BACKGROUND AND AIMS:Patients with LMNA gene variants are at high risk for dilated cardiomyopathy and heart failure (HF), but no prediction model for severe HF events exists. This study aimed to describe the incidence of severe HF events and develop a prediction model in a large cohort of patients with adult-onset laminopathies. METHODS:From a population of 660 patients enrolled in the French LMNA nationwide registry, 470 adults were included in the derivation cohort. An independent international validation cohort included 245 additional patients. Baseline characteristics at genetic testing were assessed and the cumulative incidence of the primary endpoint HF-major adverse cardiac events (HF-MACE) was calculated, defined as HF hospitalization, HF-related death, mechanical circulatory support, or heart transplantation. Predictors of HF-MACE were studied after excluding patients with left ventricular ejection fraction (LVEF) <30% at baseline using a Fine-Gray competing risk model, adjusted hazard ratio (aHR) with 95% confidence interval (CI), and Harrell's concordance (C-) index. A secondary composite endpoint, without hospitalization, was also studied. RESULTS:Among 470 patients of the derivation cohort, HF-MACE occurred in 65 over a median follow-up of 7.1 years (interquartile range: 3.4-12.1). Four independent predictors of HF-MACE were identified: male sex (aHR 1.86; 95% CI 1.060-3.290), LVEF <50% (aHR 2.18; 95% CI 1.080-4.400), missense variants in head and rod domains (aHR 2.91; 95% CI 1.110-7.630), and complete left bundle branch block (aHR 2.99; 95% CI 1.400-6.400). The C-index of the model was 0.750 (95% CI 0.720-0.780) in the derivation cohort and 0.758 (95% CI 0.720-0.800) in the validation cohort. The 5-year cumulative incidence of HF-MACE was 1.5% (95% CI 0.6-3.6), 5.0% (95% CI 1.8-8.2), and 22.0% (95% CI 15.6-28.4) among patients with 0, 1, and ≥2 risk factors, respectively. In patients with LVEF <30% at baseline, the 1-year incidence of HF-MACE was 50%, and those patients were excluded from the risk score. CONCLUSIONS:The first prediction model for severe HF events in adult laminopathies was developed, which may facilitate early and optimal preventive management. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov Unique identifier: NCT03058185.

Limb malformations are paradigmatic of altered gene regulation in human disease. Nail-Patella Syndrome (NPS) is a rare condition characterized mainly by skeletal defects, glomerulonephritis and glaucoma, with variable expressivity. NPS is caused by the haploinsufficiency or loss-of-function of LMX1B, which encodes a transcription factor involved in limb dorsalization, in the renal glomerular filtration barrier and the anterior segment of the eye. The dorsal expression of LMX1B in the developing limbs is under the control of LMX1B autoregulatory modules (LARMs), which are non-coding cis-regulatory elements (CREs) with a limb-specific enhancer activity. Here, we describe the regulatory landscape and report regulatory anomalies at the LMX1B locus in four families, including the deletion of a CRE, two structural variations disrupting the CRE-promoter interaction, and a 5’UTR variant causing an upstream open reading frame (ORF). Molecular mechanisms involving the non-coding genome can have a tissue-specific impact on gene expression, resulting in incomplete forms of the syndrome, and sometimes modifying its classical mode of inheritance. While approximately 95% of individuals with NPS carry pathogenic variants in the coding regions of LMX1B, non-coding alterations explain the remaining cases. This work highlights the importance of genomic diagnosis (gene ORF versus CRE alteration) for precision medicine and genetic counselling in rare diseases.

