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Chromatinopathy; Syndromic neurodevelopmental disorder; Syndromic obesity Cromatinopatia; Trastorn sindròmic del neurodesenvolupament; Obesitat sindròmica Cromatinopatía; Trastorno sindrómico del neurodesarrollo; Obesidad sindrómica Purpose Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyzes the methylation of arginine residues on several protein substrates. Biallelic pathogenic PRMT7 variants have previously been associated with a syndromic neurodevelopmental disorder characterized by short stature, brachydactyly, intellectual developmental disability, and seizures. To our knowledge, no comprehensive study describes the detailed clinical characteristics of this syndrome. Thus, we aim to delineate the phenotypic spectrum of PRMT7-related disorder. Methods We assembled a cohort of 51 affected individuals from 39 different families, gathering clinical information from 36 newly described affected individuals and reviewing data of 15 individuals from the literature. Results The main clinical characteristics of the PRMT7-related syndrome are short stature, mild to severe developmental delay/intellectual disability, hypotonia, brachydactyly, and distinct facial morphology, including bifrontal narrowing, prominent supraorbital ridges, sparse eyebrows, short nose with full/broad nasal tip, thin upper lip, full and everted lower lip, and a prominent or squared-off jaw. Additional variable findings include seizures, obesity, nonspecific magnetic resonance imaging abnormalities, eye abnormalities (i.e., strabismus or nystagmus), and hearing loss. Conclusion This study further delineates and expands the molecular, phenotypic spectrum and natural history of PRMT7-related syndrome characterized by a neurodevelopmental disorder with skeletal, growth, and endocrine abnormalities. The authors thank all patients and families for participation in this study. Part of this research was possible thanks to the Deciphering Developmental Disorders study. The Deciphering Developmental Disorders study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003). This study makes use of DECIPHER (http://www.deciphergenomics.org), which is funded by Wellcome. See www.ddduk.org/access.html for full acknowledgment. This study was also supported by the Wellcome Trust (WT093205MA and WT104033AIA to H.H. and 203141/Z/16/Z to M.P.F. and J.C.T.), Medical Research Council (H.H.), European Community’s Seventh Framework Programme (FP7/2007-2013, under grant agreement No. 2012-305121 to H.H.), the National Institute for Health Research (NIHR), University College London Hospitals, Biomedical Research Centre, and Fidelity Foundation. The Yale Center for Mendelian Genomics (UM1HG006504) is funded by the National Human Genome Research Institute. D.B. is supported by NIHR Research Professorship (RP-2016-07-011). F.L. and A.G. received funding from European Union and Région Normandie in the context of Recherche Innovation Normandie 2018. Europe gets involved in Normandie with the European Regional Development Fund. The authors thank the families and KFMC Research Centre for the partial support (Intramural Research Fund; Demography of Recessive Diseases in KSA; Grant No. 019-052). This work was also supported by King Salman Center for Disability research through Research Group RG-2022-010.

Colombia has a high prevalence of mucopolysaccharidosis (MPS) type IVA. Nevertheless, data regarding the mutation spectrum for MPS IVA in this population have not been completely characterized. Forty-seven families and 53 patients from seven different Colombian regions were tested for MPS IVA mutations. We compared the sequences with the N-acetylgalactosamine-6-sulfatase (GALNS) reference sequence NM_000512.4, and gene variants were reported. Bioinformatics analysis was performed using SWISS-MODEL. The mutant proteins were generated by homology from the wild-type GALNS 4FDJ template obtained from the PDB database, and visualization was performed using Swiss-PDBViewer and UCSF Chimera. The predictive analysis was run using different bioinformatic tools, and the deleterious annotation of genetic variants was performed using a neural network. We found that 79% and 21% of the cohort was homozygous and compound heterozygous, respectively. The most frequent mutation observed was p.Gly301Cys (78.3% of alleles), followed by p.Arg386Cys (10.4% of alleles). A novel mutation (p.Phe72Ile) was described and classified in silico as a pathogenic variant. This study reveals the mutation spectrum of MPS IVA in Colombia. The high prevalence of the p.Gly301Cys mutation suggests a founder effect of this variant in the Colombian population that causes diseases in the Andean region (via migration). These data can facilitate genetic counseling, prenatal diagnosis, and the design of therapeutic interventions.

