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Individuals with biallelic TBCK pathogenic variants present in infancy with distinctive facial features, profound hypotonia, severe intellectual impairment and epilepsy. Although rare, it may mimic other neurogenetic disorders leading to extensive investigations. Improved understanding of the clinical phenotype can support early monitoring of complications due to respiratory insufficiency. We present six individuals who were found to have pathogenic biallelic TBCK variants. The clinico-radiological and diagnostic records were reviewed. Five individuals were diagnosed with hypoventilation, requiring respiratory support, highlighting the need for early respiratory surveillance. Characteristic brain imaging in our cohort included periventricular leukomalacia-like changes. We recommend screening for TBCK in hypotonic children with periventricular leukomalacia-like changes, particularly in the absence of prematurity.

HNRNPU encodes a multifunctional RNA-binding protein that plays critical roles in regulating pre-mRNA splicing, mRNA stability, and translation. Aberrant expression and dysregulation of HNRNPU have been implicated in various human diseases, including cancers and neurological disorders. We applied a next generation sequencing based assay (EPIC-NGS) to investigate genome-wide methylation profiling for > 2M CpGs for 7 individuals with a neurodevelopmental disorder associated with HNRNPU germline pathogenic loss-of-function variants. Compared to healthy individuals, 227 HNRNPU-associated differentially methylated positions were detected. Both hyper- and hypomethylation alterations were identified but the former predominated. The identification of a methylation episignature for HNRNPU-associated neurodevelopmental disorder (NDD) implicates HNPRNPU-related chromatin alterations in the aetiopathogenesis of this disorder and suggests that episignature profiling should have clinical utility as a predictor for the pathogenicity of HNRNPU variants of uncertain significance. The detection of a methylation episignaure for HNRNPU-associated NDD is consistent with a recent report of a methylation episignature for HNRNPK-associated NDD.

Pathogenic variants in heterogeneous nuclear ribonucleoprotein U (HNRNPU) results in a novel neurodevelopmental disorder recently delineated. Here, we report on 17 previously unpublished patients carrying HNRNPU pathogenic variants. All patients were found to harbor de novo loss-of-function variants except for one individual where the inheritance could not be determined, as a parent was unavailable for testing. All patients had seizures which started in early childhood, global developmental delay, intellectual disability, and dysmorphic features. In addition, hypotonia, behavioral abnormalities (such as autistic features, aggression, anxiety, and obsessive-compulsive behaviors), and cardiac (septal defects) and/or brain abnormalities (ventriculomegaly and corpus callosum thinning/agenesis) were frequently observed. We have noted four recurrent variants in the literature (c.1089G>A p.(Trp363*), c.706_707del p.(Glu236Thrfs*6), c.847_857del p.(Phe283Serfs*5), and c.1681dels p.(Gln561Serfs*45)).

This document is written on behalf of the two professional bodies in the United Kingdom that represent genetic counsellors (the Association of Genetic Nurses and Counsellors) and clinical geneticists (the Clinical Genetics Society) and aims to support multidisciplinary working of these professional groups highlighting within a quick-reference format, areas of shared practice and the distinctions between role profiles for a Consultant Clinical Geneticist, Principal/Consultant Genetic Counsellor and the new support role that we have termed ‘Genomic Associate’, see AGNC career structure [1]. This builds on published documents that articulate the scope of practice of the clinical genetics workforce [2] and specifically the genetic counsellor [3] and clinical geneticist [4] roles.

We describe clinical details, including novel findings, of two further children with the newly defined TLK2-related disorder. One patient was recruited to the Deciphering Developmental Delay (DDD) Study to identify underlying etiology of global developmental delay. The other was detected on whole-exome sequencing as part of second line investigations following normal microarray. Both patients were found to have de novo heterozygous pathogenic TLK2 variants. A novel c.6del p.(Glu3Lysfs*) loss-of-function frameshift variant was found in Patient 1. A c.1121+1G>A splice-donor variant was detected in Patient 2. TLK2-related neurodevelopmental disorder is a specific syndrome that has been recently described. Global developmental delay, behavioral problems, gastrointestinal disorders, and typical facial dysmorphism are common features. Neuropsychiatric disorders, ophthalmic, musculoskeletal and cranial abnormalities, as well as short stature, have also all been described. The novel findings we describe include sleep disturbance, nondifferentiation of lateral semi-circular canals (where asymmetric semi-circular canals were a feature in the previous cohort), vesico-ureteric reflux, and bilateral periauricular skin tags. Here, we report a novel TLK2 variant and previously undescribed features of TLK2-related disorder, to expand the clinical phenotype and provide further genotype-phenotype correlation.

