NSD1 Gene Research Articles

Aberrant Fetal Brain Sulcus Formation: A Clue to the Diagnosis of Sotos Syndrome.

This study aims to elucidate two distinct fetal ultrasound features associated with aberrant brain sulcus formation as potential prenatal markers for Sotos syndrome caused by mutations in the NSD1 gene. This retrospective study investigated three fetuses across two pregnancies, including a pair of monochorionic diamniotic twins, all diagnosed with Sotos syndrome via whole exome sequencing (WES). Comprehensive clinical and laboratory data were collected and analyzed. Each fetus underwent a series of specialized neurosonographic assessments to evaluate the development of the cerebral cortex. All three fetuses exhibited aberrant brain sulcus formation characterized by Sylvian fissure (SF) abnormalities and shallow parietooccipital sulcus (POS). WES revealed the presence of two de novo NSD1 variants in these fetuses. Fetal aberrant brain sulcus formation may represent a distinctive ultrasound feature indicative of Sotos syndrome, thereby offering additional diagnostic insights for the identification of this condition.

Sotos Syndrome: Deep Neuroimaging Phenotyping Reveals a High Prevalence of Malformations of Cortical Development.

Sotos syndrome is a rare autosomal dominant condition caused by pathogenic mutations in the NSD1 gene that presents with craniofacial dysmorphism, overgrowth, seizures, and neurodevelopmental delay. Macrocephaly, ventriculomegaly, and corpus callosal dysmorphism are typical neuroimaging features that have been described in the medical literature. The purpose of this study was to expand on the neuroimaging phenotype by detailed analysis of a large cohort of patients with genetically proved Sotos syndrome. This multicenter, multinational, retrospective observational cohort study systematically analyzed the clinical characteristics and neuroimaging features of 77 individuals with genetically diagnosed Sotos syndrome, via central consensus review with 3 pediatric neuroradiologists. In addition to previously described features, malformations of cortical development were identified in most patients (95.0%), typically dysgyria (92.2%) and polymicrogyria (22.1%), varying in location and distribution. Incomplete rotation of the hippocampus was observed in 50.6% of patients and was associated with other imaging findings, in particular with dysgyria (100% versus 84.2%, P = .012). Our findings show a link between the genetic-biochemical basis and the neuroimaging features and aid in better understanding the underlying clinical manifestations and possible treatment options. These findings have yet to be described to this extent and correspond with recent studies that show that NSD1 participates in brain development and has interactions with other known relevant genetic pathways.

Impact of NSD1 Alternative Transcripts in Actin Filament Formation and Cellular Division Pathways in Fibroblasts.

Germline variants in the NSD1 gene are responsible for Sotos syndrome, while somatic variants promote neoplastic cell transformation. Our previous studies revealed three alternative RNA isoforms of NSD1 present in fibroblast cell lines (FBs): the canonical full transcript and 2 alternative transcripts, termed AT2 (NSD1 Δ5Δ7) and AT3 (NSD1 Δ19-23 at the 5' end). The precise molecular pathways affected by each specific isoform of NSD1 are uncharacterized to date. To elucidate the role of these isoforms, their expression was suppressed by siRNA knockdown in FBs and protein expression and transcriptome data was explored. We demonstrate that one gene target of NSD1 isoform AT2 is ARP3 actin-related protein 3 homolog B (ACTR3B). We show that loss of both canonical NSD1 and AT2 isoforms impaired the ability of fibroblasts to regulate the actin cytoskeleton, and we observed that this caused selective loss of stress fibers. Our findings provide novel insights into NSD1 function by distinguishing isoform function and demonstrating an essential role of NSD1 in regulating the actin cytoskeleton and stress fiber formation in fibroblasts.

A series of four patients with Sotos syndrome harboring novel NSD1 mutations: clinical and molecular description.

Sotos syndrome is a rare and complex genetic disorder caused by haploinsufficiency of the NSD1 gene. This syndrome is characterized by rapid early childhood growth, distinct facial features, a learning disability, and multiple other developmental and behavioral challenges. In this work, we describe four Moroccan patients with variable clinical presentations of Sotos syndrome, in whom we identified four novel NSD1 monoallelic pathogenic variants by conducting targeted Next Generation Sequencing. Genetic testing allowed us to provide a precise medical diagnosis to our patients and tailor interventions to each patient's needs. Being the first work describing a series of Moroccan patients with this syndrome, this case series contributes to the growing body of literature on Sotos syndrome and provides valuable insights into the clinical and molecular characteristics of this rare disorder.

