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Objective: Adult onset Still's disease (AOSD) is a severe, autoimmune disease that can be challenging to treat with conventional therapeutics and biologicals in a considerable number of cases. Therefore, there is a high need to understand its pathogenesis better. As major clinical symptoms overlap between AOSD and hereditary periodic fever syndromes (HPFS), we analysed four known HPFS genes in AOSD. Methods: We performed Sanger sequencing and quantitative analysis of all coding regions of MEFV, TNFRSF1A, MVK and NLRP3 in 40 AOSD patients. All rare coding variants ( n = 6) were evaluated for several aspects to classify them as benign to pathogenic variants. Statistical analysis was performed to analyse whether variants classified as (likely) pathogenic were associated with AOSD. Results: We identified three rare variants in MEFV, one previously not described. Association to the three likely pathogenic MEFV variants was significant ( p = 2.34E− 03), and two of the three carriers had a severe course of disease. We observed strong evidence for significant association to mutations in TNFRSF1A ( p = 2.40E− 04), as 5% of patients (2/40) carried a (likely) pathogenic variant in this gene. Both of them received a biological for treatment. Conclusion: Our results indicate TNFRSF1A as a relevant gene in AOSD, especially in patients with a more challenging course of disease, while causal variants remain to be identified in the majority of patients. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which analyzes the association between psoriasis vulgaris and psoriatic arthritis with four loss-of-function mutations in the interleukin-36 receptor antagonist (IL36RN) gene in German patients.

OBJECTIVE: Single-nucleotide polymorphisms (SNPs) of the tumor necrosis factor gene TNF at positions -238 and -308 have been associated with psoriasis vulgaris and psoriatic arthritis (PsA). The strong linkage disequilibrium (LD) at chromosome region 6p21, a region known to harbor risk factors for psoriasis susceptibility (PSORS1) other than just SNPs of the TNF gene, renders the interpretation of these findings difficult. The aim of this study was to analyze several SNPs of the TNF gene and its neighboring LTA gene for independent and dependent carriage of the PSORS1 risk allele. METHODS: SNPs in the promoter of the TNF (-238G/A, -308G/A, -857C/T, and -1031T/C), LTA (+252A/G), TNLFRSF1A (+36A/G), and TNLFRSF1B (+676T/G) genes were genotyped in 375 psoriasis patients, 375 PsA patients, and 376 controls. The Trp- Trp-Cys-Cys haplotype of the CCHCR1 gene (CCHCR1*WWCC) was used as an estimate of the risk allele PSORS1. RESULTS: Whereas we were able to confirm the previously described strong association of allele TNF*-238A with psoriasis, our study revealed that this association was completely dependent on carriage of the PSORS1 risk allele. For PsA, but not psoriasis vulgaris without joint involvement, a strong association with the allele TNF*-857T (odds ratio 1.956 [95% confidence interval 1.334-2.881]; corrected P = 0.0025) was also detected in patients negative for the PSORS1 risk allele. CONCLUSION: Our results indicate that there are genetic differences between psoriasis vulgaris patients with and without joint manifestations. While the previously reported association between TNF*-238A and psoriasis seems to primarily reflect LD with PSORS1, TNF*-857T may represent a risk factor for PsA that is independent of the PSORS1 allele. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To analyze the genetic impact of allelic variants of the protein tyrosine phosphatase N22 (PTPN22) and HLA-DRB1 alleles on IgG autoantibody formation directed toward an immunodominant conformational epitope (C1(III); amino acid residues 359-369) of type II collagen (CII) in early rheumatoid arthritis (RA). METHODS: Sera obtained at study inclusion from an inception cohort of RA patients (n = 221; mean symptom duration 6 months) were analyzed for circulating anti-C1(III) IgG autoantibodies. An enzyme-linked immunosorbent assay based on solid-phase-coupled synthetic triple-helical collagen peptides was used to quantify humoral autoimmune responses. HLA-DRB1 genotypes were determined by allele-specific polymerase chain reaction amplification of genomic DNA and sequence-specific hybridization. PTPN22*620W genotyping was performed using an allelic discrimination TaqMan assay. RESULTS: Anti-C1(III) IgG autoantibody titers were significantly elevated in patients with early RA as compared with those in healthy controls (n = 70). The increased titers were more pronounced