Background and ObjectivesDevelopmental and epileptic encephalopathies (DEEs) with early burst-suppression EEG (EIDEE-BS) are among the most severe neonatal epileptic syndromes, typically presenting in the first months of life with refractory seizures and profound neurodevelopmental impairment. Although variants in the KCNQ2, STXBP1, and SCN2A genes are recognized as major causes, the full genetic spectrum remains uncertain. We aimed to delineate the electroclinical characteristics, genetic etiologies, and long-term outcomes in a large MRI-negative EIDEE-BS cohort.MethodsWe retrospectively analyzed 110 patients with BS EEG enrolled from a database of 1,540 individuals with suspected genetic epilepsies (2008-2023). Clinical, EEG, and genetic data were systematically collected. Patients were stratified into 4 groups: KCNQ2, STXBP1, "other pathogenic variants," and "without a genetic diagnosis." EEG traces were reviewed independently, and outcomes were assessed through long-term follow-up.ResultsPathogenic or likely pathogenic variants were identified in 62.7% of patients and involved 23 genes, including 2 copy number variants. KCNQ2 (n = 24) and STXBP1 (n = 16) accounted for one-third of diagnoses, whereas SCN2A (n = 3) and KCNT1 (n = 2) were less frequent. In KCNQ2 cases, seizures and BS onset occurred earlier than in STXBP1 cases: mean 2 days vs 6 weeks for seizures and 3 days vs 2 months for BS, respectively. A typical BS pattern (bursts longer than suppressions) strongly correlated with KCNQ2 and STXBP1 variants. Novel associations were found with DPM1, GRIN2A, KCNT2, PIGO, PURA, WWOX, and candidate genes (KMT2E, SNAP25, and SYT1). Most variants were de novo heterozygous; however, recessive and X-linked inheritance patterns were also observed. Mortality was high (25%), primarily from status epilepticus and complications of severe disability. Most patients (72.5%) had persistent seizures at follow-up (a mean of 6.5 years), as well as profound intellectual disabilities, irrespective of genotype.DiscussionThis large series highlights the strong monogenic basis of EIDEE-BS. KCNQ2, STXBP1, and SCN2A were the most commonly affected genes. Early EEG features, particularly BS timing and morphology, can help anticipate the underlying genotype and guide precision therapy, including the early use of sodium channel blockers in selected cases. These findings support recent ILAE reclassification efforts and underscore the importance of comprehensive genomic testing for improved diagnosis and counseling.

Small nuclear RNAs (snRNAs) are essential components of the spliceosome. De novo variants in snRNA genes RNU4-2 (ReNU syndrome), RNU5B-1 and RNU2-2 have been linked to dominant neurodevelopmental disorders (NDDs), revealing a large unexpected contribution of noncoding RNA genes to genetic diseases. Here, through international collaborations, we analyze systematically 200 potentially functional snRNA genes in a French cohort of 34,329 people with rare disorders. We report RNU2-2 variants in 141 individuals, including 35 with recurrent dominant pathogenic variants and 91 affected members from 73 families with biallelic variants. Recessive RNU2-2 NDD is at least twice as frequent as the dominant form and often involves a de novo variant in trans with an inherited allele, consistent with the high mutability of snRNA genes. Dominant and recessive RNU2-2 NDDs share overlapping clinical features, with frequent epilepsy. Blood transcriptomics and DNA methylation analyses revealed subtle, variant-specific effects on splicing and episignatures. Our results support a gradient-of-impact model bridging dominant and recessive inheritance, and establish RNU2-2 variants as a principal contributor to NDDs, nearly as prevalent as ReNU syndrome.

Titinopathies are complex neuromuscular disorders with multiple phenotypes. The gene's size, comprising 364 exons, as well as the protein's size of 3.8 MDa and its extensive network of protein interactors, are key factors underlying this complexity. Various phenotypes characterize titinopathies, and this study focuses on two of them: arthrogryposis and myofibrillar myopathies. The protein deregulations associated with these two phenotypes remain unknown or have been minimally explored; however, understanding these consequences is essential for better characterizing the pathophysiological aspects of these titinopathies.The objective was to analyze protein deregulations in two cohorts of French patients with titinopathies exhibiting the arthrogryposis and myofibrillar myopathy phenotypes, and to compare them with control individuals. Protein extracts were obtained from muscle biopsies of patients, and changes in protein levels within these two groups were analyzed by mass spectrometry. The results indicate specific deregulations in each group. The networks analyzed revealed deregulation of proteins involved in fibrosis mechanisms or in the actomyosin complex for the arthrogryposis phenotype. Regulation of the muscle contraction system through deregulation of proteins involved in the cytoskeleton is impacted in patients with myofibrillar myopathy. The proteins that are quantitatively abnormal in these two groups also provide insights into the major signaling networks disrupted in titinopathies. These findings will contribute to a more precise characterization of titinopathies, enabling the identification of phenotype-specific biomarkers and potentially guiding the search for targeted therapies for these neuromuscular disorders.

