Epilepsy and overgrowth-intellectual disability syndromes: a patient organization perspective on collaborating to accelerate pathways to treatment.

Overgrowth-intellectual disability (OGID) syndromes are a collection of rare genetic disorders with overlapping clinical profiles. In addition to the cardinal features of general overgrowth (height and/or head circumference at least two standard deviations above the mean) and some degree of intellectual disability, the OGID syndromes are often associated with neurological anomalies including seizures. In an effort to advance research in directions that will generate meaningful treatments for people with OGID syndromes, a new collaborative partnership called the Overgrowth Syndromes Alliance (OSA) formed in 2023. By taking a phenotype-first approach, OSA aims to unite research and patient communities traditionally siloed by genetic disorder. OSA has galvanized OGID patient organizations around shared interests and developed a research roadmap to identify and address our community's greatest unmet needs. Here, we describe the literature regarding seizures among those with overgrowth syndromes and present the OSA Research Roadmap. This patient-driven guide outlines the milestones essential to reaching the outcome of effective treatments for OGID syndromes and offers resources for reaching those milestones.

Working together to speed up treatments for rare genetic syndromes linked to excessive growth and intellectual disability To address the shared challenges experienced among those affected by overgrowth­intellectual disability (OGID) syndromes, we recently formed the Overgrowth Syndromes Alliance (OSA). The OSA unites patient advocacy organizations that have typically worked independently of one another, in hopes of accelerating our progress toward treatments. Here, we summarize the OGID syndromes represented by the OSA, the prevalence of seizures in these disorders, and efforts by the OSA to tackle the most pressing needs of the overgrowth community. We also present the steps patient organizations can take in pursuit of developing treatments. We hope the work of our alliance can be a template for creating collaborative, patient-led advances in diagnosis, management guidelines, and, eventually, treatment of rare genetic disorders.

Massive open online courses (MOOCs) in genomic variant interpretation: An innovative education strategy for the growing genetic counselor workforce.

The growth in genomic testing in healthcare requires a highly trained specialist workforce to ensure evidence based clinical germline variant interpretation. Genetic counselors form a core part of the clinical genomics multidisciplinary team (MDT) and represent a growing workforce participating in variant interpretation from data analysis to the patient consultation. Standardized, high-quality variant interpretation training for Genetic Counselors has historically been ad hoc and variable, with existing programs lacking capacity to reach the entire workforce. To address the requirement for scalable variant interpretation training for genomics healthcare professionals (HCPs), two Massive Open Online Courses (MOOCs) were developed. We analyzed the data from 17 Genetic counselors, as part of an evaluation cohort completing the first run of these MOOCs. Overall genetic counselors enjoyed the courses, felt they were clinically relevant and would recommend them to colleagues. Common challenges amongst the genetic counseling workforces included utilizing relevant databases and finding time in the workday to complete training. These findings suggest MOOCs could be an acceptable option to ensure a consistent and transferrable high standard of training, complimentary to existing curricula. They also hold the potential to facilitate large-scale education to update the genetic counseling workforce when changes in variant interpretation guidance occur.

Evaluation of two Massive Open Online Courses (MOOCs) in genomic variant interpretation for the NHS workforce.