in RA patients harboring alleles of the RA-associated HLA-DRB1 shared epitope (SE) consensus sequence than in those lacking the SE. In addition, the PTPN22*620W variant was strongly associated with a vigorous humoral autoimmune response to the cartilage-specific CII determinant C1(III). CONCLUSION: Allelic variants encoding the binding pocket for peptide presentation (SE) to T cells and a functional domain of a negative regulator of T cell receptor signaling (PTPN22*620W), respectively, synergize in early RA to break self tolerance toward C1(III), an evolutionarily conserved cartilage determinant that is also frequently targeted in arthritogenic humoral autoimmunity in mice. [ABSTRACT FROM AUTHOR]

ANK3 encodes ankyrin-G, a protein involved in neuronal development and signaling. Alternative splicing gives rise to three ankyrin-G isoforms comprising different domains with distinct expression patterns. Mono- or biallelic ANK3 variants are associated with non-specific syndromic intellectual disability in 14 individuals (seven with monoallelic and seven with biallelic variants). In this study, we describe the clinical features of 13 additional individuals and review the data on a total of 27 individuals (16 individuals with monoallelic and 11 with biallelic ANK3 variants) and demonstrate that the phenotype for biallelic variants is more severe. The phenotypic features include language delay (92%), autism spectrum disorder (76%), intellectual disability (78%), hypotonia (65%), motor delay (68%), attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD) (57%), sleep disturbances (50%), aggressivity/self-injury (37.5%), and epilepsy (35%). A notable phenotypic difference was presence of ataxia in three individuals with biallelic variants, but in none of the individuals with monoallelic variants. While the majority of the monoallelic variants are predicted to result in a truncated protein, biallelic variants are almost exclusively missense. Moreover, mono- and biallelic variants appear to be localized differently across the three different ankyrin-G isoforms, suggesting isoform-specific pathological mechanisms., (© 2024 The Author(s). Clinical Genetics published by John Wiley & Sons Ltd.)

The vacuolar H + -ATPase (V-ATPase) is a functionally conserved multimeric complex localized at the membranes of many organelles where its proton-pumping action is required for proper lumen acidification. The V-ATPase complex is composed of several subunits, some of which have been linked to human disease. We and others previously reported pathogenic dominantly acting variants in ATP6V1B2, the gene encoding the V1B2 subunit, as underlying a clinically variable phenotypic spectrum including dominant deafness-onychodystrophy (DDOD) syndrome, Zimmermann-Laband syndrome (ZLS), and deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures (DOORS) syndrome. Here, we report on an individual with features fitting DOORS syndrome caused by dysregulated ATP6V1C1 function, expand the clinical features associated with ATP6V1B2 pathogenic variants, and provide evidence that these ATP6V1C1/ATP6V1B2 amino acid substitutions result in a gain-of-function mechanism upregulating V-ATPase function that drives increased lysosomal acidification. We demonstrate a disruptive effect of these ATP6V1B2/ATP6V1C1 variants on lysosomal morphology, localization, and function, resulting in a defective autophagic flux and accumulation of lysosomal substrates. We also show that the upregulated V-ATPase function affects cilium biogenesis, further documenting pleiotropy. This work identifies ATP6V1C1 as a new gene associated with a neurodevelopmental phenotype resembling DOORS syndrome, documents the occurrence of a phenotypic continuum between ZLS, and DDOD and DOORS syndromes, and classify these conditions as lysosomal disorders., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Palmoplantar pustulosis (PPP) is a chronic inflammatory skin disorder that affects palms and soles. Patients suffer significant pain, itching, and daily activity impairment. Guselkumab, an interleukin-23 inhibitor, has been approved for PPP treatment in Japan. However, there is no effective therapy licensed for PPP in Europe and the USA., Objective: To explore the efficacy and safety of guselkumab in patients with moderate-to-severe PPP in the Caucasian population., Methods: A multicenter, single-arm, phase II study involving 50 patients with moderate-to-severe PPP treated with 100 mg guselkumab subcutaneously for 24 weeks was conducted (GAP). Primary endpoint was the reduction of palmoplantar-pustulosis psoriasis area and severity index (PPPASI) at week 24 compared to baseline. Secondary endpoints included physician-assessed and patient-reported measures. Serum samples were taken for exploratory studies., Results: The primary endpoint was met with a significant median PPPASI reduction by 59.6% at week 24 compared to baseline ( P  < .001). The proportions of patients achieving PPPASI-50 and PPPASI-75 at week 24 were 66.0% and 34.0%, respectively. Median dermatology life quality index dropped from 15 at baseline to 5 at week 24 ( P  < .001). Week 4 changes in interleukin-19 serum levels predicted week 24 clinical response., Conclusion: Guselkumab may be a promising therapeutic option for PPP in Caucasian patients., Competing Interests: Dr Wilsmann-Theis has been an advisor, speaker, or investigator for Abbvie, Almirall, Amgen, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Hexal, Incyte, Janssen-Cilag, Leo Pharma, Eli Lilly, Medac, Merck Sharp & Dohme Corp., Novartis, Pfizer, and UCB Pharma. Author Patt has been investigator for and/ or received grants from AbbVie, AnaptysBio, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Galderma, Incyte, Janssen, LEO Pharma, Novartis Pharma, OM Pharma, Pfizer, Regeneron, and UCB Pharma. Dr Pinter has served as an advisor and/or paid speaker for and/or participated in clinical trials sponsored by: AbbVie, Almirall-Hermal, Amgen, Biogen Idec, Biontec, BMS, Boehringer-Ingelheim, Celgene, Celltrion, GSK, Eli-Lilly, Eva Pharma, Galderma, Hexal, Incyte, Janssen-Cilag, Klinge Pharma LEO-Pharma, MC2, Medac, Merck Serono, Mitsubishi, Moonlake, MSD, Novartis, Pascoe, Pfizer, Tigercat Pharma, Regeneron, Roche, Sandoz Biopharmaceuticals, Sanofi-Genzyme, Schering-Plough, UCB Pharma, and Zuellig Pharma. Dr Gerdes has been an advisor and/or received speakers' honoraria and/or received grants and/or participated in clinical trials of the following companies: AbbVie, Acylering, Affibody AB, Akari Therapeutics Plc, Almirall-Hermal, Amgen, Anaptys Bio, Argenx BV, AstraZeneca AB, Bioskin, Bristol-Myers Squibb, Boehringer-Ingelheim, Celgene, Dermira, Eli Lilly, Galderma, Hexal AG, Incyte Inc., Janssen-Cilag, Johnson & Johnson, Klinge Pharma, Kymab, Leo Pharma, Medac, Neubourg Skin Care GmbH, Novartis, Pfizer, Principia Biopharma, Regeneron Pharmaceutical, Sandoz Biopharmaceuticals, Sanofi-Aventis, and UCB Pharma. N Magnolo has received honoraria as an advisor, speaker, and/or consultant AbbVie, Almirall, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Janssen-Cilag, La Roche-Posay, LEO Pharma, Lilly, Novartis, Pfizer, Dr Wolff, and UCB Pharma. Drs Németh, Paul, Hüffmeier has no conflict of interest to declare. Author Schmitz has no conflict of interest to declare. Dr Paul has no conflict of interest to declare. Dr Augustin has served as a consultant, lecturer or researcher, and/or has received research grants from companies manufacturing drugs for psoriasis, including AbbVie, Almirall, Amgen, Biogen, Boehringer Ingelheim, BMS, Celgene, Centocor, Eli Lilly, Galderma, Hexal, Janssen, Klinge, LEO, Medac, MSD, Mylan B.V., Novartis, Pfizer, Sandoz, Takeda, UCB, and Viatris. Dr Staubach has received research grants, travel grants, consulting or lecturer's honoraria from Abbvie, Allergika, Almirall-Hermal, Amgen, Avene, Unna Akademie, Biocryst, BMS, Boehringer-Ingelheim, Celgene, CSL-Behring, Eli-Lilly, Galderma, GSK, Janssen, Klinge, LEO-Pharma, L'Oreal, Novartis, Octapharma, Pfizer, Pharming, Regeneron, Shire, Takeda, Sanofi-Genzyme, and UCB Pharma. Dr Weyergraf has served as a speaker, advisor and/or researcher for AbbVie, Almirall, Amgen, Arctic Bioscience, Biogen, Bristol-Myers-Squibb, Celgene, Hermal, Janssen, LEO, Lilly, Novartis, Pfizer, Sanofi, and UCB. Dr Wolk has received research grants or contracts for clinical trials (payment to her institution), support for attending congresses, scientific awards, consulting fees or honoraria for participation in advisory boards, or honoraria for lectures for one or more of the following: Celgene/Amgen, Celgene/Bristol Myers Squibb, Charité Research Organization, Flexopharm, Janssen-Cilag, Novartis Pharma, Sanofi–Aventis, TFS Trial Form Support, University hospital Magdeburg, European HS foundation (EHSF), and the Symposium on Hidradenitis Suppurativa Advances (SHSA); she also has an non-financial relationship to the HS task force of the German Consortium for Dermatological Research (ADF). Dr Sabat has received research grants, clinical trial contracts, scientific awards, or honoraria for consulting, participation in advisory boards, or for lectures for one or more of the following: AbbVie, Almirall Hermal, Amgen, Bayer Schering