Background/ObjectivesIn England, children (0–18 years) with severe, complex and atypical osteogenesis imperfecta (OI) are managed by four centres (Birmingham, Bristol, London, Sheffield) in a ‘Highly Specialised Service’ (HSS OI); affected children with a genetic origin for their disease that is not in COL1A1 or COL1A2 form the majority of the ‘atypical’ group, which has set criteria for entry into the service. We have used the data from the service to assess the range and frequency of non-collagen pathogenic variants resulting in OI in a single country.MethodsChildren with atypical OI were identified through the HSS OI service database. All genetic testing for children with OI in the service were undertaken at the Sheffield Diagnostic Genetics Service. Variant data were extracted and matched to individual patients. This study was done as part of a service evaluation project registered with the Sheffield Children’s Hospital Clinical Governance Department.ResultsOne hundred of 337 children in the HSS met the ‘atypical’ criteria. Eighty have had genetic testing undertaken; 72 had genetic changes detected, 67 in 13 genes known to be causative for OI. The most frequently affected genes were IFITM5 (22), P3H1 (12), SERPINF1 (8) and BMP1 (6).ConclusionAmong children with more severe forms of OI (approximately one-third of all children with OI), around 20% have pathogenic variants in non-collagen genes. IFITM5 was the most commonly affected gene, followed by genes within the P3H1 complex. These data provide additional information regarding the likelihood of different genetic origins of the disease in children with OI, which may influence clinical care.

Background and ObjectivesATP1A3 is associated with a broad spectrum of predominantly neurologic disorders, which continues to expand beyond the initially defined phenotypes of alternating hemiplegia of childhood, rapid-onset dystonia parkinsonism, and cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss syndrome. This phenotypic variability makes it challenging to assess the pathogenicity of an ATP1A3 variant found in an undiagnosed patient. We describe the phenotypic features of individuals carrying a pathogenic/likely pathogenic ATP1A3 variant and perform a literature review of all ATP1A3 variants published thus far in association with human neurologic disease. Our aim is to demonstrate the heterogeneous clinical spectrum of the gene and look for phenotypic overlap between patients that will streamline the diagnostic process.MethodsUndiagnosed individuals with ATP1A3 variants were identified within the cohort of the Deciphering Developmental Disorders study with additional cases contributed by collaborators internationally. Detailed clinical data were collected with consent through a questionnaire completed by the referring clinicians. PubMed was searched for publications containing the term “ATP1A3” from 2004 to 2021.ResultsTwenty-four individuals with a previously undiagnosed neurologic phenotype were found to carry 21 ATP1A3 variants. Eight variants have been previously published. Patients experienced on average 2–3 different types of paroxysmal events. Permanent neurologic features were common including microcephaly (7; 29%), ataxia (13; 54%), dystonia (10; 42%), and hypotonia (7; 29%). All patients had cognitive impairment. Neuropsychiatric diagnoses were reported in 16 (66.6%) individuals. Phenotypes were extremely varied, and most individuals did not fit clinical criteria for previously published phenotypes. On review of the literature, 1,108 individuals have been reported carrying 168 different ATP1A3 variants. The most common variants are associated with well-defined phenotypes, while more rare variants often result in very rare symptom correlations, such as are seen in our study. Combined Annotation-Dependent Depletion (CADD) scores of pathogenic and likely pathogenic variants were significantly higher and variants clustered within 6 regions of constraint.DiscussionOur study shows that looking for a combination of paroxysmal events, hyperkinesia, neuropsychiatric symptoms, and cognitive impairment and evaluating the CADD score and variant location can help identify an ATP1A3-related condition, rather than applying diagnostic criteria alone.

The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.

