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Purpose: This study aims to comprehensively delineate the phenotypic spectrum of ACTL6B-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear., Methods: We identified 105 affected individuals, including 39 previously reported cases, and systematically analysed detailed clinical and genetic data for all individuals. Additionally, we conducted knockdown experiments in neuronal cells to investigate the role of ACTL6B in ribosome biogenesis., Results: Biallelic variants in ACTL6B are associated with severe-to-profound global developmental delay/intellectual disability (GDD/ID), infantile intractable seizures, absent speech, autistic features, dystonia, and increased lethality. De novo monoallelic variants result in moderate-to-severe GDD/ID, absent speech, and autistic features, while seizures and dystonia were less frequently observed. Dysmorphic facial features and brain abnormalities, including hypoplastic corpus callosum, parenchymal volume loss/atrophy, are common findings in both groups. We reveal that in the nucleolus, ACTL6B plays a crucial role in ribosome biogenesis, in particular in pre-rRNA processing., Conclusion: This study provides a comprehensive characterization of the clinical spectrum of both autosomal recessive and dominant forms of ACTL6B-associated disorders. It offers a comparative analysis of their respective phenotypes provides a plausible molecular explanation and suggests their inclusion within the expanding category of 'ribosomopathies'., (Copyright © 2024. Published by Elsevier Inc.)

Background: No F8 genetic abnormality is detected in approximately 1% to 2% of patients with severe hemophilia A (HA) using conventional genetic approaches. In these patients, deep intronic variation or F8 disrupting genomic rearrangement could be causal., Objectives: The study aimed to identify the causal variation in families with a history of severe HA for whom genetic investigations failed., Methods: We performed whole F8 gene sequencing in 8 propositi. Genomic rearrangements were confirmed by Sanger sequencing of breakpoint junctions and/or quantitative polymerase chain reaction., Results: A structural variant disrupting F8 was found in each propositus, so that all the 815 families with a history of severe HA registered in our laboratory received a conclusive genetic diagnosis. These structural variants consisted of 3 balanced inversions, 3 large insertions of gained regions, and 1 retrotransposition of a mobile element. The 3 inversions were 105 Mb, 1.97 Mb, and 0.362 Mb in size. Among the insertions of gained regions, one corresponded to the insertion of a 34 kb gained region from chromosome 6q27 in F8 intron 6, another was the insertion of a 447 kb duplicated region from chromosome 9p22.1 in F8 intron 14, and the last one was the insertion of an Xq28 349 kb gained in F8 intron 5., Conclusion: All the genetically unsolved cases of severe HA in this cohort were due to structural variants disrupting F8. This study highlights the effectiveness of whole F8 sequencing to improve the molecular diagnosis of HA when the conventional approach fails., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber disease, is a dominant inherited vascular disorder. The clinical diagnosis is based on the Curaçao criteria and pathogenic variants in the ENG and ACVRL1 genes are responsible for most cases of HHT. Four families with a negative targeted gene panel and selected by a multidisciplinary team were selected and whole-genome sequencing was performed according to the recommendations of the French National Plan for Genomic Medicine. Structural variations were confirmed by standard molecular cytogenetic analysis (FISH). In two families with a definite diagnosis of HHT, we identified two different paracentric inversions of chromosome 9, both disrupting the ENG gene. These inversions are considered as pathogenic and causative for the HHT phenotype of the patients. This is the first time structural variations are reported to cause HHT. As such balanced events are often missed by exon-based sequencing (panel, exome), structural variations may be an under-recognized cause of HHT. Genome sequencing for the detection of these events could be suggested for patients with a definite diagnosis of HHT and in whom no causative pathogenic variant was identified., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Purpose: BCL11B-related disorder (BCL11B-RD) arises from rare genetic variants within the BCL11B gene, resulting in a distinctive clinical spectrum encompassing syndromic neurodevelopmental disorder, with or without intellectual disability, associated with facial features and impaired immune function. This study presents an in-depth clinico-biological analysis of 20 newly reported individuals with BCL11B-RD, coupled with a characterization of genome-wide DNA methylation patterns of this genetic condition., Methods: Through an international collaboration, clinical and molecular data from 20 individuals were systematically gathered, and a comparative analysis was conducted between this series and existing literature. We further scrutinized peripheral blood DNA methylation profile of individuals with BCL11B-RD, contrasting them with healthy controls and other neurodevelopmental disorders marked by established episignature., Results: Our findings unveil rarely documented clinical manifestations, notably including Rubinstein-Taybi-like facial features, craniosynostosis, and autoimmune disorders, all manifesting within the realm of BCL11B-RD. We refine the intricacies of T cell compartment alterations of BCL11B-RD, revealing decreased levels naive CD4 + T cells and recent thymic emigrants while concurrently observing an elevated proportion of effector-memory expressing CD45RA CD8 + T cells (TEMRA). Finally, a distinct DNA methylation episignature exclusive to BCL11B-RD is unveiled., Conclusion: This study serves to enrich our comprehension of the clinico-biological landscape of BCL11B-RD, potentially furnishing a more precise framework for diagnosis and follow-up of individuals carrying pathogenic BCL11B variant. Moreover, the identification of a unique DNA methylation episignature offers a valuable diagnosis tool for BCL11B-RD, thereby facilitating routine clinical practice by empowering physicians to reevaluate variants of uncertain significance within the BCL11B gene., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2023 American College of Medical Genetics and Genomics. All rights reserved.)