Pharma, Boehringer Ingelheim Pharma, Bruno Bloch Stiftung, Celgene/Amgen, Celgene/Bristol Myers Squibb, Charité Research Organisation, CSL Behring, ICON, IQVIA RDS, Incyte, Janssen-Cilag/Janssen Research & Development, MoonLake Immunotherapeutics, Novartis Pharma, Parexel, Rheinischen Friedrich-Wilhelms-Universität Bonn, Sanofi–Aventis, TFS, UCB Biopharma, Universitätsmedizin Greifswald, and Wundnetz Berlin-Brandenburg e. V. Dr Mӧßner has been an advisor and/or received speakers’ honoraria and/or received grants and/or participated in clinical trials of the following companies: Abbvie, Allmirall, Biogen IDEC GmbH, Böhringer-Ingelheim, Celgene, Janssen-Cilag GmbH, Leo Pharma GmbH, Eli Lilly and Company, Merck Serono GmbH, MSD SHARP & DOHME GmbH, Novartis Pharma GmbH, Pfizer GmbH, and UCB., (© 2024 by the American Academy of Dermatology, Inc. Published by Elsevier Inc.)

Chronic nonbacterial osteomyelitis (CNO), an autoinflammatory bone disease primarily affecting children, can cause pain, hyperostosis and fractures, affecting quality-of-life and psychomotor development. This study investigated CNO-associated variants in P2RX7, encoding for the ATP-dependent trans-membrane K + channel P2X7, and their effects on NLRP3 inflammasome assembly. Whole exome sequencing in two related transgenerational CNO patients, and target sequencing of P2RX7 in a large CNO cohort (N = 190) were conducted. Results were compared with publicly available datasets and regional controls (N = 1873). Findings were integrated with demographic and clinical data. Patient-derived monocytes and genetically modified THP-1 cells were used to investigate potassium flux, inflammasome assembly, pyroptosis, and cytokine release. Rare presumably damaging P2RX7 variants were identified in two related CNO patients. Targeted P2RX7 sequencing identified 62 CNO patients with rare variants (32.4%), 11 of which (5.8%) carried presumably damaging variants (MAF <1%, SIFT "deleterious", Polyphen "probably damaging", CADD >20). This compared to 83 of 1873 controls (4.4%), 36 with rare and presumably damaging variants (1.9%). Across the CNO cohort, rare variants unique to one (Median: 42 versus 3.7) or more (≤11 patients) participants were over-represented when compared to 190 randomly selected controls. Patients with rare damaging variants more frequently experienced gastrointestinal symptoms and lymphadenopathy while having less spinal, joint and skin involvement (psoriasis). Monocyte-derived macrophages from patients, and genetically modified THP-1-derived macrophages reconstituted with CNO-associated P2RX7 variants exhibited altered potassium flux, inflammasome assembly, IL-1β and IL-18 release, and pyroptosis. Damaging P2RX7 variants occur in a small subset of CNO patients, and rare P2RX7 variants may represent a CNO risk factor. Observations argue for inflammasome inhibition and/or cytokine blockade and may allow future patient stratification and individualized care., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Numerous contiguous gene deletion syndromes causing neurodevelopmental disorders have previously been defined using cytogenetics for which only in the current genomic era the disease-causing genes have become elucidated. One such example is deletion at Xq22.2, previously associated with a neurodevelopmental disorder which has more recently been found to be caused by de novo loss-of-function variants in TCEAL1. So far, a single study reported six unrelated individuals with this monogenetic disorder, presenting with syndromic features including developmental delay especially affecting expressive speech, intellectual disability, autistic-like behaviors, hypotonia, gait abnormalities and mild facial dysmorphism, in addition to ocular, gastrointestinal, and immunologic abnormalities. Here we report on four previously undescribed individuals, including two adults, with de novo truncating variants in TCEAL1, identified through trio exome or genome sequencing, further delineating the phenotype of the TCEAL1-related disorder. Whereas overall we identify similar features compared to the original report, we also highlight features in our adult individuals including hyperphagia, obesity, and endocrine abnormalities including hyperinsulinemia, hyperandrogenemia, and polycystic ovarian syndrome. X chromosome inactivation and RNA-seq studies further provide functional insights in the molecular mechanisms. Together this report expands the phenotypic and molecular spectrum of the TCEAL1-related disorder which will be useful for counseling of newly identified individuals and their families., (© 2024. The Author(s).)