Contains fulltext : 291387.pdf (Publisher’s version ) (Open Access) De novo truncating and splicing pathogenic variants in the Additional Sex Combs-Like 3 (ASXL3) gene are known to cause neurodevelopmental delay, intellectual disability, behavioral difficulties, hypotonia, feeding problems and characteristic facial features. We previously reported 45 patients with ASXL3-related disorder including three individuals with a familial variant. Here we report the detailed clinical and molecular characteristics of these three families with inherited ASXL3-related disorder. First, a father and son with c.2791_2792del p.Gln931fs pathogenic variant. The second, a mother, daughter and son with c.4534C > T, p.Gln1512Ter pathogenic variant. The third, a mother and her daughter with c.4441dup, p.Leu1481fs maternally inherited pathogenic variant. This report demonstrates intrafamilial phenotypic heterogeneity and confirms heritability of ASXL3-related disorder. 01 januari 2023

SATB2-Associated syndrome (SAS) is an autosomal dominant, multisystemic, neurodevelopmental disorder due to alterations in SATB2 at 2q33.1. A limited number of individuals with 2q33.1 contiguous deletions encompassing SATB2 (ΔSAS) have been described in the literature. We describe 17 additional individuals with ΔSAS, review the phenotype of 33 previously published individuals with 2q33.1 deletions (n=50, mean age=8.5±7.8 years), and provide a comprehensive comparison to individuals with other molecular mechanisms that result in SAS (non-ΔSAS). Individuals in the ΔSAS group were often underweight for age (20/41=49%) with a progressive decline in weight (95% CI=-2.3 to -1.1, p

Enrichment of heterozygous missense and truncating SMAD6 variants was previously reported in nonsyndromic sagittal and metopic synostosis, and interaction of SMAD6 variants with a common polymorphism near BMP2 (rs1884302) was proposed to contribute to inconsistent penetrance. We determined the occurrence of SMAD6 variants in all types of craniosynostosis, evaluated the impact of different missense variants on SMAD6 function, and tested independently whether rs1884302 genotype significantly modifies the phenotype. We performed resequencing of SMAD6 in 795 unsolved patients with any type of craniosynostosis and genotyped rs1884302 in SMAD6-positive individuals and relatives. We examined the inhibitory activity and stability of SMAD6 missense variants. We found 18 (2.3%) different rare damaging SMAD6 variants, with the highest prevalence in metopic synostosis (5.8%) and an 18.3-fold enrichment of loss-of-function variants comparedwith gnomAD data (P

In 2016, guidelines for diagnostic Next Generation Sequencing (NGS) have been published by EuroGentest in order to assist laboratories in the implementation and accreditation of NGS in a diagnostic setting. These guidelines mainly focused on Whole Exome Sequencing (WES) and targeted (gene panels) sequencing detecting small germline variants (Single Nucleotide Variants (SNVs) and insertions/deletions (indels)). Since then, Whole Genome Sequencing (WGS) has been increasingly introduced in the diagnosis of rare diseases as WGS allows the simultaneous detection of SNVs, Structural Variants (SVs) and other types of variants such as repeat expansions. The use of WGS in diagnostics warrants the re-evaluation and update of previously published guidelines. This work was jointly initiated by EuroGentest and the Horizon2020 project Solve-RD. Statements from the 2016 guidelines have been reviewed in the context of WGS and updated where necessary. The aim of these recommendations is primarily to list the points to consider for clinical (laboratory) geneticists, bioinformaticians, and (non-)geneticists, to provide technical advice, aid clinical decision-making and the reporting of the results. This work was supported by the Solve-RD project (European Union’s Horizon 2020 grant agreement No 779257) to MS, SB, OR and CG, and the National Centre for medical genomics (www.ncmg.cz, CZ.02.1.01/0.0/0.0/16_026/000844, LM2018132 (MSMT.cz) and 00064203/6003 (MZCR.cz) to MM). OR received financial support from Illumina for implementing whole genome sequencing into clinical diagnostics (Ge-Med project)

Undiagnosed individuals withTwenty-four individuals with a previously undiagnosed neurologic phenotype were found to carry 21Our study shows that looking for a combination of paroxysmal events, hyperkinesia, neuropsychiatric symptoms, and cognitive impairment and evaluating the CADD score and variant location can help identify an

