Reviews
Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype
… Immunological abnormalities as well as recurrent infections, which represent a common morbidity and mortality cause in WHS, 24 were infrequent in the NSD2 cohort, where patient 5-I …
Publication: P Zanoni, K Steindl, D Sengupta, P Joset, A Bahr… - Genetics in …, 2021 - nature.com
The study investigates nsd2 gene haploinsufficiency and its association with developmental disorders and intellectual disability (ID). A series of individual cases with nsd2 mutations such as frameshifts and nonsense mutations implicate the gene's loss-of-function in ID and related phenotypes. While the inheritance of these mutations is not universally tested, some cases exhibit de novo mutations. For instance, patient 13-I with a frameshift variant p.Cys1183Valfs*146 and patient 14-I with a nonsense mutation p.Arg600*, both present with learning difficulties. Functional studies further corroborate the link between nsd2 dysfunction and disease, demonstrating a significant reduction in methyltransferase activity. Specifically, an in vitro methylation assay reveals that mutations like those identified in patients 10-I (S1137F) and 5-I (E1091K) disrupt the protein's ability to methylate histone H3. Overexpression studies are in agreement, showing reduced methylation levels upon expression of patient-associated nsd2 variants. In vitro enzymatic function assessments indicate that missense variant Cys869Tyr from patient 1-I, likely pathogenic, did not significantly disrupt methylation activity, suggesting additional nsd2 functions may contribute to disease pathogenesis. Collectively, the data from this cohort provide a compelling argument for nsd2 haploinsufficiency playing a critical role in developmental disorders and ID, backed by both genetic evidence from patient mutations and functional validation of impaired enzymatic activity.
From Wolf-Hirschhorn syndrome to NSD2 haploinsufficiency: a shifting paradigm through the description of a new case and a review of the literature
… We describe a patient with a de novo variant of NSD2 and discuss the clinical … of NSD2 haploinsufficiency. Remarkably, seizures are not usually part of the clinical spectrum of NSD2 …
Publication: LC Wiel, I Bruno, E Barbi, F Sirchia - Italian Journal of Pediatrics, 2022 - Springer
In a case study, a 6-year-old boy exhibiting a phenotype characterized by intrauterine growth restriction, low birth weight, neonatal hypotonia, psychomotor delay, marphanoid habitus, muscle hypotrophy, facial dysmorphisms, cryptorchidism, shawl scrotum, mild clinodactyly of the right little finger, bilateral syndactyly of the II and III toes with sandal gap, delayed bone age, and mild mitral prolapse was identified as having a heterozygous de novo deletion in the NSD2 gene (c.2523delG), predicted to cause a loss of function. The deletion was verified as de novo, indicating that it was not inherited from the patient's parents. The clinical features associated with NSD2 gene haploinsufficiency are commonly growth restriction, facial gestalt, intellectual disability, microcephaly, clinodactyly, and developmental delay, with autism spectrum disorder reported in a subset of NSD2-haploinsufficient children. Functional studies, including exome sequencing analyses and observational investigations, support the correlation between loss-of-function variants like disruptions in NSD2 and clinical outcomes such as developmental delay and autism spectrum disorder. Such evidence underpins the consideration of NSD2 haploinsufficiency as contributing to the clinical spectrum consistent with atypical or partial Wolf-Hirschhorn Syndrome (WHS).