BACKGROUND: The implementation of the National Genomic Medicine Service in the UK has increased patient access to germline genomic testing. Increased testing leads to more genetic diagnoses but does result in the identification of genomic variants of uncertain significance (VUS). The rigorous process of interpreting these variants requires multi-disciplinary, highly trained healthcare professionals (HCPs). To meet this training need, we designed two Massive Open Online Courses (MOOCs) for HCPs involved in germline genomic testing pathways: Fundamental Principles (FP) and Inherited Cancer Susceptibility (ICS). METHODS: An evaluation cohort of HCPs involved in genomic testing were recruited, with additional data also available from anonymous self-registered learners to both MOOCs. Pre- and post-course surveys and in-course quizzes were used to assess learner satisfaction, confidence and knowledge gained in variant interpretation. In addition, granular feedback was collected on the complexity of the MOOCs to iteratively improve the resources. RESULTS: A cohort of 92 genomics HCPs, including clinical scientists, and non-genomics clinicians (clinicians working in specialties outside of genomics) participated in the evaluation cohort. Between baseline and follow-up, total confidence scores improved by 38% (15.2/40.0) (95% confidence interval [CI] 12.4-18.0) for the FP MOOC and 54% (18.9/34.9) (95%CI 15.5-22.5) for the ICS MOOC (p < 0.0001 for both). Of those who completed the knowledge assessment through six summative variant classification quizzes (V1-6), a mean of 79% of respondents classified the variants such that correct clinical management would be undertaken (FP: V1 (73/90) 81% Likely Pathogenic/Pathogenic [LP/P]; V2 (55/78) 70% VUS; V3 (59/75) 79% LP/P; V4 (62/72) 86% LP/LP. ICS: V5 (66/91) 73% VUS; V6 (76/88) 86% LP/P). A non-statistically significant higher attrition rate was seen amongst the non-genomics workforce when compared to genomics specialists for both courses. More participants from the non-genomics workforce rated the material as "Too Complex" (FP n = 2/7 [29%], ICS n = 1/5 [20%]) when compared to the specialist genomics workforce (FP n = 1/43 [2%], ICS n = 0/35 [0%]). CONCLUSIONS: After completing one or both MOOCs, self-reported confidence in genomic variant interpretation significantly increased, and most respondents could correctly classify variants such that appropriate clinical management would be instigated. Genomics HCPs reported higher satisfaction with the level of content than the non-genomics clinicians. The MOOCs provided foundational knowledge and improved learner confidence, but should be adapted for different workforces to maximise the benefit for clinicians working in specialties outside of genetics.

Implementation of precision medicine in healthcare-A European perspective.

The technical development of high-throughput sequencing technologies and the parallel development of targeted therapies in the last decade have enabled a transition from traditional medicine to personalized treatment and care. In this way, by using comprehensive genomic testing, more effective treatments with fewer side effects are provided to each patient-that is, precision or personalized medicine (PM). In several European countries-such as in England, France, Denmark, and Spain-the governments have adopted national strategies and taken "top-down" decisions to invest in national infrastructure for PM. In other countries-such as Sweden, Germany, and Italy with regionally organized healthcare systems-the profession has instead taken "bottom-up" initiatives to build competence networks and infrastructure to enable equal access to PM. In this review, we summarize key learnings at the European level on the implementation process to establish sustainable governance and organization for PM at the regional, national, and EU/international levels. We also discuss critical ethical and legal aspects of implementing PM, and the importance of access to real-world data and performing clinical trials for evidence generation, as well as the need for improved reimbursement models, increased cross-disciplinary education and patient involvement. In summary, PM represents a paradigm shift, and modernization of healthcare and all relevant stakeholders-that is, healthcare, academia, policymakers, industry, and patients-must be involved in this system transformation to create a sustainable, non-siloed ecosystem for precision healthcare that benefits our patients and society at large.

The PHF21A neurodevelopmental disorder: an evaluation of clinical data from 13 patients.

Potocki-Shaffer syndrome (PSS) is a rare neurodevelopmental disorder caused by deletions involving the 11p11.2-p12 region, encompassing the plant homeodomain finger protein 21A (PHF21A) gene. PHF21A has an important role in epigenetic regulation and PHF21A variants have previously been associated with a specific disorder that, whilst sharing some features of PSS, has notable differences. This study aims to expand the phenotype, particularly in relation to overgrowth, associated with PHF21A variants. Analysis of phenotypic data was undertaken on 13 individuals with PHF21A constitutional variants including four individuals described in the current series. Of those individuals where data were recorded, postnatal overgrowth was reported in 5/6 (83%). In addition, all had both an intellectual disability and behavioural issues. Frequent associations included postnatal hypotonia (7/11, 64%); and at least one afebrile seizure episode (6/12, 50%). Although a recognizable facial gestalt was not associated, subtle dysmorphic features were shared amongst some individuals and included a tall broad forehead, broad nasal tip, anteverted nares and full cheeks. We provide further insight into the emerging neurodevelopmental syndrome associated with PHF21A disruption. We present some evidence that PHF21A might be considered a new member of the overgrowth-intellectual disability syndrome (OGID) family.