Cousin syndrome (MIM#260660) is a rare genetic disorder characterized by short stature, pelvi-scapular dysplasia and craniofacial dysmorphism, due to biallelic pathogenic variants in the TBX15 gene. So far, only six molecularly confirmed cases have been reported in the literature. Herein, we report three novel individuals from two unrelated families carrying homozygous novel variants in the TBX15 gene causing Cousin syndrome with detailed phenotypic description. We review the literature and discuss differential diagnoses. This report confirms that Cousin syndrome is a clinically recognizable condition, with typical dysmorphic features, short stature, hypoplastic scapula and iliac wings, a high prevalence of hip dislocation and humero-radial synostosis, transmission deafness and strabismus. More case descriptions are needed to precise the prevalence of intellectual disability in this condition, a feature that seems strikingly variable among reports.

Background: Germline heterozygous variants in the ETS transcription factor, ERG , cause “ERG deficiency syndrome”, characterised by bone marrow failure (BMF), haematological malignancy and primary lymphoedema predisposition. Given the recent discovery of ERG deficiency syndrome and the limited number of reported cases, the full phenotypic spectrum of the disorder remains to be defined. Methods: Through international collaborations, we ascertained germline ERG variants in individuals with aortic/mitral valve abnormalities and/or aortic aneurysm. We conducted explorative genotype/phenotype analysis of population and disease databases, including in-depth analysis of the UK Biobank, to identify additional variants. To assess both variant-level evidence demonstrating a damaging effect on gene function (DNA binding, transactivation) and experimental evidence supporting the role of the gene in related phenotypic features, we performed functional assays and characterised ERG expression during a critical timepoint of murine aortic valve development. Results: We report 10 heterozygous ERG variants (7 likely pathogenic/pathogenic) in 11 patients (including one family) with aortic/mitral valve abnormalities and aortic aneurysm (6 co-segregate with a BMF or lymphoedema), before 50 years of age, broadening the phenotypic landscape of ERG deficiency syndrome. Providing a possible molecular explanation for aortic valve defects, ERG is present at high levels in aortic valves at a critical point of murine aortic valve development. Explorative genotype/phenotype analysis of population and disease databases identified 3 ERG variants, demonstrating that rare pathogenic variants are hidden within such cohorts. Seven variants are predicted to cause premature protein termination and all three missense variants disrupted transactivation and/or DNA-binding in vitro . Further in-depth analysis of the UK Biobank identified two predicted pathogenic ERG missense variants in ostensibly asymptomatic individuals obscured by somatic genetic rescue, a competitive, ERG-deficiency-driven stem cell phenomenon. Conclusion: ERG deficiency syndrome encompasses a broader clinical phenotype than previously recognised, including cardiovascular manifestations; aortic and mitral valve abnormalities and aortic aneurysms. Identification of patients with hidden germline ERG variants and the expansion of clinical features of ERG deficiency will improve genetic diagnosis and direct clinical management to individuals and families.