Case report: A de novo NSD2 truncating variant in a child with Rauch-Steindl syndrome
… support that haploinsufficiency of NSD2 is … with NSD2 variants, our patient also lacked seizures or seizure-like episodes, further indicating that seizures are not associated with the NSD2 …
Publication: Q Yang, D Gong, S Yi, J Luo, Q Zhang - Frontiers in Pediatrics, 2023 - frontiersin.org
This study presents the genetic analysis of several patients exhibiting symptoms of Rauch–Steindl syndrome and similar phenotypes, with a focus on mutations in the NSD2 gene and their clinical consequences. A 7-year-old girl with a de novo frameshift deletion mutation c.2721delT(p.Asn907Lysfs*5) presented with typical Rauch–Steindl syndrome features, while a proband with a missense variant exhibited delayed development, growth issues among other clinical signs. Functional studies of NSD2 haploinsufficiency via analysis of de novo frameshift variant and comparison with the clinical phenotype conclude that NSD2 deficiency leads to multisystem abnormalities associated with Rauch–Steindl syndrome. Importantly, the supporting evidence of haploinsufficiency includes inheritance information, showing de novo mutations, highlighting a novel NSD2 gene mutation, and linking predicted loss-of-function variants to specific clinical phenotypes. However, one individual showed atypical mild manifestation of WHS without detailed mutation data or inheritance testing, suggesting the NSD2 gene's contribution to the WHS phenotype might be limited. Functional analysis supports the link between NSD2 gene haploinsufficiency and disease, with mouse models and methylation activity studies backing the role of loss-of-function variants in presenting clinical signs.
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From Wolf-Hirschhorn syndrome to NSD2 haploinsufficiency: a shifting paradigm through the description of a new case and a review of the literature
… We describe a patient with a de novo variant of NSD2 and discuss the clinical … of NSD2 haploinsufficiency. Remarkably, seizures are not usually part of the clinical spectrum of NSD2 …
Publication: LC Wiel, I Bruno, E Barbi, F Sirchia - Italian Journal of Pediatrics, 2022 - Springer
Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype
… Immunological abnormalities as well as recurrent infections, which represent a common morbidity and mortality cause in WHS, 24 were infrequent in the NSD2 cohort, where patient 5-I …
Publication: P Zanoni, K Steindl, D Sengupta, P Joset, A Bahr… - Genetics in …, 2021 - nature.com
A novel syndrome caused by the constitutional gain-of-function variant p.Glu1099Lys in NSD2
… by NSD2 haploinsufficiency. … in NSD2 had been associated with a milder NDD entity with distinct facial appearance (Rauch-Steindl syndrome; RAUST). Thus, NSD2 haploinsufficiency …
Publication: B Popp, M Brugger, S Poschmann, T Bartolomaeus… - medRxiv, 2022 - medrxiv.org
NSD2 as a promising target in hematological disorders
… NSD2 is frequently altered in several types of tumors—especially in hematological malignancies. Herein, we discuss the role of NSD2 … A larger screening of patient’s samples, part of the …
Publication: A Azagra, C Cobaleda - International Journal of Molecular Sciences, 2022 - mdpi.com
The role of NSD1, NSD2, and NSD3 histone methyltransferases in solid tumors
… In this review, we discuss the effect of alterations in NSDs on cancer patient’s prognosis and response to treatment. We summarize the current understanding of the biological functions …
Publication: I Topchu, RP Pangeni, I Bychkov, SA Miller… - Cellular and Molecular …, 2022 - Springer
NSD1 mutations deregulate transcription and DNA methylation of bivalent developmental genes in Sotos syndrome
… compensate for NSD1 haploinsufficiency. Importantly, … that is defined by overexpression of NSD2 (also known as WHSC1) (… M) is the mother of a patient whose sample was not analyzed …
Publication: K Brennan, H Zheng, JA Fahrner, JH Shin… - Human molecular …, 2022 - academic.oup.com