Purpose: The human chromosome 19q13.11 deletion syndrome is associated with a variable phenotype that includes aplasia cutis congenita (ACC) and ectrodactyly as specific features. UBA2 (ubiquitin-like modifier-activating enzyme 2) lies adjacent to the minimal deletion overlap region. We aim to define the UBA2-related phenotypic spectrum in humans and zebrafish due to sequence variants and to establish the mechanism of disease. Methods: Exome Sequencing was used to detect UBA2 sequence variants in 16 subjects in 7 unrelated families. uba2 loss-of-function was modeled in zebrafish. Effects of human missense variants were assessed in zebrafish rescue experiments. Results: 7 human UBA2 loss-of-function and missense sequence variants were detected. UBA2-phenotypes included ACC, ectrodactyly, neurodevelopmental abnormalities, ectodermal, skeletal, craniofacial, cardiac, renal, and genital anomalies. uba2 was expressed in zebrafish eye, brain, and pectoral fins; uba2-null fish showed deficient growth, microcephaly, microphthalmia, mandibular hypoplasia, and abnormal fins. uba2-mRNAs with human missense variants failed to rescue nullizygous zebrafish phenotypes. Conclusion: UBA2 variants cause a recognizable syndrome with a wide phenotypic spectrum. Our data suggest that loss of UBA2 function underlies the human UBA2 monogenic disorder and highlights the importance of SUMOylation in the development of affected tissues.

Transformer2 proteins (Tra2α and Tra2β) control splicing patterns in human cells, and no human phenotypes have been associated with germline variants in these genes. The aim of this work was to associate germline variants in the TRA2B gene to a novel neurodevelopmental disorder.Twelve individuals from 11 unrelated families who had predicted loss-of-function monoallelic variants, mostly de novo, were recruited. RNA-seq and Western blot analyses of Tra2β-1 and Tra2β-3 isoforms from patient-derived cells were performed. Tra2β1-GFP, Tra2β3-GFP and CHEK1 exon 3 plasmids were transfected into HEK-293 cells.All variants clustered in the 5' part of TRA2B, upstream of an alternative translation start site responsible for the expression of non-canonical Tra2β-3 isoform. All of affected individuals presented intellectual disability and/or developmental delay, frequently associated with infantile spasms, microcephaly, brain anomalies, autism spectrum disorder, feeding difficulties, and short stature. Experimental studies showed that these variants decreased the expression of the canonical Tra2β-1 isoform, while they increased the expression of the Tra2β-3 isoform, which is shorter and lacks the N-terminal RS1 domain. Increased expression of Tra2β-3-GFP were shown to interfere with the incorporation of CHEK1 exon 3 into its mature transcript, normally incorporated by Tra2β-1.Predicted loss-of-function variants clustered in the 5' portion of TRA2B cause a new neurodevelopmental syndrome through an apparently dominant negative disease mechanism involving the use of an alternative translation start site and the overexpression of a shorter, repressive Tra2β protein.

Patients with Anderson-Fabry disease (AFD) have an elevated incidence of resting arrhythmias and ischemic heart disease, but their exercise arrhythmia burden and ischemic changes are not well understood. In addition, little research has been done on heart rate recovery in these patients. We retrospectively reviewed charts of patients with AFD who underwent maximal effort cardiopulmonary exercise testing (CPET) (n=44; 38.2 ± 13.8 yr; 23 men) from 2012 through 2018. Electrocardiographic, Holter monitoring, echocardiographic, cardiac magnetic resonance imaging, and patient demographic data were collected. No patient had adverse events that necessitated CPET termination, whereas 25 (57%) had ectopy during CPET, including 3 (7%) with frequent premature atrial contractions and 5 (11%) with frequent premature ventricular contractions. The ectopic burden was higher during resting electrocardiographic monitoring before exercise. In addition, 7 patients (16%) had pathologic ST-segment or T-wave changes on CPET, defined as ST-segment changes ≥2 mm. Among the patients who had concurrent cardiac magnetic resonance findings with their CPET (n=27), ST-segment or T-wave changes were associated with left ventricular myocardial mass (r=0.43, P=0.02). Chronotropic incompetence was seen during CPET in 28 patients (64%); however, only 2 patients (4%) had abnormal heart rate recovery at 1 minute. This study shows that patients with AFD can safely undergo exercise testing but have a high incidence of exercise-induced arrhythmias and ischemic changes. Ischemic electrocardiographic changes during exercise testing are associated with myocardial mass. Despite the chronotropic incompetence associated with AFD, heart rate recovery appears to be generally preserved in these patients.