Objectives\ud \ud Osteogenesis Imperfecta (OI) is a heterogeneous condition mainly characterised by bone fragility; extra-skeletal features in OI include blue sclerae, dentinogenesis imperfecta, skin laxity and joint hyper-extensibility. Most patients with OI are thought to have a low bone mass but contrary to expectations there are certain forms of OI with high bone mass which this study explores in further detail.\ud \ud \ud \ud Method\ud \ud A cohort of n = 6 individuals with pathogenic variants in BMP1 and the C-propeptide cleavage variants in COL1A1 were included in this study. Detailed clinical and radiological phenotyping was done and correlated with genotype to identify patterns of clinical presentation and fracture history in this cohort of patients. This data was compared to previously reported literature in this group.\ud \ud \ud \ud Results\ud \ud 2 patients with BMP1 and 4 patients with pathogenic variants in C-propeptide region in COL1A1 were deep-phenotyped as part of this study and 1 patient with C-propeptide variant in COL1A1, showed low bone mineral density. In those with an elevated bone mineral density, this became even more apparent on bisphosphonate therapy. Patients in this cohort had variable clinical presentation ranging from antenatal presentation to more of an insidious course resulting in later confirmation of genetic diagnosis up to 19 years of age.\ud \ud \ud \ud Conclusions\ud \ud Patients with pathogenic variants in the C-propeptide region of COL1A1/A2 and BMP1 appear to have a high bone mass phenotype with increased sensitivity to bisphosphonate therapy. It is important to closely monitor patients with these genotypes to assess their response to therapy and tailor their treatment regime accordingly.

Vascular Ehlers-Danlos Syndrome (vEDS) and Osteogenesis Imperfecta (OI) are two forms of connective tissue disorders. Previously, transmission electron microscopy of skin biopsies was routinely performed on all patients who were clinically suspected to have vEDS. At present, molecular genetics using genomic DNA extracted from a blood sample is the first line investigation for these patients. However, when variants of uncertain clinical significance are identified on genetic testing and individuals do not have the classical features of OI or vEDS, additional phenotypic information obtained from a skin biopsy can be valuable for contributing to the evidence for re-classifying pathogenicity of variants.We present a cohort of six patients with molecularly confirmed vEDS and one patient with a severe form of OI, who each had expanded (or dilated), protein-filled, rough endoplasmic reticulum identified on transmission electron microscopy. The patients were identified through retrospective screening of medical records, and biopsies were taken between 1999-2016. We discuss the potential role for assessing rough endoplasmic reticulum expansion as a useful tool to allow further phenotyping of these individuals.

BackgroundSecreted protein, acidic, cysteine rich (SPARC)-related osteogenesis imperfecta (OI), also referred to as OI type XVII, was first described in 2015, since then there has been only one further report of this form of OI. SPARC is located on chromosome 5 between bands q31 and q33. The encoded protein is necessary for calcification of the collagen in bone, synthesis of extracellular matrix and the promotion of changes to cell shape.MethodsWe describe a further two patients with previously unreported homozygous SPARC variants with OI: one splice site; one nonsense pathogenic variant. We present detailed information on the clinical and radiological phenotype and correlate this with their genotype. There are only two previous reports by Mendozo-Londono et al and Hayat et al with clinical descriptions of patients with SPARC variants.ResultsFrom the data we have obtained, common clinical features in individuals with OI type XVII caused by SPARC variants include scoliosis (5/5), vertebral compression fractures (5/5), multiple long bone fractures (5/5) and delayed motor development (3/3). Interestingly, 2/4 patients also had abnormal brain MRI, including high subcortical white matter changes, abnormal fluid-attenuated inversion in the para-atrial white matter and a large spinal canal from T10 to L1. Of significance, both patients reported here presented with significant neuromuscular weakness prompting early workup.ConclusionCommon phenotypic expressions include delayed motor development with neuromuscular weakness, scoliosis and multiple fractures. The data presented here broaden the phenotypic spectrum establishing similar patterns of neuromuscular presentation with a presumed diagnosis of ‘myopathy’.

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.\ud \ud \ud We obtained clinical descriptions of sixteen 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.\ud \ud \ud 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.\ud \ud \ud 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.

Osteogenesis imperfecta (OI) is the commonest form of heritable bone fragility. It is mainly characterized by fractures, hearing loss and dentinogenesis imperfecta. OI patients are at increased risk of cardiovascular disease of variable severity. Aortic aneurysm/dissection is one of the rarer but potentially serious cardiovascular complications of OI. So far, only six patients with aortic dissection and OI have been reported. As such, present OI diagnostic guidelines do not recommend systematic screening of patients for aortopathy. Here, we report on the clinical and molecular characteristics of three new OI patients and one additional patient with a first degree relative who presented with aortic dissection and/or aneurysm surgery. This observation further opens up the discussion on the need for and extent of cardiovascular screening in adult patients with OI.