Steric clash in the SET domain of histone methyltransferase NSD1 as a cause of Sotos syndrome and its genetic heterogeneity in a Brazilian cohort
… intellectual disability caused by haploinsufficiency of the nuclear … human paralogs of NSD1, NSD2 and NSD3 (Figure 3). … Our patient DGDP186 with a novel nonsense mutation has a …
Publication: K Ha, P Anand, JA Lee, JR Jones, CA Kim, DR Bertola… - Genes, 2016 - mdpi.com
Investigating cortical features of Sotos syndrome using mice heterozygous for Nsd1
… At a genetic level, haploinsufficiency for the nuclear receptor … exhibit phenotypes that reflect patient clinical symptoms, including … The expression of Nsd2 and Nsd3 was not significantly …
Publication: S Oishi, O Zalucki, MS Vega, D Harkins… - Genes, Brain and …, 2020 - Wiley Online Library
Case report: A de novo NSD2 truncating variant in a child with Rauch-Steindl syndrome
… support that haploinsufficiency of NSD2 is … with NSD2 variants, our patient also lacked seizures or seizure-like episodes, further indicating that seizures are not associated with the NSD2 …
Publication: Q Yang, D Gong, S Yi, J Luo, Q Zhang - Frontiers in Pediatrics, 2023 - frontiersin.org
NSD1 mutations in Sotos syndrome
… In 2002, the gene for Sotos syndrome was identified in a patient carrying an apparently balanced de … The NSD2 and NSD3 genes were recently tested as potential candidates for NSD1-…
Publication: F Faravelli - American Journal of Medical Genetics Part C …, 2005 - Wiley Online Library
Epigenetic causes of overgrowth syndromes
… genes with 2 other members, NSD2 and NSD3, all of which … is not caused by simple haploinsufficiency of EZH2. Consistent … The patient’s mother and maternal grandmother were …
Publication: JC Lui, J Baron - The Journal of Clinical Endocrinology & …, 2024 - academic.oup.com
De novo loss-of-function variants in NSD2 (WHSC1) associate with a subset of Wolf–Hirschhorn syndrome
… evidence that haploinsufficiency of a specific gene within this critical region, NSD2 (WHSC1), is … All have a similar molecular diagnosis from clinical exome sequencing; each patient has …
Publication: ES Barrie, MP Alfaro, RB Pfau… - Molecular …, 2019 - molecularcasestudies.cshlp.org
Developmental delay and failure to thrive associated with a loss‐of‐function variant in WHSC1 (NSD2)
… -of-function variant identified in our patient is likely contributing to her … Our patient's features were nonspecific, making a clinical … Haploinsufficiency of genes in the WHS critical region, …
Publication: NJ Boczek, CA Lahner, T Nguyen… - American Journal of …, 2018 - Wiley Online Library
Nsd1: A lysine methyltransferase between developmental disorders and cancer
… -bound NSD2 and NSD3 [24]. They observed that binding of NSD2 and NSD3 causes DNA … However, it seems unclear whether SOTOS is based on simple NSD1 haploinsufficiency, or …
Publication: S Tauchmann, J Schwaller - Life, 2021 - mdpi.com
Clinical details of individuals with Rauch–Steindl syndrome due to NSD2 truncating variants
… in NSD2 haploinsufficiency. A recent study has revealed that truncated variants in NSD2 exhibit a … This suggests that the loss of NSD2 function may partially contribute to the epigenetic …
Publication: E Nishi, K Yanagi, T Kaname… - Molecular Genetics & …, 2024 - Wiley Online Library
The NSD family of protein methyltransferases in human cancer
… The NSD family of protein lysine methyltransferases consists of NSD1, NSD2/WHSC1/MMSET and NSD3/WHSC1L1. NSD2 haploinsufficiency causes Wolf-Hirschhorn syndrome, while …
Publication: T Vougiouklakis, R Hamamoto, Y Nakamura… - …, 2015 - Future Medicine
RNA Analysis and clinical characterization of a novel splice variant in the NSD1 gene causing familial sotos syndrome
… Haploinsufficiency of the nuclear receptor SET domain-… lies in the fact that the patient needs to follow precise medical … The NSD family members, consisting of NSD1, NSD2 and NSD3 …
Publication: O Villate, H Maortua, MI Tejada, I Llano-Rivas - Frontiers in Pediatrics, 2022 - frontiersin.org