METB-02. GENETIC COUNSELLING IN SOTOS AND NS1-RELATED OVERGROWTH SYNDROMES PREDISPOSING TO BRAIN TUMORS

Abstract BACKGROUND Sotos and many other overgrowth syndromes are among the rare tumor predisposition syndromes that might be under-recognized in pediatric neuro-oncology practice. NSD1 gene (5q35), belonging to the histone lysine methyltransferases family, is involved in the majority of Sotos patients who exhibited haploinsufficiency and loss-of-function variants of the gene, but also in other overgrowth entities such as Beckwith-Wiedemann syndrome. Somatic mutations in this gene are likewise responsible of numerous cancers, particularly brain tumors. Here, we aim to assess the neurologic cancer risks and provide genetic counseling for appropriate clinical follow-up in Sotos syndrome. METHODS From our genetic counseling database at the medical University of Sfax (Tunisia), we selected among patients presented for genetic management of overgrowth syndromes, those with Sotos syndrome. RESULTS Only two Tunisian consanguineous pedigrees were enrolled in this study. Two boys were diagnosed with typical Sotos syndrome based on the three major clinical manifestations: specific facial dysmorphism, mental retardation and excessive growth including advanced bone age and macrocephaly. Chromosomes 5 in both pedigrees did not show structural abnormalities. During genetic counselling, parents were informed about the molecular testing options and the advantage of the exome sequencing. Furthermore, they were informed about the rate of cancer predisposition (3%) and the gains of neurologic and neuro-oncologic management, particularly regarding the intellectual disability and the increased risk of developing neural crest tumors, astrocytoma, glioma/glioblastoma and neuroblastoma cancer, during childhood. CONCLUSIONS Neurological pediatric malignancies are described in patients with Sotos syndrome, but the genotype-phenotype correlation is still unclear. It is suggested that NDS1 disruptions in Sotos patients trigger specific patterns of DNA methylation alterations leading to the development of cancer. Accurate molecular exploration is needed in the heterogeneous Sotos condition in order to improve the management according to the implicated gene and to benefit in the future from targeted therapies.

Combination of Psoriasis and Vitiligo in a Child with Sotos Syndrome: Clinical Case

Background. Psoriasis and vitiligo are chronic, relatively common dermatological diseases. Meanwhile, their combination in children is rare. The combination of psoriasis and vitiligo in a child with Sotos syndrome has not been previously described. Clinical case description. The boy, 10 years old, was hospitalized with complaints (according to his mother) of rashes on the scalp, body, and limbs, with mild itching that was not related to the time of day. The pathological skin process was widespread. The patient was hyperactive, restless, emotionally labile, irritable. Complaints of rashes was mentioned firstly at the age of 7. Sotos syndrome was established at the age of 8 (variant c.6559C>T (p.Arg2187Ter) in 23 exon of the NSD1 gene (5q35.3), autosomal dominant type of inheritance (pathological allele de novo)). Psoriasis vulgaris was diagnosed with secondary vitiligo (localized form) at the age of 8.5 years. Symptomatic antipruritic and external pathogenetic therapy was performed in the hospital. Phototherapy was not prescribed due to the relative contradiction (small retrocerebral cyst) and the peculiarities of major disease (hyperactivity, restlessness) that complicated to place the child in the phototherapy booth. Positive dynamics was noted during the treatment (14 days): no itching, decrease of peeling severity, flattening and blanching of psoriatic rash elements to spots of post-inflammatory hypopigmentation. The lesion (focus of depigmentation) on the right knee joint skin remained unchanged. The patient was discharged to outpatient care. The prognosis for Sotos syndrome and skin lesions is favorable. Conclusion. The first medical observation of the child with Sotos syndrome burdened with psoriasis and vitiligo is presented. The pathogenetic correlation of these diseases is not clearly defined. Management of such cases requires the joint collaboration of dermatologists, geneticists and pediatricians.

Neuropsychiatric Aspects of Sotos Syndrome: Explorative Review Building Multidisciplinary Bridges in Clinical Practice.