The SRPX2 gene (Sushi-repeat-containing protein, X-linked, 2, OMIM*300642), located on Xq22.1, encodes a secreted protein that is highly expressed in neurons of cerebral cortex. SRPX2 was first implicated in neurodevelopment, learning and rolandic seizure when two patients with potentially pathogenic variants, c.980A>G (p.Asn327Ser) and c.215A>C (p.Tyr72Ser), in SRPX2 gene were identified. Subsequent experimental studies demonstrated that SRPX2 is needed for vocalization and synapse formation in mice, and that both silencing SRPX2 and injecting (p.Asn327Ser) in mouse models results in alteration in neuronal migration in cerebral cortex and epilepsy. A number of studies demonstrated that SRPX2 interacts with FOXP2 (Foxhead box protein P2), a gene responsible for speech and language disorder, and that FoxP2 controls timing and level of expression of SRPX2. Despite the supportive evidence for the role of SRPX2 in speech and language development and disorders, there are questions over its definitive association with neurodevelopmental disorders and epilepsy. In this paper, the role of SRPX2 as one in a network of many genes involved in speech and language is discussed. The goal of this paper is to examine the role of SRPX2 variants through describing two patients with potentially pathogenic variants in SRPX2, c.751G>C (p.Ala251Pro) and c.762G>T (p.Lys254Asn) presenting with language and motor delay, intellectual disability as well as congenital anomalies. We explore the contribution of SRPX2 variants to clinical phenotype in our patients and conclude that these variants at least partially explain the phenotype. Further studies are necessary to establish and confirm the association between SRPX2 and neurodevelopment particularly speech and language development.

Background Congenital disorders of glycosylation (CDG) are a group of rare metabolic diseases due to impaired lipid and protein glycosylation. It comprises a characteristic high frequency of intellectual disability (ID) and a wide range of clinical phenotypes. Objective To identify the underlying diagnosis in two families each with two siblings with variable level of ID through trio whole exome sequencing. Methods Both the families were recruited to the Deciphering Developmental Disorders (DDD) study to identify the aetiology for their ID. Further work-up included isoelectric focusing (IEF) of serum transferrin done to add evidence to the molecular diagnosis. Results These patients were found to have three novel variants in MAN1B1 inherited from their healthy parents. Serum transferrin IEF showed a type 2 pattern. Discussion MAN1B1 variants were initially described in association with non-syndromic ID; subsequent literature suggested that variants in MAN1B1 resulted in a CDG-type II syndrome. However, there remains a paucity of literature on detailed clinical phenotyping and it still remains a rare form of CDG. The present patients showed the phenotype previously reported in MAN1B1-CDG: a characteristic facial dysmorphism, hypotonia, truncal obesity and in some, behavioural problems. Conclusions In unexplained ID, serum transferrin should be included in the first-line screening. With advances in genomic medicine, it is important to diagnose CDG as this has implications for management and recurrence risk counselling.

Marked by incomplete division of the embryonic forebrain, holoprosencephaly is one of the most common human developmental disorders. Despite decades of phenotype-driven research, 80-90% of aneuploidy-negative holoprosencephaly individuals with a probable genetic aetiology do not have a genetic diagnosis. Here we report holoprosencephaly associated with variants in the two X-linked cohesin complex genes, STAG2 and SMC1A, with loss-of-function variants in 10 individuals and a missense variant in one. Additionally, we report four individuals with variants in the cohesin complex genes that are not X-linked, SMC3 and RAD21. Using whole mount in situ hybridization, we show that STAG2 and SMC1A are expressed in the prosencephalic neural folds during primary neurulation in the mouse, consistent with forebrain morphogenesis and holoprosencephaly pathogenesis. Finally, we found that shRNA knockdown of STAG2 and SMC1A causes aberrant expression of HPE-associated genes ZIC2, GLI2, SMAD3 and FGFR1 in human neural stem cells. These findings show the cohesin complex as an important regulator of median forebrain development and X-linked inheritance patterns in holoprosencephaly., National Human Genome Research Institute Intramural Research Program; Dutch Cancer Society (KWF); Netherlands Organisation of Scientific Research (NWO); National Institute of Environmental Health Sciences of the National Institutes of Health

Cutaneous venous malformations frequently present with blue-pink lesions on the skin or mucosal surfaces. They can be problematic for patients who experience pain or unsightly lesions and can also be associated with significant bleeding. A proportion of venous malformations have been noted to occur in families, in particular glomuvenous malformations (GVMs). A ‘two-hit’ occurrence of genetic pathogenic variants appears to explain the appearance of GVMs, with the initial change in the germline copy ofGLMNfollowed by a second somatic hit. Here we discuss a report of siblings experiencing such lesions, which were diagnosed as GVMs by genetic testing. We include a review of the literature regarding the clinical and genetic differences between these groups of venous malformations.