Heterogeneity of NSD1 alterations in 116 patients with Sotos syndrome
… patient harboring a 5q35 deletion smaller than 1Mb (Patient 2; … We excluded large deletions in the NSD2, NSD3, and NZIP1 in … Sotos syndrome and haploinsufficiency of NSD1: clinical …
Publication: P Saugier‐Veber, C Bonnet, A Afenjar… - Human …, 2007 - Wiley Online Library
NSD1 and sotos syndrome
… Sotos syndrome is caused by haploinsufficiency of the Nuclear … syndrome and translocations of NSD2 have been described in … patient per family is included. There is an overlap with the …
Publication: R Visser, N Matsumoto - Inborn Errors …, 2008 - scholarlypublications …
DNA methylation analysis of multiple imprinted DMRs in Sotos syndrome reveals IGF2‐DMR0 as a DNA methylation‐dependent, P0 promoter‐specific enhancer
… SoS is caused by NSD1 haploinsufficiency resulting from … imprinted DMR for a given patient was compared with the normal … In addition, we measured the mRNA levels of NSD2 and …
Publication: H Watanabe, K Higashimoto, N Miyake… - The FASEB …, 2020 - Wiley Online Library
Genome-wide SNP array analysis in patients with features of sotos syndrome
… SoS is caused by haploinsufficiency of the NSD1 gene at … , the NSD gene family members NSD2 and NSD3 were screened but no … Two younger siblings of the proband showed normal …
Publication: R Visser, A Gijsbers, C Ruivenkamp… - Hormone research in …, 2010 - karger.com
De novo damaging variants associated with congenital heart diseases contribute to the connectome
… 3,684 unique, previously published, proband/parent trios with CHD and … Haploinsufficiency of NSD2, a histone lysine … While little is known about the neurobiology of NSD2 variants…
Publication: W Ji, D Ferdman, J Copel, D Scheinost, V Shabanova… - Scientific reports, 2020 - nature.com
Transcriptome-directed analysis for Mendelian disease diagnosis overcomes limitations of conventional genomic testing
… (B) PCR confirmation of deletion in proband absent from mother and control … NSD2 expression, the diagnosis of NSD2-associated neurodevelopmental disorder was made. The proband…
Publication: DR Murdock, H Dai, LC Burrage… - The Journal of …, 2021 - Am Soc Clin Investig
P804: Prenatal diagnosis of atypical Holt-Oram syndrome caused by a novel inherited intragenic TBX5 duplication: A rare mechanism with variable …
… , or deletions resulting in a null allele and haploinsufficiency. Here we report a case of an … The variant was paternally inherited and de novo in the proband’s father. The proband has …
Publication: M Mackley, R Silver, N Watkins, E Greenfeld… - Genetics in Medicine …, 2024 - gimopen.org
Kabuki syndrome genes KMT2D and KDM6A: functional analyses demonstrate critical roles in craniofacial, heart and brain development
… We hypothesized that the distinctive craniofacial features observed in KS are predominantly caused by haploinsufficiency of KMT2D or KDM6A during development. To test this, we …
Publication: PM Van Laarhoven, LR Neitzel… - Human molecular …, 2015 - academic.oup.com
P701: Novel presentation of dextrocardia in TGIF1-related holoprosencephaly
… Here, we present a proband with laterality defects in addition to HPE, who was found to have a pathogenic TGIF1 frameshift variant. Historically, TGIF1 has been associated with …
Publication: C Thornton, N Owen, E Mizerik, C Rose… - Genetics in Medicine …, 2024 - gimopen.org
A Massively Parallel Screen of 5′ UTR Mutations Identifies Variants Impacting Translation and Protein Production in Neurodevelopmental Disorder Genes
… D) A G>A transition variant from a proband in the 5′UTR of NSD2 introduces an uAUG, … is far from haploinsufficiency in cases of LOF mutations. Meanwhile, NSD2 mutations cause …
Publication: SP Plassmeyer, CP Florian, MJ Kasper, R Chase… - medRxiv, 2023 - ncbi.nlm.nih.gov
P707: Additional evidence supporting and expanding the phenotype associated with MED12L loss-of-function variants