Background: Sotos syndrome is a genetic disorder caused by NSD1 gene (nuclear receptor binding SET domain containing protein 1) variants and characterized by overgrowth, macrocephaly, learning disabilities, and co-occurring neuropsychiatric symptoms. Methods: Literature sources published in 2002-2023 were selected and analyzed from PubMed and Google Scholar databases. Results: Neuropsychiatric symptoms are observed among children and adolescents with Sotos syndrome. The majority have intellectual disabilities or borderline intellect. Verbal IQ is higher than performance IQ. Individuals display difficulties in expressing language. Aggression is reported by parents. Children express autistic behavior, ADHD, anxiety based on phobias, and early bedtime-wake times. Conclusions: Sotos syndrome is associated with neuropsychiatric disorders in children. Slow intellectual and language development, aggressive outbursts, anxiety, autism spectrum disorder, and hyperactivity are present in the newest studies. Comprehensive assistance is needed for Sotos syndrome patients in responding to areas of difficulty. There is still a lack of research on the developmental characteristics of these children and the possibilities of improving psychosocial adaptation by providing multidisciplinary long-term medical, educational, and social care.

Congenital Heart Defects in Patients with Molecularly Confirmed Sotos Syndrome.

Sotos syndrome is an autosomal dominant condition characterized by overgrowth with advanced bone age, macrodolicocephaly, motor developmental delays and learning difficulties, and characteristic facial features caused by heterozygous pathogenetic variants in the NSD1 gene located on chromosome 5q35. The prevalence of heart defects (HDs) in individuals with Sotos syndrome is estimated to be around 15-40%. Septal defects and patent ductus arteriosus are the most commonly diagnosed malformations, but complex defects have also been reported. The aim of our study was to analyze the prevalence of HD, the anatomic types, and the genetic characteristics of 45 patients with Sotos syndrome carrying pathogenetic variants of NSD1 or a 5q35 deletion encompassing NSD1, who were followed at Bambino Gesù Children's Hospital in Rome. Thirty-nine of the forty-five patients (86.7%) had a mutation in NSD1, while six of the forty-five (13.3%) had a deletion. Most of the patients (62.2%, 28/45) were male, with a mean age of 14 ± 7 years (range 0.2-37 years). A total of 27/45 (60.0%) of the patients had heart defects, isolated or combined with other defects, including septal defects (12 patients), aortic anomalies (9 patients), mitral valve and/or tricuspid valve dysplasia/insufficiency (1 patient), patent ductus arteriosus (3 patients), left ventricular non-compaction/hypertrabeculated left ventricle (LV) (4 patients), aortic coarctation (1 patient), aortopulmonary window (1 patient), and pulmonary valve anomalies (3 patients). The prevalences of HD in the two subgroups (deletion versus intragenic mutation) were similar (66.7% (4/6) in the deletion group versus 58.91% (23/39) in the intragenic variant group). Our results showed a higher prevalence of HD in patients with Sotos syndrome in comparison to that described in the literature, with similar distributions of patients with mutated and deleted genes. An accurate and detailed echocardiogram should be performed in patients with Sotos syndrome at diagnosis, and a specific cardiological follow-up program is needed.

Sleep disturbances and behavioral symptoms in pediatric Sotos syndrome.

Sotos syndrome (SoS) is a rare overgrowth genetic disease caused by intragenic mutations or microdeletions of the NSD1 gene located on chromosome 5q35. SoS population might present cognitive impairment and a spectrum of behavioral characteristics, with a worse profile in patients with microdeletion. Although patients with SoS are known to have impaired sleep habits, very little data are available. The present study aimed to assess the prevalence of sleep disorders (SDs) in a pediatric cohort of patients with SoS and their correlation with neuropsychiatric profiles. We included patients with a SoS diagnosis and age < 18 years; all patients underwent a comprehensive neuropsychological assessment, including evaluation of cognition, adaptive functions through the Adaptive Behavior Assessment System-Second Edition (ABAS-II), and behavioral problems using the Achenbach Child Behavior Checklist (CBCL) and Conners' Parent Rating Scale-Revised (CPRS-R:L) questionnaire. To investigate the presence of SD parents, the Sleep Disturbance Scale for Children (SDSC) was completed. Thirty-eight patients (M 61%, F 39%, mean age 11.1 ± 4.65 years) were included in the study. Although only two had a prior SD diagnosis, 71.1% (N = 27) exhibited pathological scores on SDSC. No statistically significant associations were found between positive SDSC results and genetic microdeletion, intellectual disability (ID), or other medical conditions/treatments. However, a positive correlation emerged between SDSC scores and Conners' Global Index (p = 0.048) and Restless/Impulsive (p = 0.01) scores, CBCL externalizing (p = 0.02), internalizing (p = 0.01), and total scores (p = 0.05). Conversely, a negative linear relationship was observed between the SDSC score and the ABAS GAC and ABAS CAD scores (p = 0.025). We detected an SD in 71.1% of our sample, with a positive relation between SD and internalizing and externalizing symptom levels, especially hyperactivity and impulsivity. Our study demonstrated a high prevalence of SD in pediatric patients with SoS, highlighting that all patients should be screened for this problem, which has a great impact on the quality of life of patients and their families.