Genetic architecture of developmental disorders The genetics of developmental disorders (DDs) is complex. Martin et al. wanted to determine the degree of recessive inheritance of DDs in protein-coding genes. They examined the exomes of more than 6000 families in populations with high and low proportions of consanguineous marriages. They found that 3.6% of DDs in individuals of European ancestry involved recessive coding disorders, less than a tenth of the levels previously estimated. Furthermore, among South Asians with high parental relatedness, rather than most of the disorders arising from inherited variants, fewer than half had a recessive coding diagnosis. Science , this issue p. 1161

Secreted protein, acidic, cysteine rich (We describe a further two patients with previously unreported homozygousFrom the data we have obtained, common clinical features in individuals with OI type XVII caused byCommon phenotypic expressions include delayed motor development with neuromuscular weakness, scoliosis and multiple fractures. The data presented here broaden the phenotypic spectrum establishing similar patterns of neuromuscular presentation with a presumed diagnosis of 'myopathy'.

Diaphonospondylodysotosis (DSD) and ischiospinal dysostosis (ISD) are rare skeletal dysplasias with variants in the bone morphogenetic protein-binding endothelial regulator (BMPER). There is a continuum of clinical presentation, with DSD at the severe end of the spectrum whilst ISD is towards the milder end. Both are caused due to pathogenic variants in BMPER. Previous studies have reported 20 patients from 13 families. Common features in the cohort reported so far are spinal and rib anomalies but other findings illustrate phenotypic variation. Survival ranges from death within the neonatal period to alive and well at 19 years. We present three siblings with variable phenotype, adding to the evidence for a single definition of BMPER-related skeletal dysplasia. We highlight the need for ongoing care planning and guarded prognostication, with regular review by clinical teams.

Trastornos del espectro autista; Prueba genética Trastorns de l'espectre autista; Prova genètica Autism spectrum disorders; Genetic testing Witteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ 8 years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common. Behaviour problems were reported in a minority. In patients ≥2 years, three were diagnosed with Autism Spectrum Disorder (ASD) and four with Attention Deficit Hyperactivity Disorder (ADHD). We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10–12. Funding for the project was provided by the Wellcome Trust and by grants from the Netherlands Organization for Health Research and Development (ZonMw grant 91718310 and the Dutch Scientific Organization (NWO, grant NWA 1160.18.320). WKC is supported by grants from SFARI and the JPB Foundation

Purpose Biallelic pathogenic NBAS variants manifest as a multisystem disorder with heterogeneous clinical phenotypes such as recurrent acute liver failure, growth retardation, and susceptibility to infections. This study explores how NBAS-associated disease affects cells of the innate and adaptive immune system. Methods Clinical and laboratory parameters were combined with functional multi-parametric immunophenotyping methods in fifteen NBAS-deficient patients to discover possible alterations in their immune system. Results Our study revealed reduced absolute numbers of mature CD56dim natural killer (NK) cells. Notably, the residual NK cell population in NBAS-deficient patients exerted a lower potential for activation and degranulation in response to K562 target cells, suggesting an NK cell–intrinsic role for NBAS in the release of cytotoxic granules. NBAS-deficient NK cell activation and degranulation was normalized upon pre-activation by IL-2 in vitro, suggesting that functional impairment was reversible. In addition, we observed a reduced number of naïve B cells in the peripheral blood associated with hypogammaglobulinemia. Conclusion In summary, we demonstrate that pathogenic biallelic variants in NBAS are associated with dysfunctional NK cells as well as impaired adaptive humoral immunity.