… The authors proposed that haploinsufficiency of MED12L is … of this condition, and confirm haploinsufficiency of MED12L as a … No medical concerns were reported for the proband’s twin …
Publication: K Rasmussen, C Runke, S Barnett… - Genetics in Medicine …, 2024 - gimopen.org
P280: Expansion of TAOK1 related developmental delay phenotype
… Haploinsufficiency of TAOK1 has been associated with developmental delay, intellectual … Our proband presented to the NIH at 7 years of age with a history of multi-sutural …
Publication: R Johnson, L Wolfe, E Macnamara… - Genetics in Medicine …, 2024 - gimopen.org
Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
… Haploinsufficiency of SPEN is considered a candidate for the 1p36 deletion syndrome … For CTCF, we clustered and translated proband phenotype data into the corresponding Human …
Publication: T Wang, K Hoekzema, D Vecchio, H Wu… - Nature …, 2020 - nature.com
P724: A unique presentation of triple X syndrome with four copies of SHOX and additional low-level aneuploidy mosaicism
… With respect to Xp abnormalities, haploinsufficiency of SHOX is a known cause of short … 1.3 Mb duplication of SHOX, corresponding to the proband's Xp22.33 gain; FISH confirmed the …
Publication: J Spaulding, F Ammouri, S Nielsen… - Genetics in Medicine …, 2024 - gimopen.org
Molecular diagnostics of rare inherited SYNDROMES with a view on diagnostic test development
… Analysis of the promoter region of the NSD1 gene and the NSD2 and NSD3 genes did not … proteins with NSD2 (MMSET/ WHSC1) and NSD3 (WHSC1L1). The NSD2 deletion is …
Publication: P Pohjola - 2012 - utupub.fi
Poland-Möbius syndrome: a case report implicating a novel mutation of the PLXND1 gene and literature review
… It is also unclear if parent-of-origin effects may be playing a role as the proband’s mother is unaffected. A larger family study could address this possibility. It should nonetheless be of …
Publication: GE Glass, S Mohammedali, B Sivakumar, MA Stotland… - BMC pediatrics, 2022 - Springer
Gain-of-function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions
DNA methylation and Polycomb are key factors in the establishment of vertebrate cellular identity and fate. Here we report de novo missense mutations in DNMT3A, which encodes the …
Publication: P Heyn, CV Logan, A Fluteau, RC Challis… - Nature …, 2019 - nature.com
Evaluation of NSD2 and NSD3 in overgrowth syndromes
… Eight Weaver cases were also negative for mutations suggesting that NSD2 and NSD3 are not responsible for this phenotype. Although we identified three Weaver cases with NSD1 …
Publication: J Douglas, K Coleman, K Tatton-Brown… - European Journal of …, 2005 - nature.com
Genotype-phenotype associations in Sotos syndrome: an analysis of 266 individuals with NSD1 aberrations
… 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 …
Publication: K Tatton-Brown, J Douglas, K Coleman… - The American Journal of …, 2005 - cell.com
Analysis of the NSD1 promoter region in patients with a Sotos syndrome phenotype
… Haploinsufficiency of the nuclear receptor binding SET … of patients with a typical SoS phenotype, no abnormalities are … in patients with a SoS phenotype, but without confirmed NSD1 …
Publication: R Visser, T Hasegawa, N Niikawa… - Journal of human …, 2006 - nature.com
5q35 duplication presents with psychiatric and undergrowth phenotypes mediated by NSD1 overexpression and mTOR signaling downregulation
… , contributing to the emerging phenotype, highlighting psychiatric phenotypes in older affected individuals. Focusing specifically on the undergrowth phenotype, we have modeled the …
Publication: F Quintero-Rivera, CC Eno, C Sutanto, KL Jones… - Human genetics, 2021 - Springer
Loss-of-function in NSD2 causes DNA methylation signature similar to that in Wolf-Hirschhorn syndrome
… the NSD2 variants in Cases 1–3 are NSD2 loss-of-function … methylation signature in NSD2 loss-of-function variants and … (Pro905Leu) is a loss-of-function variant. Opposite DNA …
Publication: T Kawai, S Kinoshita, Y Takayama, E Ohnishi… - Genetics in Medicine …, 2024 - Elsevier