Mainstreaming of genomics in oncology: a nationwide survey of the genomics training needs of UK oncologists.

OBJECTIVE: Genomics is rapidly changing treatment paradigms for cancers, obligating oncologists to have good genomics knowledge. Through this survey, we aimed to assess the current understanding of cancer genomics among UK oncologists. METHODS: We conducted a web-based nation-wide self-assessment survey of the cancer genomics knowledge of UK clinical and medical oncology trainees and consultants. RESULTS: In total, 150 oncologists (81 consultants and 69 trainees) responded, representing 10% of UK oncologists.Formal training in genomics had not been received by 38.7% of oncologists and 92.7% identified a need for additional genomics training.In total, 71.3% self-reported to have good knowledge of defining somatic and germline mutations, falling to 35.3% for understanding principles of gene expression and regulation. Knowledge of cancer-predisposing syndromes was highest for Lynch syndrome (40.7% good knowledge) and lowest for multiple endocrine neoplasia (14.0% good knowledge).Overall, 49.0% of respondents had consented patients for germline testing, but 80.7% reported a lack of training in genetic counselling. CONCLUSION: Large knowledge gaps have been identified through this survey, highlighting the need for incorporation of improved formal training in cancer genomics for consultants and trainees, with an aim to equip oncologists for advances in clinical practice and to take up genetic mainstreaming confidently.

ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy.

The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modelling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased vacuolar H+-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behaviour, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder and provides insight into disease mechanisms.

Systematic Profiling of DNMT3A Variants Reveals Protein Instability Mediated by the DCAF8 E3 Ubiquitin Ligase Adaptor.

Clonal hematopoiesis is a prevalent age-related condition associated with a greatly increased risk of hematologic disease; mutations in DNA methyltransferase 3A (DNMT3A) are the most common driver of this state. DNMT3A variants occur across the gene with some particularly associated with malignancy, but the functional relevance and mechanisms of pathogenesis of the majority of mutations are unknown. Here, we systematically investigated the methyltransferase activity and protein stability of 253 disease-associated DNMT3A mutations, and found that 74% were loss-of-function mutations. Half of these variants exhibited reduced protein stability and, as a class, correlated with greater clonal expansion and acute myeloid leukemia development. We investigated the mechanisms underlying the instability using a CRISPR screen and uncovered regulated destruction of DNMT3A mediated by the DCAF8 E3 ubiquitin ligase adaptor. We establish a new paradigm to classify novel variants that has prognostic and potential therapeutic significance for patients with hematologic disease. SIGNIFICANCE: DNMT3A has emerged as the most important epigenetic regulator and tumor suppressor in the hematopoietic system. Our study represents a systematic and high-throughput method to characterize the molecular impact of DNMT3A missense mutations and the discovery of a regulated destruction mechanism of DNMT3A offering new prognostic and future therapeutic avenues.See related commentary by Ma and Will, p. 23.This article is highlighted in the In This Issue feature, p. 1.

Quantifying evidence toward pathogenicity for rare phenotypes: The case of succinate dehydrogenase genes, SDHB and SDHD.