Hyperinsulinemia in Sotos Syndrome with a de novo NSD1 Deletion.

Sotos syndrome belongs to the group of diseases characterised by features such as facial dysmorphism, intellectual disability, hypotonia and overgrowth. Usually, Sotos syndrome is caused by heterozygous mutations in the NSD1 gene at chromosome 5q35 or by large genomic deletions of the same region. Genotype-phenotype correlations have mainly been reported as an association of significant or major abnormalities and presence of 5q35 deletions rather than intragenic deletions or point mutations in NSD1. The congenital hyperinsulinaemic hypoglycaemia (CHI) has been described as an uncommon feature in the presentation of Sotos syndrome. Most of the patients with Sotos syndrome and transient CHI were carriers of 5q35 deletions while persistent CHI has been recently reported in individuals with point mutations or small NSD1 deletions. We report the clinical features and medical treatment in a new-born child with Sotos syndrome and CHI that was present for almost two years. Genetic cause of Sotos syndrome in this case was a novel, large genomic deletion encompassing 24 OMIM genes including the entire NSD1 gene and 6 other Morbid genes. Our report shows challenges in diagnostics and management of this rare genetic condition. We propose, that in neonatal diagnostics, the phenotypic spectrum of Sotos syndrome should include CHI as a characteristic feature and molecular genetic testing should be done by whole genome analysis.

Investigation of Mutations in H19, IGF2, CDKN1C, KCNQ1, and NSD1 Genes in Iranian Children Suspected of Silver-Russell Syndrome (SRS) and Beckwith-Wiedemann Syndrome (BWS) with MS-MLPA

Background: Silver-Russell Syndrome (SRS) and Beckwith-Wiedemann Syndrome (BWS) are two syndromes that are poorly diagnosed in many affected people due to mild and subtle symptoms, genetic complexity, and lack of familiarity with the hallmarks. Objective: The present study was conducted with the aim of determining mutations in H19, IGF2, CDKN1C, KCNQ1, and NSD1 genes in Iranian children suspected of SRS and BWS by the MS-MLPA method. Methods: In this case series study, which was conducted in 2022 in Pars Genome Laboratory, Karaj, Iran, 10 children suspected of SRS or BWS syndrome were included. These 10 Iranian children were referred by pediatric endocrinologists. 5 ml of peripheral blood was taken per patient for DNA extraction. MS-MLPA method was undertaken for possible mutations (methylation and deletion) in H19, IGF2, CDKN1C, KCNQ1, and NSD1 genes. Results: The interpretation of MS-MLPA results showed that out of 10 children (4 boys and 6 girls) suspected of having SRS or BWS syndrome (based on the pediatric endocrinologist’s diagnosis), only 3 children were definitively diagnosed with SRS or BWS syndrome. Based on this, methylation changes in the promoter of ICR1 and ICR2, which are related to the genes H19, IGF2, CDKN1C, KCNQ1, and NSD1, lead to the development of SRS or BWS syndrome. Conclusion: The present findings showed that methylation changes in H19, IGF2, CDKN1C, KCNQ1, and NSD1 genes are associated with the occurrence of SRS or BWS syndrome. In this study, we show that MS-MLPA can serve as a rapid, inexpensive, and reliable method for the molecular diagnosis of these syndromes.

Orthodontic Management of Severe Hypodontia and Impacted Maxillary Second Molars in a Patient with Sotos Syndrome.