Defects in L-serine biosynthesis are a group of autosomal recessive diseases resulting in a wide phenotypic spectrum ranging from viable to lethal presentations and caused by variants in the three genes encoding the L-serine biosynthesis enzymes, PHGDH, PSAT1, and PSPH. Neu-Laxova syndrome (NLS) is the fetal form of this group, characterized by multiple congenital anomalies including severe intrauterine growth retardation, cutaneous lesions extending from ichthyosis to severe restrictive dermopathy with ectropion and eclabion, edema, microcephaly, central nervous system abnormalities, and flexion contractures. Here we report on two unrelated fetuses with an attenuated phenotype of NLS, that initially evoked Taybi-Linder syndrome. They carry biallelic pathogenic variants in the PHGDH gene. These observations expand the phenotypic continuum of L-serine biosynthesis defects, and illustrate the phenotypic overlap between NLS and microcephalic primordial dwarfism., Competing Interests: Declaration of competing interest All authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Purpose: Dominant variants in the retinoic acid receptor beta (RARB) gene underlie a syndromic form of microphthalmia, known as MCOPS12, which is associated with other birth anomalies and global developmental delay with spasticity and/or dystonia. Here, we report 25 affected individuals with 17 novel pathogenic or likely pathogenic variants in RARB. This study aims to characterize the functional impact of these variants and describe the clinical spectrum of MCOPS12., Methods: We used in vitro transcriptional assays and in silico structural analysis to assess the functional relevance of RARB variants in affecting the normal response to retinoids., Results: We found that all RARB variants tested in our assays exhibited either a gain-of-function or a loss-of-function activity. Loss-of-function variants disrupted RARB function through a dominant-negative effect, possibly by disrupting ligand binding and/or coactivators' recruitment. By reviewing clinical data from 52 affected individuals, we found that disruption of RARB is associated with a more variable phenotype than initially suspected, with the absence in some individuals of cardinal features of MCOPS12, such as developmental eye anomaly or motor impairment., Conclusion: Our study indicates that pathogenic variants in RARB are functionally heterogeneous and associated with extensive clinical heterogeneity., Competing Interests: Conflict of Interest J.R.L. owns stock in 23andMe and is a paid consultant for Genome International. All other authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The disease-causative variant remains unidentified in approximately 0.5% to 2% of hemophilia B patients using conventional genetic investigations, and F9 deep intronic variations could be responsible for these phenotypes., Objectives: This study aimed to characterize deep intronic variants in hemophilia B patients for whom genetic investigations failed., Methods: We performed whole F9 sequencing in 17 genetically unsolved hemophilia B patients. The pathogenic impact of the candidate variants identified was studied using both in silico analysis (MaxEntScan and spliceAI) and minigene assay., Results: In total, 9 candidate variants were identified in 15 patients; 7 were deep intronic substitutions and 2 corresponded to insertions of mobile elements. The most frequent variants found were c.278-1806A>C and the association of c.278-1244A>G and c.392-864T>G, identified in 4 and 6 unrelated individuals, respectively. In silico analysis predicted splicing impact for 4 substitutions (c.278-1806A>C, c.392-864T>G, c.724-2385G>T, c.723+4297T>A). Minigene assay showed a deleterious splicing impact for these 4 substitutions and also for the c.278-1786_278-1785insLINE. In the end, 5 variants were classified as likely pathogenic using the American College of Medical Genetics and Genomics guidelines, and 4 as of unknown significance. Thus, the hemophilia B-causing variant was identified in 13/17 (76%) families., Conclusion: We elucidated the causing defect in three-quarters of the families included in this study, and we reported new F9 deep intronic variants that can cause hemophilia B., (Copyright © 2022 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Xq25 microduplication involving exclusively STAG2 is a new distinctive cohesinopathy including mild to moderate intellectual disability, speech delay and facial dysmorphism. Seizures seem to be scarce, but detailed seizure type descriptions are missing. We report the case of an 8-year-old boy with mild intellectual disability and eyelid myoclonia with onset at age of 3 years, initially misinterpreted as tics. An ictal VIDEO-EEG documented eye closure elicited generalized 3 Hz spike-waves or polyspike-waves concomitant to eyelid myoclonia, sometimes associated to brief clinically observable absences. Intermittent