VEXAS syndrome is a recently identified autoinflammatory systemic disease caused by an acquired somatic mutation of the X-linked UBA1 gene, the key enzyme of the first step of ubiquitylation. The acronym VEXAS stands for the characteristics Vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic. The disease occurs in advanced adulthood preferentially in men and is characterized by hematological, rheumatological and dermatological symptoms. The latter include neutrophil-rich lesions reminiscent of Sweet's syndrome, erythema nodosum- and panniculitis-like skin manifestations and recurrent polychondritis of the nose and auricles. The presence of cytoplasmic vacuoles in myeloid and erythroid precursors in the bone marrow is characteristic. In up to half of the cases, VEXAS syndrome is associated with myelodysplastic syndrome. Dermatologists should be familiar with the clinical picture, as skin symptoms are often the first indicator of the disease. Molecular diagnostics are essential for confirming the diagnosis and risk stratification of affected patients. In this minireview we provide an overview of the pathophysiology, diagnosis and therapy of VEXAS syndrome and illustrate its clinical picture with two own cases., (© 2023 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

The psoriatic field includes both rare and common subtypes. Common complex forms include psoriasis vulgaris and psoriatic arthritis. In these subtypes, certain HLA alleles remain the most relevant genetic factors, although genome-wide association studies lead to the detection of more than 80 susceptibility loci. They mainly affect innate and adaptive immunity and explain over 28 % of the heritability. Pustular psoriasis comprises a group of rarer subtypes. Using exome sequencing, several disease genes were identified for mainly generalized pustular psoriasis, and an oligogenic inheritance is likely. Treatment studies based on the affected IL-36 pathway indicate a high response rate in this subtype further supporting the pathophysiological relevance of the affected gene products., Competing Interests: Competing interests: Authors state no conflict of interest., (© 2023 bei den Autorinnen und Autoren, publiziert von De Gruyter.)

We report on a female individual with feeding difficulties, constipation, poor overall growth, periventricular lesions resembling gliosis in brain MRI, recurrent otitis media with palsy of facial nerve, distinct facial features, and pronounced delay in speech development. The latter was the most prominent feature. Molecular karyotyping revealed a heterozygous de novo deletion of 4.353 Mb at chromosome 12q21.33q22. This report expands the number of described individuals with heterozygous deletions at 12q21.33, their clinical spectrum and highlights the clinical variability, even in individuals with deletion of the same genes. Furthermore, our findings indicate a role of BTG1 (OMIM *109580) in speech development., Competing Interests: Declaration of competing interest The authors declare to have no conflicts of interest., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Only few copy number variants at chromosome 19p13.11 have been reported, thus associated clinical information is scarce. Proximal to these copy number losses, we now identified deletions in five unrelated individuals with neurodevelopmental disorders. They presented with psychomotor delay as well as behavioral and sleeping disorders, while complex cardiovascular, skeletal, and various other malformations were more variable. Dysmorphic features were rather unspecific and not considered as a recognizable gestalt. Neither of the analyzed parents carried their offsprings' deletions, indicating de novo occurrence. The deletion sizes ranged between 0.7 and 5.2 Mb, were located between 18 and 24 megabases from the telomere, and contained a variable number of protein-coding genes (n = 25-68). Although not all microdeletions shared a common region, the smallest common overlap of some of the deletions provided interesting insights in the chromosomal region 19p13.11p12. Diligent literature review using OMIM and Pubmed did not identify a satisfying candidate gene for neurodevelopmental disorders. In the literature, a de novo in-frame deletion in MAU2 was considered pathogenic in an individual with Cornelia de Lange syndrome. Therefore, the clinical differential diagnosis of this latter syndrome in one individual and the encompassment of MAU2 in three individuals' deletions suggest clinical and genetic overlap with this specific syndrome. Three of the four here reported individuals with deletion encompassing GDF1 had different congenital heart defects, suggesting that this gene's haploinsufficiency might contribute to the cardiovascular phenotype, however, with reduced penetrance. Our findings indicate an association of microdeletions at 19p13.11/ 19p13.11p12 with neurodevelopmental disorders, variable symptoms, and malformations, and delineate the phenotypic spectrum