BACKGROUND AND OBJECTIVES:Developmental and epileptic encephalopathies (DEEs) with early burst-suppression EEG (EIDEE-BS) are among the most severe neonatal epileptic syndromes, typically presenting in the first months of life with refractory seizures and profound neurodevelopmental impairment. Although variants in the KCNQ2, STXBP1, and SCN2A genes are recognized as major causes, the full genetic spectrum remains uncertain. We aimed to delineate the electroclinical characteristics, genetic etiologies, and long-term outcomes in a large MRI-negative EIDEE-BS cohort. METHODS:We retrospectively analyzed 110 patients with BS EEG enrolled from a database of 1,540 individuals with suspected genetic epilepsies (2008-2023). Clinical, EEG, and genetic data were systematically collected. Patients were stratified into 4 groups: KCNQ2, STXBP1, "other pathogenic variants," and "without a genetic diagnosis." EEG traces were reviewed independently, and outcomes were assessed through long-term follow-up. RESULTS:Pathogenic or likely pathogenic variants were identified in 62.7% of patients and involved 23 genes, including 2 copy number variants. KCNQ2 (n = 24) and STXBP1 (n = 16) accounted for one-third of diagnoses, whereas SCN2A (n = 3) and KCNT1 (n = 2) were less frequent. In KCNQ2 cases, seizures and BS onset occurred earlier than in STXBP1 cases: mean 2 days vs 6 weeks for seizures and 3 days vs 2 months for BS, respectively. A typical BS pattern (bursts longer than suppressions) strongly correlated with KCNQ2 and STXBP1 variants. Novel associations were found with DPM1, GRIN2A, KCNT2, PIGO, PURA, WWOX, and candidate genes (KMT2E, SNAP25, and SYT1). Most variants were de novo heterozygous; however, recessive and X-linked inheritance patterns were also observed. Mortality was high (25%), primarily from status epilepticus and complications of severe disability. Most patients (72.5%) had persistent seizures at follow-up (a mean of 6.5 years), as well as profound intellectual disabilities, irrespective of genotype. DISCUSSION:This large series highlights the strong monogenic basis of EIDEE-BS. KCNQ2, STXBP1, and SCN2A were the most commonly affected genes. Early EEG features, particularly BS timing and morphology, can help anticipate the underlying genotype and guide precision therapy, including the early use of sodium channel blockers in selected cases. These findings support recent ILAE reclassification efforts and underscore the importance of comprehensive genomic testing for improved diagnosis and counseling.

SEMA6A is a transmembrane protein that plays a role in axon guidance and cell migration. Sema6a null mice have cerebral anatomical defects and altered social interactions and working memory. However, the phenotypes associated with loss of SEMA6A function have not been clearly defined in humans. Here we describe 11 individuals who are heterozygous for putatively damaging variants affecting SEMA6A. All of these individuals (100%) had neurodevelopmental phenotypes that included developmental delay, intellectual disability, and/or autism spectrum disorder. Abnormal behaviors were seen in 73% with oppositional defiant disorder being diagnosed in 27% and acting out, overeating, and tantrums each being described in 18% of individuals. Disorders of attention were documented in 45%. Among the six individuals who had a brain MRI, 50% had at least one abnormal finding. Of the eight SEMA6A variants with known inheritance, five were inherited. Taken together, our data suggest that loss of SEMA6A function may be associated with an increased risk of neurodevelopmental phenotypes, abnormal behaviors, disorders of attention, and brain anomalies. Additional studies will be needed to determine if SEMA6A haploinsufficiency is best characterized as an autosomal dominant disorder with incomplete penetrance or as a risk factor for these phenotypes.