photic stimulation revealed a photoparoxysmal response. Array CGH identified a 199 kb copy number gain in Xq25 including the whole STAG2 gene, inherited from his asymptomatic mother. To the best of our knowledge, this is the first case of STAG2 encephalopathy fulfilling all electroclinical criteria for epilepsy with eyelid myoclonia and absences (EMA), formally named Jeavons syndrome (JS). As for other Genetic Generalized Epilepsy syndromes, EMA/JS usually occurs in normally developing children. Intellectual disability of variable degree is occasionally reported. On the background of other genes responsible for Developmental and Epileptic Encephalopathies, linked to specific generalized seizure types or seizure combinations, we discuss the contribution of pathogenic variants in CHD2, SYNGAP1 and some other genes as, RORB, NEXMIF and KCNB1 to this peculiar EMA phenotype., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Purpose: KLHL20 is part of a CUL3-RING E3 ubiquitin ligase involved in protein ubiquitination. KLHL20 functions as the substrate adaptor that recognizes substrates and mediates the transfer of ubiquitin to the substrates. Although KLHL20 regulates neurite outgrowth and synaptic development in animal models, a role in human neurodevelopment has not yet been described. We report on a neurodevelopmental disorder caused by de novo missense variants in KLHL20., Methods: Patients were ascertained by the investigators through Matchmaker Exchange. Phenotyping of patients with de novo missense variants in KLHL20 was performed., Results: We studied 14 patients with de novo missense variants in KLHL20, delineating a genetic syndrome with patients having mild to severe intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, hyperactivity, and subtle dysmorphic facial features. We observed a recurrent de novo missense variant in 11 patients (NM_014458.4:c.1069G>A p.[Gly357Arg]). The recurrent missense and the 3 other missense variants all clustered in the Kelch-type β-propeller domain of the KLHL20 protein, which shapes the substrate binding surface., Conclusion: Our findings implicate KLHL20 in a neurodevelopmental disorder characterized by intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, and hyperactivity., Competing Interests: Conflict of Interest M.M.M. and R.E.S. are employees of GeneDx, Inc. All other authors declare no conflict interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Purpose: Germline loss-of-function variants in CTNNB1 cause neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; OMIM 615075) and are the most frequent, recurrent monogenic cause of cerebral palsy (CP). We investigated the range of clinical phenotypes owing to disruptions of CTNNB1 to determine the association between NEDSDV and CP., Methods: Genetic information from 404 individuals with collectively 392 pathogenic CTNNB1 variants were ascertained for the study. From these, detailed phenotypes for 52 previously unpublished individuals were collected and combined with 68 previously published individuals with comparable clinical information. The functional effects of selected CTNNB1 missense variants were assessed using TOPFlash assay., Results: The phenotypes associated with pathogenic CTNNB1 variants were similar. A diagnosis of CP was not significantly associated with any set of traits that defined a specific phenotypic subgroup, indicating that CP is not additional to NEDSDV. Two CTNNB1 missense variants were dominant negative regulators of WNT signaling, highlighting the utility of the TOPFlash assay to functionally assess variants., Conclusion: NEDSDV is a clinically homogeneous disorder irrespective of initial clinical diagnoses, including CP, or entry points for genetic testing., Competing Interests: Conflict of Interest F.M. and M.M.M. are employees of GeneDX, Inc. All other authors declare no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Large F8 deletions represent 3-5% of the variations found in severe hemophilia A patients, but only a few deletion breakpoints have been characterized precisely., Objectives: Resolving at the nucleotide level 24 F8 large deletions to provide new data on the mechanisms involved in these rearrangements., Methods: Breakpoint junctions of 24 F8 large deletions were characterized using a combination of long-range polymerase chain reaction, whole F8 NGS sequencing, and Sanger sequencing. Repeat elements, non-B DNA, and secondary structures were analyzed around the breakpoints., Results: Deletions ranged from 1.667 kb to 0.5 Mb in size. Nine involved F8 neighboring genes. Simple blunt ends and 2-4 bp microhomologies were identified at the breakpoint junctions of 10 (42%) and 8 (33%) deletions, respectively. Five (21%) deletions resulted from homeologous recombination between two Alu elements. The remaining case corresponded to a more complex rearrangement with an insertion of a 19 bp-inverted sequence at the junction. Four different breakpoints were located in a 562-bp region in F8 intron 6. This finding suggested that this region, composed of two Alu elements, is a DNA breakage hotspot. Non-B DNA and secondary structures were identified in the junction regions and may contribute to DNA breakage., Conclusion: Molecular characterization of deletion breakpoints revealed that non-homologous non-replicative DNA repair mechanisms and replication-based mechanisms seemed to be the main causative mechanisms of F8 large deletions. Moreover, we identified a possible F8 DNA breakage hotspot involved in non-recurrent rearrangements., (© 2022 International Society on Thrombosis and Haemostasis.)