De novo nonsense mutation in WHSC1 (NSD2) in patient with intellectual disability and dysmorphic features
… However, the evidence is not sufficient to determine whether loss-of-function WHSC1 mutations could be considered the cause of WHS or rather a distinct WHSC1-associated clinical …
Publication: ER Lozier, FA Konovalov, IV Kanivets… - Journal of Human …, 2018 - nature.com
Correspondence on “Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental …
… -old patient showing a previously unreported frameshift variant in NSD2 (loss-of-function; … In conclusion, data from the literature and from our patient support evidence that NSD2-related …
Publication: AM Cueto-González, P Fernández-Álvarez… - Genetics in …, 2022 - gimjournal.org
DNA methylation signature in NSD2 loss-of-function variants appeared similar to that in Wolf-Hirschhorn syndrome
… changes for NSD2 variants remain unknown. In this study, we define WHS-related DNA methylation signatures and determine whether NSD2 loss of function established through …
Publication: T Kawai, S Kinoshita, Y Takayama, E Onishi, H Kamura… - bioRxiv, 2023 - biorxiv.org
Role of NSD1 as potential therapeutic target in tumor
… However, the role of NSD1 loss-of-function in HNSC is complex. Increasing evidence … NSD1 inhibitory activity and is different from NSD2 and NSD3 for H3K36 methylation inhibition, …
Publication: C Yang, K Wang, Q Liang, TT Tian, Z Zhong - Pharmacological Research, 2021 - Elsevier
Chromatin dysregulation associated with NSD1 mutation in head and neck squamous cell carcinoma
… In order to demonstrate that our observations in patient-derived material are a direct … translocation that drives overexpression of NSD2, reducing NSD2 levels results in depletion …
Publication: N Farhangdoost, C Horth, B Hu, E Bareke, X Chen, Y Li… - Cell reports, 2021 - cell.com
Dissecting the differences between NSD1 and NSD2 function in Head and Neck Squamous Cell Carcinoma
… Loss of function mutations in the gene NSD2, another histone methyltransferase known for … NSD2 overactivity are found in other cancers (Oyer et al., 2014). Moreover, NSD1 and NSD2 …
Publication: K Skowronek - 2022 - search.proquest.com
Mutation spectra of histone methyltransferases with canonical SET domains and EZH2-targeted therapy
… Germline mutations in ASH1L, MLL3, MLL5, NSD2 and SUV420H1 … loss-of-function mutations in the SMARCA4, SMARCB1 or ARID1A genes. In Phase I clinical trial, an adult patient …
Publication: M Katoh - Epigenomics, 2016 - Future Medicine
The role of nuclear receptor–binding SET domain family histone lysine methyltransferases in cancer
… Homozygous loss-of-function embryos are able to gastrulate … of NSD2 specifically binds to H3K36me2 to stabilize NSD2 at … reported in one patient with AML, one patient with therapy-…
Publication: RL Bennett, A Swaroop… - Cold Spring …, 2017 - perspectivesinmedicine.cshlp.org
De novo truncating variant in NSD2gene leading to atypical Wolf-Hirschhorn syndrome phenotype
… a & b Facial features of the proband including wide-spaced eyes, prominent nasal … NSD2 with very detailed clinical information further supported that loss-of-function variants in NSD2 …
Publication: Y Jiang, H Sun, Q Lin, Z Wang, G Wang, J Wang… - BMC medical …, 2019 - Springer
The first familial NSD2 cases with a novel variant in a Chinese father and daughter with atypical WHS facial features and a 7.5-year follow-up of growth …
… NSD2 LOF mutations. Phenotypic features and clinical data of subjects with NSD2 loss-of-function … Our proband is the first NSD2 patient underwent GH therapy. After a 7.5-year treatment…
Publication: X Hu, D Wu, Y Li, L Wei, X Li, M Qin, H Li, M Li… - BMC Medical …, 2020 - Springer
Genetically unresolved case of Rauch-Steindl syndrome diagnosed by its Wolf-Hirschhorn associated DNA methylation episignature
… The proband was also noted to have global developmental delay during his admission (at 7… missed frameshift variant was observed in NSD2. Loss of function variants in this gene are …