De novo variants are a leading cause of neurodevelopmental disorders (NDDs), but because every monogenic NDD is different and usually extremely rare, it remains a major challenge to understand the complete phenotype and genotype spectrum of any morbid gene. According to OMIM, heterozygous variants in KDM6B cause "neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities."Here, by examining the molecular and clinical spectrum of 85 reported individuals with mostly de novo (likely) pathogenic KDM6B variants, we demonstrate that this description is inaccurate and potentially misleading. Cognitive deficits are seen consistently in all individuals, but the overall phenotype is highly variable. Notably, coarse facies and distal skeletal anomalies, as defined by OMIM, are rare in this expanded cohort while other features are unexpectedly common (e.g., hypotonia, psychosis, etc.). Using 3D protein structure analysis and an innovative dual Drosophila gain-of-function assay, we demonstrated a disruptive effect of 11 missense/in-frame indels located in or near the enzymatic JmJC or Zn-containing domain of KDM6B. Consistent with the role of KDM6B in human cognition, we demonstrated a role for the Drosophila KDM6B ortholog in memory and behavior. Taken together, we accurately define the broad clinical spectrum of the KDM6B-related NDD, introduce an innovative functional testing paradigm for the assessment of KDM6B variants, and demonstrate a conserved role for KDM6B in cognition and behavior. Our study demonstrates the critical importance of international collaboration, sharing of clinical data, and rigorous functional analysis of genetic variants to ensure correct disease diagnosis for rare disorders.

Variants in spliceosomal small nuclear RNA (snRNA) genes RNU4-2 (ReNU syndrome), RNU5B-1, and RNU2-2 have recently been linked to dominant neurodevelopmental disorders (NDDs), revealing a major, previously overlooked role for noncoding snRNAs in human disease. Here, we systematically analysed 200 potentially functional snRNA genes in a French cohort comprising 26,911 individuals with rare disorders and through international collaborations. We identify de novo and biallelic variants in RNU2-2 associated with both dominant and recessive NDDs in 126 individuals from 108 unrelated families. Recessive RNU2-2 NDD is at least twice as frequent as the dominant NDD caused by n.4G>A and n.35A>G, and often arises from a de novo variant in trans with an inherited allele, reflecting the high mutability of snRNA genes. Dominant and recessive RNU2-2-NDDs share overlapping clinical features with frequent epilepsy. Blood transcriptomics and DNA methylation analyses revealed subtle, variant-specific effects on splicing and episignatures. Our findings support a gradient-of-impact model and a continuum between dominant and recessive inheritance, establishing RNU2-2 variants as a frequent cause of NDDs, nearly as prevalent as ReNU syndrome.

The non-homologous end joining (NHEJ) pathway is essential to repair DNA double-strand breaks. XRCC4 acts as a stabilizer of the DNA ligase LIG4 in the NHEJ process. In humans, XRCC4 pathogenic variants are responsible for a microcephalic primordial dwarfism syndrome (MPD). Currently, 17 patients have been reported with XRCC4-related MPD and we report 7 new patients from 6 different families, including one fetus. The patients present with short stature, severe microcephaly, neurodevelopmental disorder and additional features, such as transient increase in nuchal translucency, congenital glaucoma, thumb anomalies, hepatic steatosis, seizures, essential tremor and oligodontia which have not been previously described. Hyper- and hypopigmented skin macules, dermatofibrosarcoma, mandibular osteoid osteoma and pancytopenia are also new features, reminiscent of cancer susceptibility syndromes. Functional studies were performed on two patients carrying the known pathogenic p.(Trp43Arg) variant in homozygous state, using a fast, cost-effective and non-invasive approach on PBMCs: (1) Survival analyses after ionizing radiation confirm important radiosensitivity. (2) Flow cytometry showed the lack of TCR-Va7+ T-lymphocytes, suggesting recombination defect of V(D)J coding segments. (3) This was confirmed by multiplexed RT-PCR (PROMIDISα biomarker), analyzing the diversity of V(D)J coding segments in a subset of the TCRα repertoire. We therefore extend the phenotype of XRCC4-related MPD and suggest a combination of three functional assays, based on radiosensitivity and V(D)J recombination defect, to improve the interpretation of XRCC4 variants in fast, cost-effective and non-invasive manner. These findings will improve the diagnosis, genetic counselling, follow-up and management of these patients.