of deletions within this genomic region., Competing Interests: Declaration of competing interest The authors declare to have no conflict of interest., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Generalized pustular psoriasis is a severe psoriatic subtype characterized by epidermal neutrophil infiltration. Although variants in IL36RN and MPO have been shown to affect immune cells, a systematic analysis of neutrophils and PBMC subsets and their differential gene expression dependent on MPO genotypes was not performed yet. We assessed the transcriptomes of MPO-deficient patients using single-cell RNA sequencing of PBMCs and RNA sequencing of neutrophils in a stable disease state. Cell-type annotation by multimodal reference mapping of single-cell RNA-sequencing data was verified by flow cytometry of surface and intracellular markers; the proportions of CD4 + cytotoxic T lymphocytes and other CD4 + effector cells were increased in generalized pustular psoriasis, whereas the frequencies of naïve CD4 + T cells were significantly lower. The expression of FGFBP2 marking CD4 + cytotoxic T lymphocytes and CD8 + effector memory T cells was elevated in patients with generalized pustular psoriasis with disease-contributing variants compared with that in noncarriers (P = 0.0015). In neutrophils, differentially expressed genes were significantly enriched in genes of the classical complement activation pathway. Future studies assessing affected cell types and pathways will show their contribution to generalized pustular psoriasis's pathogenesis and indicate whether findings can be transferred to the acute epidermal situation and whether depletion or inactivation of CD4 + cytotoxic T lymphocytes may be a reasonable therapeutic approach., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

ZMYND11 is the critical gene in chromosome 10p15.3 microdeletion syndrome, a syndromic cause of intellectual disability. The phenotype of ZMYND11 variants has recently been extended to autism and seizures. We expand on the epilepsy phenotype of 20 individuals with pathogenic variants in ZMYND11. We obtained clinical descriptions of 16 new and nine published individuals, plus detailed case history of two children. New individuals were identified through GeneMatcher, ClinVar and the European Network for Therapies in Rare Epilepsy (NETRE). Genetic evaluation was performed using gene panels or exome sequencing; variants were classified using American College of Medical Genetics (ACMG) criteria. Individuals with ZMYND11 associated epilepsy fell into three groups: (i) atypical benign partial epilepsy or idiopathic focal epilepsy (n = 8); (ii) generalised epilepsies/infantile epileptic encephalopathy (n = 4); (iii) unclassified (n = 8). Seizure prognosis ranged from spontaneous remission to drug resistant. Neurodevelopmental deficits were invariable. Dysmorphic features were variable. Variants were distributed across the gene and mostly de novo with no precise genotype-phenotype correlation. ZMYND11 is one of a small group of chromatin reader genes associated in the pathogenesis of epilepsy, and specifically ABPE. More detailed epilepsy descriptions of larger cohorts and functional studies might reveal genotype-phenotype correlation. The epileptogenic mechanism may be linked to interaction with histone H3.3., (© 2021 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

Background: An identical homozygous missense variant in EIF3F, identified through a large-scale genome-wide sequencing approach, was reported as causative in nine individuals with a neurodevelopmental disorder, characterized by variable intellectual disability, epilepsy, behavioral problems and sensorineural hearing-loss. To refine the phenotypic and molecular spectrum of EIF3F-related neurodevelopmental disorder, we examined independent patients., Results: 21 patients were homozygous and one compound heterozygous for c.694T>G/p.(Phe232Val) in EIF3F. Haplotype analyses in 15 families suggested that c.694T>G/p.(Phe232Val) was a founder variant. All affected individuals had developmental delays including delayed speech development. About half of the affected individuals had behavioral problems, altered muscular tone, hearing loss, and short stature. Moreover, this study suggests that microcephaly, reduced sensitivity to pain, cleft lip/palate, gastrointestinal symptoms and ophthalmological symptoms are part of the phenotypic spectrum. Minor dysmorphic features were observed, although neither the individuals' facial nor general appearance were obviously distinctive. Symptoms in the compound heterozygous individual with an additional truncating variant were at the severe end of the spectrum in regard to motor milestones, speech delay, organic problems and pre- and postnatal growth of body and head, suggesting some genotype-phenotype correlation., Conclusions: Our study refines the phenotypic and expands the molecular spectrum of EIF3F-related syndromic neurodevelopmental disorder.