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Objectives\ud \ud This study sought to identify the clinical and biochemical characteristics that would help distinguish hypophosphatasia (HPP) from other metabolic bone diseases in adult patients attending a metabolic bone clinic by comparing patients who have genetically confirmed HPP with a group of patients with low bone mineral density (BMD) in the osteoporotic or osteopenic range.\ud \ud \ud Methods\ud \ud Data were collected from February 2016 to October 2018 for 41 patients (n = 20 in the HPP group, n = 21 in the low-BMD group) attending the metabolic bone clinic at Sheffield, United Kingdom (UK) or who were recruited via the Rare UK Diseases Study (RUDY) platform during the same period. A study questionnaire was administered to all patients, and assessments were conducted for laboratory values, physical functions, BMD, and spine imaging.\ud \ud \ud Results\ud \ud Patients with HPP were characterized as being younger, more likely to have metatarsal or femoral shaft fractures, and less likely to have vertebral fractures compared with patients in the low-BMD group. The HPP group had lower total and bone-specific alkaline phosphatase, higher pyridoxal 5′-phosphate (PLP), and lower, albeit sufficient, 25-hydroxyvitamin D. Low-BMD group had lower C-terminal telopeptide and tartrate-resistant acid phosphatase 5b (61.9% were on bisphosphonates at enrollment). Dual X-ray absorptiometry (DXA) analysis found that the HPP group had higher total hip and lumbar BMD T- and Z-scores compared with the low-BMD group. There were no differences found between the two groups with physical functional assessments. Results of receiver operating characteristic analysis indicated strong diagnostic accuracy of these biomarkers for HPP. Thresholds of total alkaline phosphatase (ALP) activity of 43 IU/L or less and PLP level of 120 nmol/L or more were determined to be potentially clinically useful for distinguishing HPP from other metabolic bone diseases.\ud \ud \ud Conclusion\ud \ud This study supported the use of ALP and PLP measurements as predictive of HPP diagnosis along with certain demographic and clinical characteristics (younger age, metatarsal or femoral fractures without low mean BMD T- and Z-scores on a DXA scan) that can aid in recognizing adults who should be further evaluated for HPP. The critical values identified need to be applied to an independent sample to be tested for diagnostic accuracy.

Pathogenic variants in ZMYND11, which acts as a transcriptional repressor, have been associated with intellectual disability, behavioural abnormalities and seizures. Only 11 affected individuals have been reported to‐date, and the phenotype associated with pathogenic variants in this gene have not been fully defined.\ud \ud Here, we present 16 additional patients with predicted pathogenic heterozygous variants in ZMYND11, including four individuals from the same family, to further delineate and expand the genotypic and phenotypic spectrum of ZMYND11‐related syndromic intellectual disability. The associated phenotype includes developmental delay, particularly affecting speech, mild‐moderate intellectual disability, significant behavioural abnormalities, seizures, and hypotonia. There are subtle shared dysmorphic features, including prominent eyelashes and eyebrows, depressed nasal bridge with bulbous nasal tip, anteverted nares, thin vermilion of the upper lip and wide mouth. Novel features include brachydactyly and tooth enamel hypoplasia.\ud \ud Most identified variants are likely to result in premature truncation and/or nonsense mediated decay. Two ZMYND11 variants located in the final exon ‐ p.(Gln586*) (likely escaping nonsense‐mediated decay) and p.(Cys574Arg) ‐ are predicted to disrupt the MYND‐type zinc finger motif and likely interfere with binding to its interaction partners. Hence, the homogeneous phenotype likely results from a common mechanism of loss‐of‐function.

RAD21 encodes a key component of the cohesin complex, and variants in RAD21 have been associated with Cornelia de Lange Syndrome (CdLS). Limited information on phenotypes attributable to RAD21 variants and genotype–phenotype relationships is currently published. We gathered a series of 49 individuals from 33 families with RAD21 alterations [24 different intragenic sequence variants (2 recurrent), 7 unique microdeletions], including 24 hitherto unpublished cases. We evaluated consequences of 12 intragenic variants by protein modelling and molecular dynamic studies. Full clinical information was available for 29 individuals. Their phenotype is an attenuated CdLS phenotype compared to that caused by variants in NIPBL or SMC1A for facial morphology, limb anomalies, and especially for cognition and behavior. In the 20 individuals with limited clinical information, additional phenotypes include Mungan syndrome (in patients with biallelic variants) and holoprosencephaly, with or without CdLS characteristics. We describe several additional cases with phenotypes including sclerocornea, in which involvement of the RAD21 variant is uncertain. Variants were frequently familial, and genotype–phenotype analyses demonstrated striking interfamilial and intrafamilial variability. Careful phenotyping is essential in interpreting consequences of RAD21 variants, and protein modeling and dynamics can be helpful in determining pathogenicity. The current study should be helpful when counseling families with a RAD21 variation., Spanish Ministry of Science, Innovation and Universities/State Research Agency RTC-2017-6494-1 and RTI2018-094434-B-I00 (MCIU/AEI/FEDER, UE) as well as funds from the European JPIAMR-VRI network “CONNECT” to PG-P