ABSTRACTObjectiveFetal intracranial hemorrhage (FICH) is a rare and potentially deleterious condition. Fetal alloimmune thrombocytopenia and pathogenic variations in COL4A1/A2 genes are well‐recognized causes of FICH. However, pathogenic COL4A1/A2 variations are identified in only 20% of fetuses referred for FICH after excluding other known causes, leaving the majority unexplained and making genetic counseling difficult. Our main aim was to identify novel genes associated with FICH.MethodExome sequencing was performed on 113 unrelated fetuses (35 trios, 3 families and 75 probands) after negative COL4A1/A2 testing and exclusion of known risk factors. Exome analysis incorporated several strategies including analyses of de novo and biallelic variants, and a collapsing gene‐based burden test approach.ResultsNine individuals (8%) had a pathogenic or likely pathogenic variant identified. Additionally, 14 fetuses had a suspicious variant identified in a candidate gene. Causative genes involved platelet production, hemostasis (MPL, MECOM, PROC), endothelial cell adhesion (ESAM), and mitochondrial metabolism (ATP5PO, COQ2, PDHA1). These findings suggest that FICH may result from a broader range of genetic abnormalities beyond previously known COL4A1/A2 gene mutations.ConclusionFICH is characterized by extreme genetic heterogeneity with various pathways involved, underscoring the importance of exome‐wide analyses to fully understand its causes.

The major spliceosome contains five small nuclear RNAs (snRNAs; U1, U2, U4, U5 and U6) essential for splicing. Variants in RNU4-2, encoding U4, cause a neurodevelopmental disorder called ReNU syndrome. We investigated de novo variants in 50 snRNA-encoding genes in a French cohort of 23,649 individuals with rare disorders and gathered additional cases through international collaborations. Altogether, we identified 145 previously unreported probands with (likely) pathogenic variants in RNU4-2 and 21 individuals with de novo and/or recurrent variants in RNU5B-1 and RNU5A-1, encoding U5. Pathogenic variants typically arose de novo on the maternal allele and cluster in regions critical for splicing. RNU4-2 variants mainly localize to two structures, the stem III and T-loop/quasi-pseudoknot, which position the U6 ACAGAGA box for 5' splice site recognition and associate with different phenotypic severity. RNU4-2 variants result in specific defects in alternative 5' splice site usage and methylation patterns (episignatures) that correlate with variant location and clinical severity. This study establishes RNU5B-1 as a neurodevelopmental disorder gene, suggests RNU5A-1 as a strong candidate and highlights the role of de novo variants in snRNAs.

Clinical management of patients with ovarian granulosa cell tumor (GCT) remains poor. Sirtuin-1 (SIRT1), a deacetylase enzyme involved in the regulation of tumor growth and metastasis, may represent a therapeutic target because of the availability of selective pharmacologic inhibitors with minimal toxicity. We assessed the possible overexpression of SIRT1 during tumorigenesis by Western blotting and IHC. We tested the effects of SIRT1 inhibition by EX-527 on growth, proliferation, death, migration, metabolism, and gene expression by RNA sequencing in vitro on three GCT cell lines (AT29, KGN, and COV434). Tumor growth in response to EX-527 treatment was examined in nude mice carrying subcutaneous GCT cell grafts using an electronic caliper and in GCT of AT83 mice by three-dimensional ultrasound imaging system. SIRT1 abundance increased during tumorigenesis. In vitro treatment with EX-527 efficiently reduced cell growth, either by inducing apoptosis or by inhibiting proliferation. EX-527 induced alterations in mTOR-, Myc-, and E2F-driven pathways, and in those controlling cell metabolism and oxidative stress. The administration of this treatment for 4 weeks efficiently reduced tumor progression in vivo. Inhibition of SIRT1 activity may have GCT growth suppressive effects, providing a rationale for evaluating the therapeutic potential of drugs targeting SIRT1 in patients.

