siblings, 50 had disclosed the genetic condition of the affected child to the siblings as well. Sixty-eight out of 91 respondents who had not told information to affected child were planning to disclose the information in the future. Many respondents who had disclosed information did not regret this. They felt good talking about genetic conditions, and had talked about genetic conditions with the affected children following disclosure. This study contributed to our understanding of the attitudes of parents towards disclosing information to children with genetic syndromes.

Phenotype and Genotype in a Taiwanese Girl with Sotos Syndrome

Rare copy number variations have been linked to an important source of mutation in many psychopathological traits and neurodevelopmental disorders. In this study, we describe a Taiwanese girl with mental retardation and mild macrocephaly who underwent a childhood psychological evaluation for several years first. When she was 5 years old, she came to our hospital for further diagnosis. We conducted molecular cytogenetic tests and confirmed she actually has Sotos syndrome. We compared our case with two others with very similar deletion regions, but their phenotypes were heterogeneous. Sotos syndrome is very rare in Taiwan, and it is suggested that genetic analysis should be considered early if symptoms of this case are observed.

Reversal of Clinical Phenotype of Sotos Syndrome Due to Microduplication of NSD1 Gene.

Sotos syndrome is caused by heterozygous pathogenic variants or deletions in the long arm of chromosome 5 encompassing NSD1. The cardinal features of this condition are overgrowth, macrocephaly, and intellectual disability. Conversely, duplications leading to an extra copy of NSD1 result in a reverse phenotype that is observed in duplication/microduplication of the 5q region.An 11-y-old boy was referred to the genetics clinic in view of global developmental delay and general tonic-clonic seizures. Whole-exome sequencing revealed the presence of likely pathogenic copy number variation, a contiguous duplication of size ~4.11Mb spanning genomic location chr5: g.(?_171773956)_(175880045_?)dup. After validation by multiplex ligation-dependent probe amplification (MLPA) and phenotypic correlation, a diagnosis of reverse Sotos syndrome was confirmed. As far as the authors know, this is the first patient report of reverse Sotos syndrome from India. It highlights the peculiar presentation of this disorder as well as discusses the increasing potential of exome sequencing to screen for copy number variations (CNVs).