Sotos syndrome is a genetic disorder characterized by distinct craniofacial features, overgrowth in childhood, and impaired intellectual development. We herein report the successful orthodontic treatment of a 14-year-old boy with Sotos syndrome caused by a heterozygous mutation in the NSD1 gene. He showed severe hypodontia, impaction of the maxillary second molars and a skeletal Class III jaw-base relationship. Orthodontic management, including space control by protraction of the maxillary first molars and traction of the impacted molars, was performed using fixed appliances and miniscrews. As a result, acceptable occlusion was obtained without any discernible relapse 18 months postretention.

Beyond the known phenotype of sotos syndrome: a 31-individuals cohort study.

Sotos Syndrome (SS, OMIM#117550) is a heterogeneous genetic condition, recognized by three main clinical features present in most cases: overgrowth with macrocephaly, typical facial appearance and different degrees of intellectual disability. Three different types are described caused by variants or deletions/duplications in NSD1, NFIX and APC2 genes. We aimed to describe a cohort of pediatric patients reporting the typical and unexpected findings in order to expand the phenotype of this syndrome and trying to find genotype-phenotype correlations. In our referral center, we collected and analyzed clinical and genetic data of 31-patients cohort diagnosed with SS. All of them presented with overgrowth, typical dysmorphic features and different degree of developmental delay. Although structural cardiac defects have been reported in SS, non-structural diseases such as pericarditis were outstanding in our cohort. Moreover, we described here novel oncological malignancies not previously linked to SS such as splenic hamartoma, retinal melanocytoma and acute lymphocytic leukemia. Finally, five patients suffered from recurrent onychocryptosis that required surgical procedures, as an unreported prevalent medical condition. This is the first study focusing on multiple atypical symptoms in SS at the time that revisits the spectrum of clinical and molecular basis of this heterogeneous entity trying to unravel a genotype-phenotype correlation.

Knockout of the histone methyltransferase NSD1 leads to a decrease in cell proliferation and an increase in sensitivity to cisplatin in laryngeal squamous cell carcinoma

Introduction. The histone methylation regulates gene expression and plays a role in genomic stability participating in DNA repair. Dimethylation of histone 3 lysine 36 (H3K36me2) is an important histone modification which is responsible for gene expression activation. H3K36me2 is a product of methyltransferase activity of NSD1, NSD2, NSD3, and ASH1L proteins. NSD1 mutations are known to often occur in head and neck squamous carcinoma. The presence of NSD1 mutations highly correlates with increased survival, especially for patients with laryngeal cancer. The aim of this study was an in vitro investigation of the role of NSD1 in the cell proliferation of laryngeal squamous cell cancer and non-small lung cancer cells, as well as a study of the effect of disruption of the NSD1 gene expression on cisplatin treatment response.Material and Methods. Using TCGA, correlation analysis was performed to compare NSD1 wild type and mutant patient survival. NSD1 knockout cell lines models of laryngeal and non-small cell lung cancer were developed using the CRISPR/ Cas9 system. The effect of NSD1 knockout on H3K36me2 level was evaluated by western blot. Proliferation and IC50 of cisplatin in control and knockout cells were studied as well.Results. It was demonstrated that NSD1 knockout decreased the H3K36me2 level and cell proliferation in laryngeal squamous cell cancer cells and increased the sensitivity of head and neck cancer cells to cisplatin treatment, while there was no effect of NSD1 knockout in a non-small cell lung cancer cell line.Conclusion. Based on the data obtained, it can be concluded that the NSD1 protein is a potential target for inhibitor development following in vitro and in vivo testing in head-neck squamous cell carcinoma models. More studies are needed for better understanding of the regulation of tumor cell growth by NSD1.

Cognitive, adaptive and behavioral profile in Sotos syndrome children with 5q35 microdeletion or intragenic variants.