Mutations in PIK3R1 have recently been identified in patients with overgrowth syndromes and complex vascular malformations. PIK3R1 encodes p85α which acts as the regulatory subunit of the lipid kinase PI3Kα. PIK3R1 mutations result in the excessive activation of the AKT/mTOR pathway. Currently, there are no approved treatments specifically dedicated to patients with PIK3R1 mutations, and medical care primarily focuses on managing symptoms. In this study, we identified three patients, including two children, who had mosaic somatic PIK3R1 mutations affecting the iSH2 domain, along with severe associated symptoms that were unsuccessfully treated with rapamycin. We conducted in vitro experiments to investigate the impact of these mutations, including a double PIK3R1 mutation in cis observed in one patient. Our findings revealed that p85α mutants in the iSH2 domain showed sensitivity to alpelisib, a pharmacological inhibitor of PI3Kα. Based on these findings, we received authorization to administer alpelisib to all three patients. Following drug introduction, patients rapidly demonstrated clinical improvement, pain, fatigue and inflammatory flares were attenuated. Magnetic Resonance Imaging showed a mean decrease of 22.67% in the volume of vascular malformations over twelve months of treatment with alpelisib. No drug-related adverse events were reported during the course of the study. In conclusion, this study provides support for the use of PI3Kα inhibition as a promising therapeutic approach for individuals with PIK3R1-related anomalies.

Deletions of the 3q26.33q27.2 region appear to correlate with a distinct phenotype, although there are few reported cases. Here, we present seven previously unreported individuals carrying de novo 3q27 deletions (under 5 Mb), which include the AP2M1 (adaptor-related protein complex 2, mu-1 subunit) gene and summarize data from 12 previously reported cases from the literature. The overall cohort of 19 individuals demonstrates almost universal intrauterine growth restriction, intellectual disability, and post-natal microcephaly, along with common features of hypotonia, post-natal short stature, and facial dysmorphisms. Newly identified features include bicuspid aortic valve, atrial septal defect, congenital malformation of the mesentery, and metopic craniosynostosis, present in a subset of individuals. These seven newly identified individuals allow narrowing of the previously reported smallest region of overlap to 430 kb at 3q27.1. This region includes 20 protein coding genes. We propose AP2M1 as the most likely contributor to the neurodevelopmental phenotype, based on its predicted intolerance to haploinsufficiency, functional evidence in murine models, and similar phenotypes associated with other adaptor-protein-complex-family members. Furthermore, we report the first individual with a de novo loss-of-function nonsense single nucleotide variant in AP2M1 with neurodevelopmental features including severe epilepsy. We discuss the implications of this finding in the context of previously reported epileptic encephalopathy in individuals with the recurrent p.Arg170Trp variant in AP2M1. In conclusion, our study expands the phenotypic spectrum of 3q27 microdeletions and highlights the potential importance of AP2M1 in its clinical presentation.

BackgroundAarskog-Scott syndrome (AAS) is a rare condition with multiple congenital anomalies, caused by hemizygote variants in theFGD1gene. Its description was based mostly on old case reports, in whom a molecular diagnosis was not always available, or on small series. The aim of this study was to better delineate the phenotype and the natural history of AAS and to provide clues for the diagnosis and the management of the patients.MethodsPhenotypic characterisation of the largest reported AAS cohort, comprising 111 male patients with proven causative variants inFGD1, through comprehensive analyses of clinical data including congenital anomalies, growth and neurodevelopment. Review of photographs and radiographs by experts in dysmorphology and skeletal disorders.ResultsThis study refines the phenotypic spectrum of AAS, with the description of new morphological and radiological features, and refines the prevalence of the features. Short stature is less frequent than previously reported and has a prenatal onset in more than half of the patients. The growth has a specific course with a catch-up during the first decade often leading to low-normal stature in adulthood. Whereas intellectual disability is rare, patients with AAS have a high prevalence of specific learning difficulties and attention hyperactivity disorder. In light of this better knowledge of AAS, we provide management recommendations.ConclusionA better knowledge of the natural history and phenotypic spectrum of AAS will be helpful for the clinical diagnosis and for the interpretation ofFGD1variants using a retrophenotyping strategy, which is becoming the most common way of diagnosis nowadays. Recommendations for care will improve the management of the patients.