Purpose: Although haploinsufficiency of ANKRD11 is among the most common genetic causes of neurodevelopmental disorders, the role of rare ANKRD11 missense variation remains unclear. We characterized clinical, molecular, and functional spectra of ANKRD11 missense variants., Methods: We collected clinical information of individuals with ANKRD11 missense variants and evaluated phenotypic fit to KBG syndrome. We assessed pathogenicity of variants through in silico analyses and cell-based experiments., Results: We identified 20 unique, mostly de novo, ANKRD11 missense variants in 29 individuals, presenting with syndromic neurodevelopmental disorders similar to KBG syndrome caused by ANKRD11 protein truncating variants or 16q24.3 microdeletions. Missense variants significantly clustered in repression domain 2 at the ANKRD11 C-terminus. Of the 10 functionally studied missense variants, 6 reduced ANKRD11 stability. One variant caused decreased proteasome degradation and loss of ANKRD11 transcriptional activity., Conclusion: Our study indicates that pathogenic heterozygous ANKRD11 missense variants cause the clinically recognizable KBG syndrome. Disrupted transrepression capacity and reduced protein stability each independently lead to ANKRD11 loss-of-function, consistent with haploinsufficiency. This highlights the diagnostic relevance of ANKRD11 missense variants, but also poses diagnostic challenges because the KBG-associated phenotype may be mild and inherited pathogenic ANKRD11 (missense) variants are increasingly observed, warranting stringent variant classification and careful phenotyping., Competing Interests: Conflict of Interest H.Z.E. and K.G.M. are employees of GeneDx, Inc. All other authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

In the last few years, with the advent of next generation sequencing (NGS), our knowledge of genes associated with monogenic epilepsies has significantly improved. NGS is also a powerful diagnostic tool for patients with epilepsy, through gene panels, exomes and genomes. This has improved diagnostic yield, reducing the time between the first seizure and a definitive molecular diagnosis. However, these developments have also increased the complexity of data interpretation, due to the large number of variants identified in a given patient and due to the phenotypic variability associated with many of the epilepsy-related genes. In this paper, we present examples of variant classification in "real life" clinic situations. We emphasize the importance of accurate phenotyping of the epilepsies including recognising variable/milder phenotypes and expansion of previously described phenotypes. There are some important issues specific to rare epilepsies - mosaicism and reduced penetrance - which affect genetic counselling. These challenges may be overcome through multidisciplinary meetings including epileptologists, pediatric neurologists, and clinical and molecular geneticists, in which every specialist learns from the others in a process which leads to for rapid and accurate diagnosis. This is an important milestone to achieve as targeted therapiesbased on the functional effects of pathogenic variants become available., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Purpose: Rare genetic variants in CDK13 are responsible for CDK13-related disorder (CDK13-RD), with main clinical features being developmental delay or intellectual disability, facial features, behavioral problems, congenital heart defect, and seizures. In this paper, we report 18 novel individuals with CDK13-RD and provide characterization of genome-wide DNA methylation., Methods: We obtained clinical phenotype and neuropsychological data for 18 and 10 individuals, respectively, and compared this series with the literature. We also compared peripheral blood DNA methylation profiles in individuals with CDK13-RD, controls, and other neurodevelopmental disorders episignatures. Finally, we developed a support vector machine-based classifier distinguishing CDK13-RD and non-CDK13-RD samples., Results: We reported health and developmental parameters, clinical data, and neuropsychological profile of individuals with CDK13-RD. Genome-wide differential methylation analysis revealed a global