The MAPK pathway is a major growth signal that has been implicated during the development of progenitors, neurons, and glia in the embryonic brain. Here, we show that the MAPK pathway plays an important role in the generation of distinct cell types from progenitors in the ventral telencephalon. Our data reveal that phospho-p44/42 (called p-ERK1/2) and the ETS transcription factor Etv5, both downstream effectors in the MAPK pathway, show a regional bias in expression during ventral telencephalic development, with enriched expression in the dorsal region of the LGE and ventral region of the MGE at E13.5 and E15.5. Interestingly, expression of both factors becomes more uniform in ventricular zone (VZ) progenitors by E18.5. To gain insight into the role of MAPK activity during progenitor cell development, we used a cre inducible constitutively active MEK1 allele (Rosa(MEK1DD/+)) in combination with a ventral telencephalon enriched cre (Gsx2e-cre) or a dorsal telencephalon enriched cre (Emx1(cre/+)). Sustained MEK/MAPK activity in the ventral telencephalon (Gsx2e-cre; Rosa(MEK1DD/+)) expanded dorsal lateral ganglionic eminence (dLGE) enriched genes (Gsx2 and Sp8) and oligodendrocyte progenitor cell (OPC) markers (Olig2, Pdgfrα, and Sox10), and also reduced markers in the ventral (v) LGE domain (Isl1 and Foxp1). Activation of MEK/MAPK activity in the dorsal telencephalon (Emx1(cre/+); Rosa(MEK1DD/+)) did not initially activate the expression of dLGE or OPC genes at E15.5 but ectopic expression of Gsx2 and OPC markers were observed at E18.5. These results support the idea that MAPK activity as readout by p-ERK1/2 and Etv5 expression is enriched in distinct subdomains of ventral telencephalic progenitors during development. In addition, sustained activation of the MEK/MAPK pathway in the ventral or dorsal telencephalon influences dLGE and OPC identity from progenitors.

We performed an observational cohort study to assess associations between genetic factors of dengue fever (DF) severity in children in the Dominican Republic. A total of 488 participants had serologically confirmed DF. We replicated the association between the IFIH1 gene (rs1990760) and severe DF (n = 80/488, p = 0.006) and identified novel associations needing further investigation.

Background: Valvar pulmonary stenosis (vPS) accounts for 8% to 12% of congenital heart disease cases. Multiple genetic syndromes are associated with vPS, most commonly Noonan syndrome, but the cause is unknown in most cases. We analyzed genomic data from a large cohort with vPS to determine the prevalence of genetic diagnosis. Methods: The Pediatric Cardiac Genomics Consortium database was queried to identify probands with vPS without complex congenital heart disease or aneuploidy and with existing whole exome or genome sequencing. A custom analysis workflow was used to identify likely pathogenic or pathogenic variants in disease-associated genes. Demographic and phenotypic characteristics were compared between groups with and without molecular diagnoses. Results: Data from 119 probands (105 trios) were included. A molecular diagnosis was identified in 22 (18%); 17 (14%) had Noonan syndrome or a related disorder. Extracardiac and neurodevelopmental comorbidities were seen in 67/119 (56%) of probands. Molecular diagnosis was more common in those with extracardiac and neurodevelopmental phenotypes than those without (18/67 versus 4/52, P =0.0086). Conclusions: Clinicians should have high suspicion for a genetic diagnosis in individuals with vPS, particularly if additional phenotypes are present. Our results suggest that clinicians should consider offering sequencing of at least the known congenital heart disease and RASopathy genes to all individuals with vPS, regardless of whether that individual has extracardiac or neurodevelopmental phenotypes present.