Sotos syndrome (SoS) is a congenital overgrowth syndrome with variable degree of intellectual disability caused in the 90% of cases by pathogenetic variants of the Nuclear receptor binding SET Domain protein1 (NSD1) gene. NSD1 gene functions can be abrogated by different genetic alterations (i.e., small intragenic pathogenic variants like deletions/insertions, nonsense/missense pathogenic variants, partial gene deletions and whole deletions or microdeletion of 5q35 chromosomal region). Therefore, correlation of the genotype-phenotype with a possible contribution of more implicated genes to the medical, cognitive and behavioral profile is a topic of great interest. Although a more severe learning disability has been described in individuals with 5q35 microdeletion when compared to individuals with NSD1 intragenic pathogenic variants a fully delineated cognitive and behavioral phenotype has not been described yet. The importance of providing clinical characterization in relation to the genotype comes from the necessity to early identify children more at risk of developing psychopathological disorders. We characterize the cognitive, adaptive and behavioral phenotype of a pediatric sample of 64 individuals affected by SoS, performing a standardized neuropsychological evaluation. Secondly, we compare cognitive-behavioral profiles of SoS individuals carrying and not carrying the 5q35 microdeletion. SoS participants were characterized by a mild cognitive impairment of both Intellectual Quotient and adaptive skills in association to borderline symptoms of attention deficit. Our results suggest that the 5q35 microdeletion is associated with lower scores specifically concerning the cognitive, adaptive functioning and behavioral domains. However, longitudinal studies are necessary to confirm these findings and delineate a developmental trajectory of SoS.

Abstract 4756: NSD1/2 histone methyltransferases regulate cell growth in HPV-negative head and neck squamous cell carcinoma (HNSCC)

Abstract Members of the NSD protein family (NSD1, NSD2, and NSD3) are histone methyltransferases (HMTs) that catalyze lysine 36 dimethylation (K36me2) at histone H3. H3K36 modifications play an important role in regulating the function and structure of chromatin, affecting transcription, replication, and repair. Abnormal H3K36 methylation is often detected during tumor development and progression. Inactivating NSD1 mutations are frequent in head and neck squamous cell carcinoma (HNSCC). They commonly occur in HPV-negative oropharyngeal (OP) and laryngeal (LC) carcinomas, and define a prognostic subtype in LC, associated with significantly improved overall and progression-free survival. Notably, the SCC4 cell line, carrying a damaging mutation in the NSD1 gene demonstrated reduced dimethylation level of H3K36 compared to NSD1 wild-type HNSCC counterparts. To explore the biological impact of the NSD1/NSD2 loss of function in HNSCC, we established cell lines with doxycycline-inducible shRNA knockdown of NSD1 and NSD2 in the set of HNSCC cell lines originating from different sites (JHU011, JHU022, Cal27, and FaDu cell lines). The depletion of NSD1 and NSD2 led to reduction of K36me2, significant decrease in cell growth as measured by cell titer blue (CTB) and clonogenic assays. NSD1/NSD2 depletion in these HNSCC cells also caused a significant increase in apoptosis. Gene Set Enrichment Analysis (GSEA) of RNA-seq for NSD1 wt versus knockdown cells indicates that NSD1 knockdown reduced expression of E2F target genes. Among the E2F transcription factor family, E2F2 gene expression was significantly decreased in all NSD1 knockdown cell lines. NSD1 knockdown also activated gene pathways related to autophagy and response to starvation. NSD1 knockdown reduced the levels of autophagy initiation gene ULK1 at both mRNA and protein levels. We also probed for protein signaling in HNSCC cells following NSD1 depletion using a reverse protein phase array (RPPA) approach, and validated Phosphatidylinositol-5-Phosphate 4-Kinase Type 2 Beta (PIP4K2B), but not other members of this family (PIP4K2A and PIP4K2C), as NSD1-regulated. PIP4K2B was regulated at the mRNA level by NSD1 as well. The CHIP-qPCR assay demonstrated the loss of H3K36me2 at the promoter of the PIP4K2B gene in NSD1 knockdown cells, suggesting direct regulation by NSD1. Moreover, PIP4K2B siRNA depletion has also led to a significant decrease in HNSCC proliferation, which suggests that the NSD1 may regulate proliferative activity through PIP4K2B. Taken together, while this data supports the suggestion that NSD histone methyltransferases have multiple downstream targets, the underlying mechanism remain to be investigated in more detail. Further, NSD proteins are attractive targets for drug development for improving treatment strategies for HNSCC. Citation Format: Iuliia Topchu, Igor Bychkov, Petr Makhov, Evgeny Izumchenko, John Karanicolas, Jindan Yu, Jochen Lorch, Yanis Boumber. NSD1/2 histone methyltransferases regulate cell growth in HPV-negative head and neck squamous cell carcinoma (HNSCC). [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4756.

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.

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.

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.