hypomethylated profile in individuals with CDK13-RD in a highly sensitive and specific model that could aid in reclassifying variants of uncertain significance., Conclusion: We describe the novel features such as anxiety disorder, cryptorchidism, and disrupted sleep in CDK13-RD. We define a CDK13-RD DNA methylation episignature as a diagnostic tool and a defining functional feature of the evolving clinical presentation of this disorder. We also show overlap of the CDK13 DNA methylation profile in an individual with a functionally and clinically related CCNK-related disorder., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Background: The EPIGENE network was created in 2014 by four multidisciplinary teams composed of geneticists, pediatric neurologists and neurologists specialized in epileptology and neurophysiology. The ambition of the network was to harmonize and improve the diagnostic strategy of Mendelian epileptic disorders using next-generation sequencing, in France. Over the years, five additional centers have joined EPIGENE and the network has been working in close collaboration, since 2018, with the French reference center for rare epilepsies (CRéER)., Results: Since 2014, biannual meetings have led to the design of four successive versions of a monogenic epilepsy gene panel (PAGEM), increasing from 68 to 144 genes. A total of 4035 index cases with epileptic disorders have been analyzed with a diagnostic yield of 31% (n = 1265/4035). The top 10 genes, SCN1A, KCNQ2, STXBP1, SCN2A, SCN8A, PRRT2, PCDH19, KCNT1, SYNGAP1, and GRIN2A, account for one-sixth of patients and half of the diagnoses provided by the PAGEM., Conclusion: These results suggest that a gene-panel approach is an efficient first-tier test for the genetic diagnosis of Mendelian epileptic disorders. In a near future, French patients with "drug-resistant epilepsies with seizure-onset in the first two-years of life" can benefit from whole-genome sequencing (WGS), as a second line genetic screening with the implementation of the 2025 French Genomic Medicine Plan. The EPIGENE network has also promoted scientific collaborations on genetic epilepsies within CRéER., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

De novo heterozygous missense mutations in TRPM3 have been shown to cause developmental and epileptic encephalopathies (DEE). It is a very rare condition, as only 9 patients have been described to date. We report here a novel patient carrying the recurrent p.Val837Met variant and presenting new clinical features, such as trigonocephaly, expanding the phenotypical spectrum of the disease., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Purpose: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy., Methods: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy., Results: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism., Conclusion: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.

Background and Aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in cholesterol homeostasis. A common variant, the G allele in position c.1420 (c.1420G), has been associated with a decrease of both plasma PCSK9 and LDL-cholesterol concentrations. However, the functional effect of this variant is currently not well understood. We hypothesized that it could be explained by functional variants in linkage disequilibrium (LD), more specifically, by variants located in the PCSK9 3' UTR as targets for miR regulation of PCSK9 expression., Methods: Variations in LD with c.1420G were studied in 1029 patients followed for dyslipidaemia. In silico studies identified potential miRNA binding sites induced by PCSK9 3'UTR variants in LD with c.1420G. Their functionality was studied with a luciferase reporter assay in HuH-7 cells and confirmed by cotransfection of anti-miRNAs., Results: The c.*571C and c.*234T variants located in the PCSK9 3'UTR were found in tight LD with c.1420G (D' = 0.962; LOD = 163.06). The haplotype carrying c.*571C showed a 6.7% decrease in luciferase activity (p = 0.003). Inhibition of hsa-miR-1228-3p and hsa-miR-143-5p counteracted their effect on the haplotype carrying c.*571C allele, suggesting that PCSK9 expression was decreased by the endogenous binding of hsa-miR-1228-3p and hsa-miR-143-5p on its 3'UTR., Conclusions: This post-transcriptional regulation might contribute towards the association between plasma PCSK9 levels and c.1420G. Such regulation of PCSK9 expression may open new perspectives for the treatment of hypercholesterolemia and atherosclerosis cardiovascular diseases., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Mosaic Variegated Aneuploidy Syndrome (MVA) is a rare autosomal recessive disorder characterized by mosaic aneuploidies involving multiple chromosomes and tissues. Affected individuals typically present with severe intrauterine and postnatal growth retardation, microcephaly, facial dysmorphism, developmental delay and predisposition to