Publication: H McConkey, A White-Brown, J Kerkhof… - Frontiers in Cell and …, 2022 - frontiersin.org
P169: Characterizing the phenotypic spectrum and estimated penetrance of families with pathogenic loss of function variants in the FLT4 gene
… The FLT4 variant in Family 2 was inherited from the proband’s … variant, of whom only the proband was affected with TOF; the … the proband) carried the FLT4 variant; yet only the proband …
Publication: O Moran, C Somerville, M Reuter… - Genetics in Medicine …, 2024 - gimopen.org
P678: Biallelic variants in BECN1 are associated with a complex neurodevelopmental syndrome
… anomalies, we performed parentproband exome sequencing and … Zebrafish larvae with becn1 loss of function show a … the missense variants are either loss of function or hypomorphic. …
Publication: F Ullah, V Salpietro, M Coghlan, A Sharma… - Genetics in Medicine …, 2024 - gimopen.org
P668: PMP22 single exon deletion in a proband with hematologic malignancy and family history of Charcot-Marie-Tooth disease
… Duplications or gain-of-function variants in the PMP22 gene cause autosomal dominant CMT types 1A and 1E, while loss-of-function changes underlie the allelic condition Hereditary …
Publication: K Schulze, MHK Chau, H Dai, E Mizerik… - Genetics in Medicine …, 2024 - gimopen.org
P700: Heterozygous deletion of valine at position 2321 of RYR2 in two siblings with sudden cardiac death
… of calcium ions, whereas loss of function leads to CRDS through … The proband’s younger brother had previously passed away … variant in the RYR2 gene of both proband and mother, c.…
Publication: E Kao, E Mizerik, YB Moshe, N Owen… - Genetics in Medicine …, 2024 - gimopen.org
P218: SMAD6 variants in congenital heart disease
… loss-of-function variants has been observed in multiple distinct cohorts with limited phenotypic overlap, and the lack of overall loss-of-function … a single family and one proband with a de …
Publication: M Schwartz, O Moran, X Chen, R Manshaei… - Genetics in Medicine …, 2024 - gimopen.org
P173: Precision animal modeling and VUS-resolution in a novel AXIN2-related disorder
… developing eye, the variant acted as a loss-of-function. During the course of our modeling, … de novo variant of uncertain significance as our proband supports the pathogenicity of the p.…
Publication: L Burrage, D Lanza, P Marcogliese, D Lu… - Genetics in Medicine …, 2024 - gimopen.org
The constitutional gain‐of‐function variant p.Glu1099Lys in NSD2 is associated with a novel syndrome
… Recent descriptions have delineated loss-of-function (LoF) variants in NSD2 with a distinct … with increased NSD2 activity and histone methylation disturbance. The specific phenotype, …
Publication: B Popp, M Brugger, S Poschmann… - Clinical …, 2023 - Wiley Online Library
Depletion of H3K36me2 recapitulates epigenomic and phenotypic changes induced by the H3. 3K36M oncohistone mutation
… We report here that genetic ablation of NSD1 and NSD2, … , transcriptome, and phenotype reprogramming by the H3.3K36M … mutations and NSD1 loss-of-function mutations are found in …
Publication: KN Rajagopalan, X Chen… - Proceedings of the …, 2021 - National Acad Sciences
Loss of NSD2 causes dysregulation of synaptic genes and altered H3K36 dimethylation in mice
… Our analysis of transcriptomic profiles in Nsd2 KO brains showed that the loss of NSD2 led to the dysregulation of gene expression involved in synaptic transmission and formation, …
Publication: S Kinoshita, K Kojima, K Nakabayashi… - Frontiers in Genetics, 2024 - frontiersin.org
Systematic perturbations of SETD2, NSD1, NSD2, NSD3 and ASH1L reveals their distinct contributions to H3K36 methylation
… NSD1 loss of function mutations have been identified in 78 … In contrast, NSD2 truncating and missense variants have … and hyperactive variants of NSD2 and NSD3 have been identified …
Publication: GA Shipman, R Padilla, C Horth, B Hu, E Bareke… - bioRxiv, 2023 - biorxiv.org