De novo pathogenic variants in the additional sex combs-like 3 (ASXL3) gene cause a rare multi-systemic neurodevelopmental disorder. There is growing evidence that germline and somatic mosaicism are more common and play a greater role in genetic disorders than previously acknowledged. There is one previous report of ASXL3-related syndrome caused by de novo pathogenic variants in two siblings suggesting gonadal mosaicism. In this report, we present five patients with ASXL3-related syndrome, describing two families comprising two non-twin siblings harbouring apparent de novo pathogenic variants in ASXL3. Parents were clinically unaffected and there was no evidence of mosaicism from genomic DNA on exome-trio data, suggesting germline mosaicism in one of the parents. We also describe clinical details of a patient with typical features of ASXL3-related syndrome and mosaic de novo pathogenic variant in ASXL3 in 30-35% of both blood and saliva sample on trio-exome sequencing. We expand the known genetic basis of ASXL3-related syndromes and discuss mosaicism as a disease mechanism in five patients from three unrelated families. The findings of this report highlight the importance of taking gonadal mosaicism into consideration when counselling families regarding recurrence risk. We also discuss postzygotic mosaicism as a cause of fully penetrant ASXL3-related syndrome.

We aim to further delineate the phenotype associated with pathogenic variants in the SLC35A2 gene, and review all published literature to-date. This gene is located on the X chromosome and encodes a UDP-galactose transporter. Pathogenic variants in SLC35A2 cause a congenital disorder of glycosylation. The condition is rare, and less than twenty patients have been reported to-date. The phenotype is complex and has not been fully defined. Here, we present a series of five patients with de novo pathogenic variants in SLC35A2. The patients' phenotype includes developmental and epileptic encephalopathy with hypsarrhythmia, facial dysmorphism, severe intellectual disability, skeletal abnormalities, congenital cardiac disease and cortical visual impairment. Developmental and epileptic encephalopathy with hypsarrhythmia is present in most patients with SLC35A2 variants, and is drug-resistant in the majority of cases. Adrenocorticotropic hormone therapy may achieve partial or complete remission of seizures, but the effect is usually temporary. Isoelectric focusing of transferrins may be normal after infancy, therefore a congenital disorder of glycosylation should still be considered as a diagnosis in the presence of a suggestive phenotype. We also provide evidence that cortical visual impairment is part of the phenotypic spectrum. (C) 2018 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Background With increased access to genetic testing, variants of uncertain significance (VUS) where pathogenicity is uncertain are being increasingly identified. More than 85% Osteogenesis Imperfecta (OI) patients have pathogenic variants in COL1A1/A2. However, when a VUS is identified, there are no pathways in place for determining significance. Objective Define a diagnostic pathway to confirm pathogenicity, providing patients with definitive genetic diagnosis, accurate recurrence risks, and prenatal testing options. Methods Functional studies on collagen secretion from cultured patient fibroblasts combined with detailed phenotyping and segregation family studies. Results We demonstrate data from a family with a VUS identified in type I collagen. Family‐1 Six‐year‐old boy with failure‐to‐gain weight, talipes, fractures, on and off treatment with Pamidronate as diagnosis of OI uncertain. Transiliac bone biopsy at 2 years of age demonstrated active new bone formation within periosteum; bone cortices were normal thickness but increased porosity. Trabecular bone showed features of advanced osteoporosis. Genetic testing identified a de novo COL1A1 c.206_208delTGT, p.Leu69del variant. Sibling with similar phenotype but no fractures as yet, tested positive for variant raising concerns regarding her diagnosis, and management. Results from three independent experiments (cell immunofluorescence, collagen secretion assay by Western Blot, and unbiased proteomics) from cultured patient fibroblasts demonstrate COL1A1 c.206_208delTGT, p.Leu69del variant causing a substantial defect to collagen extracellular matrix assembly confirming variant pathogenicity. Conclusion Access to genetic testing in OI is increasing as advances in genetic technologies decreases cost; a clinical diagnostic pathway needs to be implemented for managing variants identified by such testing., Inherited bone fragility disorders, of which Osteogenesis Imperfecta (OI) is the commonest, are rare (1 in 15,000). In this study, we defined ways to clarify pathogenicity of a variant of uncertain significance leading to bone fragility using advanced sequencing technologies and to characterize the biological consequences of these mutations using advanced molecular cell biology.