cancer and epilepsy. Three genes, BUB1B, CEP57 and TRIP13, are involved in this syndrome. Only 7 patients carrying pathogenic variants in CEP57 are reported to date. Here we report two adult brothers born to Moroccan related parents, who presented with intrauterine and postnatal growth retardation, microcephaly, facial dysmorphism, learning disabilities, skeletal anomalies with thumb hypoplasia and dental abnormalities. Both brothers have mosaic variegated aneuploidies on blood karyotype. A previously reported homozygous 11 bp duplication was identified in CEP57 in the two brothers. We propose that a FoSTeS (Fork Stalling and Template Switching) mechanism could be involved in the occurrence of this duplication. This report expands the phenotypical spectrum associated with CEP57 and highlights the interest of blood karyotype in patients presenting with short stature and microcephaly., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

De novo pathogenic variants in the GATAD2B gene have been associated with a syndromic neurodevelopmental disorder (GAND) characterized by severe intellectual disability (ID), impaired speech, childhood hypotonia, and dysmorphic features. Since its first description in 2013, nine patients have been reported in case reports and a series of 50 patients was recently published, which is consistent with the relative frequency of GATAD2B pathogenic variants in public databases. We report the detailed phenotype of 19 patients from various ethnic backgrounds with confirmed pathogenic GATAD2B variants including intragenic deletions. All individuals presented developmental delay with a median age of 2.5 years for independent walking and of 3 years for first spoken words. GATAD2B variant carriers showed very little subsequent speech progress, two patients over 30 years of age remaining non-verbal. ID was mostly moderate to severe, with one profound and one mild case, which shows a wider spectrum of disease severity than previously reported. We confirm macrocephaly as a major feature in GAND (53%). Most common dysmorphic features included broad forehead, deeply set eyes, hypertelorism, wide nasal base, and pointed chin. Conversely, prenatal abnormalities, non-cerebral malformations, epilepsy, and autistic behavior were uncommon. Other features included feeding difficulties, behavioral abnormalities, and unspecific abnormalities on brain MRI. Improving our knowledge of the clinical phenotype is essential for correct interpretation of the molecular results and accurate patient management., (Copyright © 2020. Published by Elsevier Masson SAS.)

Purpose: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts., Methods: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts., Results: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts., Conclusion: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies.

Essentials Some hemophilia B (HB) patients with complete F9 deletion present with intellectual disability (ID). We delineate six F9 complete deletions and investigate genotype/phenotype correlation. We identify SOX3 as a candidate gene for ID, acting through haploinsufficiency, in HB patients. All complete F9 deletions in ID patients should be explored with cytogenetic microarrays., Summary: Background Large deletions encompassing both the complete F9 gene and contiguous genes have been detected in patients with severe hemophilia B (HB). Some of these patients present other clinical features, such as intellectual disability (ID). Objectives/Methods In this study, we characterized six unrelated large deletions encompassing F9, by cytogenetic microarray analysis (CMA), to investigate genotype/phenotype correlation. Results Five of the six patients included in this study presented with ID associated with HB. CMA showed that the six large deletions, ranging in size from approximately 933 kb to 9.19 Mb, were located within the Xq26.3 to Xq28 bands. In all cases, the complete deletion of F9 was associated with the loss of various neighboring genes (5-28 other genes). The smallest region of overlap for ID was a 1.26-Mb region encompassing seven OMIM genes (LOC389895, SOX3, LINC00632, CDR1, SPANXF1, LDOC1, SPANXC). SOX3, our candidate gene for ID, encodes an early transcription factor involved in pituitary development. All of the patients studied who had both HB and ID had deletion of the SOX3 gene. Conclusions All HB patients with an atypical phenotype, especially if complete deletion of F9 is suspected, should be referred to a geneticist for possible pangenomic assessment, because haploinsufficiency of genes flanking F9, such as SOX3 in particular, may result in a broader phenotype, including ID. Such assessment would be of particular value for the genetic counseling of female carriers with F9 deletions, as it would facilitate analysis of the risk of transmitting HB associated with ID., (© 2016 International Society on Thrombosis and Haemostasis.)