PURPOSE: The weight of the evidence to attach to observation of a novel rare missense variant in SDHB or SDHD in individuals with the rare neuroendocrine tumors, pheochromocytomas and paragangliomas (PCC/PGL), is uncertain. METHODS: We compared the frequency of SDHB and SDHD very rare missense variants (VRMVs) in 6328 and 5847 cases of PCC/PGL, respectively, with that of population controls to generate a pan-gene VRMV likelihood ratio (LR). Via windowing analysis, we measured regional enrichments of VRMVs to calculate the domain-specific VRMV-LR (DS-VRMV-LR). We also calculated subphenotypic LRs for variant pathogenicity for various clinical, histologic, and molecular features. RESULTS: We estimated the pan-gene VRMV-LR to be 76.2 (54.8-105.9) for SDHB and 14.8 (8.7-25.0) for SDHD. Clustering analysis revealed an SDHB enriched region (ɑɑ 177-260, P = .001) for which the DS-VRMV-LR was 127.2 (64.9-249.4) and an SDHD enriched region (ɑɑ 70-114, P = .000003) for which the DS-VRMV-LR was 33.9 (14.8-77.8). Subphenotypic LRs exceeded 6 for invasive disease (SDHB), head-and-neck disease (SDHD), multiple tumors (SDHD), family history of PCC/PGL, loss of SDHB staining on immunohistochemistry, and succinate-to-fumarate ratio >97 (SDHB, SDHD). CONCLUSION: Using methodology generalizable to other gene-phenotype dyads, the LRs relating to rarity and phenotypic specificity for a single observation in PCC/PGL of a SDHB/SDHD VRMV can afford substantial evidence toward pathogenicity.

Delineating the Smith-Kingsmore syndrome phenotype: Investigation of 16 patients with the MTOR c.5395G > A p.(Glu1799Lys) missense variant.

Smith-Kingsmore Syndrome (SKS) is a rare genetic syndrome associated with megalencephaly, a variable intellectual disability, autism spectrum disorder, and MTOR gain of function variants. Only 30 patients with MTOR missense variants are published, including 14 (47%) with the MTOR c.5395G>A p.(Glu1799Lys) variant. Limited phenotypic data impacts the quality of information delivered to families and the robustness of interpretation of novel MTOR missense variation. This study aims to improve our understanding of the SKS phenotype through the investigation of 16 further patients with the MTOR c.5395G>A p.(Glu1799Lys) variant. Through the careful phenotypic evaluation of these 16 patients and integration with data from 14 previously reported patients, we have defined major (100% patients) and frequent (>15%) SKS clinical characteristics and, using these data, proposed guidance for evidence-based management. In addition, in the absence of functional studies, we suggest that the combination of the SKS major clinical features of megalencephaly (where the head circumference is at least 3SD) and an intellectual disability with a de novo MTOR missense variant (absent from population databases) should be considered diagnostic for SKS.

Early-Onset Parkinsonism Is a Manifestation of the PPP2R5D p.E200K Mutation.

PPP2R5D-related neurodevelopmental disorder is characterized by a range of neurodevelopmental and behavioral manifestations. We report the association of early-onset parkinsonism with the PPP2R5D p.E200K mutation. Clinical characterization and exome sequencing were performed on three patients, with postmortem neuropathologic examination for one patient. All patients had mild developmental delay and developed levodopa-responsive parkinsonism between the ages of 25 and 40 years. The PPP2R5D c.598G>A (p.E200K) mutation was identified in all patients. Neuropathologic examination demonstrated uneven, focally severe neuronal loss and gliosis in the substantia nigra pars compacta, without Lewy bodies. Our findings suggest the PPP2R5D p.E200K mutation to be a possible new cause of early-onset parkinsonism. ANN NEUROL 2020;88:1028-1033.

A synonymous UPF3B variant causing a speech disorder implicates NMD as a regulator of neurodevelopmental disorder gene networks.

Loss-of-function mutations of the X-chromosome gene UPF3B cause male neurodevelopmental disorders (NDDs) via largely unknown mechanisms. We investigated initially by interrogating a novel synonymous UPF3B variant in a male with absent speech. In silico and functional studies using cell lines derived from this individual show altered UPF3B RNA splicing. The resulting mRNA species encodes a frame-shifted protein with a premature termination codon (PTC) predicted to elicit degradation via nonsense-mediated mRNA decay (NMD). UPF3B mRNA was reduced in the cell line, and no UPF3B protein was produced, confirming a loss-of-function allele. UPF3B is itself involved in the NMD mechanism which degrades both PTC-bearing mutant transcripts and also many physiological transcripts. RNAseq analysis showed that ~1.6% of mRNAs exhibited altered expression. These mRNA changes overlapped and correlated with those we identified in additional cell lines obtained from individuals harbouring other UPF3B mutations, permitting us to interrogate pathogenic mechanisms of UPF3B-associated NDDs. We identified 102 genes consistently deregulated across all UPF3B mutant cell lines. Of the 51 upregulated genes, 75% contained an NMD-targeting feature, thus identifying high-confidence direct NMD targets. Intriguingly, 22 of the dysregulated genes encoded known NDD genes, suggesting UPF3B-dependent NMD regulates gene networks critical for cognition and behaviour. Indeed, we show that 78.5% of all NDD genes encode a transcript predicted to be targeted by NMD. These data describe the first synonymous UPF3B mutation in a patient with prominent speech and language disabilities and identify plausible mechanisms of pathology downstream of UPF3B mutations involving the deregulation of NDD-gene networks.

DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes.

Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2, which encodes a core component of the Polycomb repressive complex-2 (PRC2). Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism. We also show that the signature can accurately classify sequence variants in EED and SUZ12, which encode two other core components of PRC2, and predict the presence of pathogenic variants in undiagnosed individuals with OGID. The discovery of a functionally relevant signature with utility for diagnostic classification of sequence variants in EZH2, EED, and SUZ12 supports the emerging paradigm shift for implementation of DNAm signatures into diagnostics and translational research.

Tatton-Brown-Rahman syndrome: cognitive and behavioural phenotypes.

The aim of this case series was to assess and characterize cognitive abilities, autistic traits, and adaptive behaviour in Tatton-Brown-Rahman syndrome (TBRS). The sample included 18 individuals with a clinical and genetic diagnosis of TBRS (11 males, seven females; mean age 17y 7mo, SD 9y 5mo, range 7y 2mo-33y 10mo). The British Ability Scales, Third Edition and the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2) were administered to all participants. The Social Responsiveness Scale, Second Edition and the Vineland Adaptive Behaviour Scales, Third Edition were completed by a parent/caregiver. The majority of participants (n=15) had intellectual disability and General Conceptual Ability scores ranged from 39 to 76 (mean 53.17, SD 12.13). Participants displayed a profile of better verbal ability compared with non-verbal reasoning ability and spatial ability. Autistic traits were prevalent and eight participants scored above the cut-off on the ADOS-2, although symptoms were less pronounced in older individuals. Adaptive functioning was impaired but commensurate with intellectual ability. Overall, TBRS is associated with an uneven cognitive profile and a high prevalence of autistic traits. This has implications for identifying appropriate services and support that may be beneficial for individuals with TBRS. WHAT THIS PAPER ADDS: Tatton-Brown-Rahman syndrome is associated with intellectual disability and impaired adaptive functioning. Autistic traits were prevalent within the sample. Lower intellectual ability and adaptive behaviour were associated with greater severity of autistic traits.

Approach to overgrowth syndromes in the genome era.

This introduction to the special issue of AJMG Part C: Overgrowth Syndromes updates the current understanding of overgrowth syndromes. We clarify the terminology associated with overgrowth, review some common pathways to overgrowth and present a preliminary classification based on currently known genomic and epigenetic mechanisms. We introduce the articles of this issue-new research and reviews of well-established and recently described overgrowth syndromes of the brain, body or both.

Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients.

BRWD3 has been described as a cause of X-linked intellectual disability, but relatively little is known about the specific phenotype. We report the largest BRWD3 patient series to date, comprising 17 males with 12 distinct null variants and 2 partial gene deletions. All patients presented with intellectual disability, which was classified as moderate (65%) or mild (35%). Behavioral issues were present in 75% of patients, including aggressive behavior, attention deficit/hyperactivity and/or autistic spectrum disorders. Mean head circumference was +2.8 SD (2.8 standard deviations above the mean), and mean BMI was +2.0 SD (in the context of a mean height of +1.3 SD), indicating a predominant macrocephaly/obesity phenotype. Shared facial features included a tall chin, prognathism, broad forehead, and prominent supraorbital ridge. Additional features, reported in a minority (<30%) of patients included cryptorchidism, neonatal hypotonia, and small joint hypermobility. This study delineates the clinical features associated with BRWD3 null variants and partial gene deletions, and suggests that BRWD3 should be included in the differential diagnosis of patients with an overgrowth-intellectual disability (OGID) phenotype, particularly in male patients with a mild or moderate intellectual disability associated with macrocephaly and/or obesity.

The CHD8 overgrowth syndrome: A detailed evaluation of an emerging overgrowth phenotype in 27 patients.

CHD8 has been reported as an autism susceptibility/intellectual disability gene but emerging evidence suggests that it additionally causes an overgrowth phenotype. This study reports 27 unrelated patients with pathogenic or likely pathogenic CHD8 variants (25 null variants, two missense variants) and a male:female ratio of 21:6 (3.5:1, p < .01). All patients presented with intellectual disability, with 85% in the mild or moderate range, and 85% had a height and/or head circumference ≥2 standard deviations above the mean, meeting our clinical criteria for overgrowth. Behavioral problems were reported in the majority of patients (78%), with over half (56%) either formally diagnosed with an autistic spectrum disorder or described as having autistic traits. Additional clinical features included neonatal hypotonia (33%), and less frequently seizures, pes planus, scoliosis, fifth finger clinodactyly, umbilical hernia, and glabellar hemangioma (≤15% each). These results suggest that, in addition to its established link with autism and intellectual disability, CHD8 causes an overgrowth phenotype, and should be considered in the differential diagnosis of patients presenting with increased height and/or head circumference in association with intellectual disability.

Genetics of Growth Disorders-Which Patients Require Genetic Testing?

The second 360° European Meeting on Growth Hormone Disorders, held in Barcelona, Spain, in June 2017, included a session entitled Pragmatism vs. Curiosity in Genetic Diagnosis of Growth Disorders, which examined current concepts of genetics and growth in the clinical setting, in terms of both growth failure and overgrowth. For patients with short stature, multiple genes have been identified that result in GH deficiency, which may be isolated or associated with additional pituitary hormone deficiencies, or in growth hormone resistance, primary insulin-like growth factor (IGF) acid-labile subunit deficiency, IGF-I deficiency, IGF-II deficiency, IGF-I resistance, and primary PAPP-A2 deficiency. While genetic causes of short stature were previously thought to primarily be associated with the GH-IGF-I axis, it is now established that multiple genetic anomalies not associated with the GH-IGF-I axis can result in short stature. A number of genetic anomalies have also been shown to be associated with overgrowth, some of which involve the GH-IGF-I axis. In patients with overgrowth in combination with an intellectual disability, two predominant gene families, the epigenetic regulator genes, and PI3K/AKT pathway genes, have now been identified. Specific processes should be followed for decisions on which patients require genetic testing and which genes should be examined for anomalies. The decision to carry out genetic testing should be directed by the clinical process, not merely for research purposes. The intention of genetic testing should be to direct the clinical options for management of the growth disorder.

The phenotype of Sotos syndrome in adulthood: A review of 44 individuals.

Sotos syndrome is an overgrowth-intellectual disability (OGID) syndrome caused by NSD1 pathogenic variants and characterized by a distinctive facial appearance, an intellectual disability, tall stature and/or macrocephaly. Other associated clinical features include scoliosis, seizures, renal anomalies, and cardiac anomalies. However, many of the published Sotos syndrome clinical descriptions are based on studies of children; the phenotype in adults with Sotos syndrome is not yet well described. Given that it is now 17 years since disruption of NSD1 was shown to cause Sotos syndrome, many of the children first reported are now adults. It is therefore timely to investigate the phenotype of 44 adults with Sotos syndrome and NSD1 pathogenic variants. We have shown that adults with Sotos syndrome display a wide spectrum of intellectual ability with functioning ranging from fully independent to fully dependent. Reproductive rates are low. In our cohort, median height in adult women is +1.9 SD and men +0.5 SD. There is a distinctive facial appearance in adults with a tall, square, prominent chin. Reassuringly, adults with Sotos syndrome are generally healthy with few new medical issues; however, lymphedema, poor dentition, hearing loss, contractures and tremor have developed in a small number of individuals.