Protein phosphatase 2A (PP2A) is a heterotrimeric serine/threonine phosphatase that regulates numerous biological processes. PPP2R1A encodes the scaffolding "Aα" subunit of PP2A. To date, nearly 40 patients have been previously reported with 19 different pathogenic PPP2R1A variants, with phenotypes including intellectual disability, developmental delay, epilepsy, infant agenesis/dysgenesis of the corpus callosum, and dysmorphic features. Apart from a single case, severe congenital heart defects (CHD) have not been described. We report four new unrelated individuals with pathogenic heterozygous PPP2R1A variants and CHD and model the crystal structure of several variants to investigate mechanisms of phenotype disparity. Individuals 1 and 2 have a previously described variant (c.548GA, p.R183Q) and similar phenotypes with severe ventriculomegaly, agenesis/dysgenesis of the corpus callosum, and severe CHD. Individual 3 also has a recurrent variant (c.544CT, p.R182W) and presented with agenesis of corpus callosum, ventriculomegaly, mild pulmonic stenosis, and small patent foramen ovale. Individual 4 has a novel variant (c.536CA, p.P179H), ventriculomegaly, and atrial septal defect. To conclude, we propose expansion of the phenotype of PPP2R1A neurodevelopmental disorder to include CHD. Further, the R183Q variant has now been described in three individuals, all with severe neurologic abnormalities, severe CHD, and early death suggesting that this variant may be particularly deleterious.

Intracardiac rhabdomyoma is the most common primary cardiac tumor in children. Most cases are associated with tuberous sclerosis complex (TSC). Most of them are asymptomatic in the neonate and do not require treatment. However, some develop cardiovascular symptoms such as arrhythmias, heart failure, and ventricular inflow/outflow tract obstruction in the neonatal period with early death. Many of these tumors are not candidates for surgical resection and medical management is limited. Treatment with mammalian target of rapamycin (mTOR) inhibitor is currently approved for the management of central nervous tumors and angiomyolipoma in TSC. Two patients with malignant arrhythmias related to nonsurgical multiple rhabdomyomas associated with TSC who were successfully treated with an mTOR inhibitor were described. Everolimus therapy showed significant regression of rhabdomyomas with rapid improvement of arrhythmias and heart failure prior to tumor shrinkage.

While >300 disease-causing variants have been identified in the mitochondrial DNA (mtDNA) polymerase γ, no mitochondrial phenotypes have been associated with POLRMT, the RNA polymerase responsible for transcription of the mitochondrial genome. Here, we characterise the clinical and molecular nature of POLRMT variants in eight individuals from seven unrelated families. Patients present with global developmental delay, hypotonia, short stature, and speech/intellectual disability in childhood; one subject displayed an indolent progressive external ophthalmoplegia phenotype. Massive parallel sequencing of all subjects identifies recessive and dominant variants in the POLRMT gene. Patient fibroblasts have a defect in mitochondrial mRNA synthesis, but no mtDNA deletions or copy number abnormalities. The in vitro characterisation of the recombinant POLRMT mutants reveals variable, but deleterious effects on mitochondrial transcription. Together, our in vivo and in vitro functional studies of POLRMT variants establish defective mitochondrial transcription as an important disease mechanism., POLRMT is key for transcription of the mitochondrial genome, yet has not been implicated in mitochondrial disease to date. Here, the authors identify mutations in POLRMT in individuals with mitochondrial disease-related phenotypes and characterise underlying defects in mitochondrial transcription.

We describe 10 females with ornithine transcarbamylase (OTC) deficiency and liver dysfunction, revealing a unique pattern of hepatocyte injury in which initial hyperammonemia and coagulopathy is followed by a delayed peak in aminotransferase levels. None of the patients required urgent liver transplantation, though five eventually underwent transplant for recurrent metabolic crises. We intend that this novel observation will initiate further investigations into the pathophysiology of liver dysfunction in OTC-deficient patients, and ultimately lead to the development of therapies and prevent the need for liver transplant.

Our aim was to characterize the phenotype and genotype of individuals with Noonan syndrome in Colombia. There are published cohorts of Noonan individuals from several countries in Latin America including Brazil, Chile, and Argentina, but none from Colombia. We described 26 individuals with NS from a single large referral center in the South West of Colombia using an established database in the genetics department and hospital records search using ICD-10 codes. All patients included in this study were evaluated by a medical geneticist and have molecular confirmation of NS diagnosis. The median age at referral was 3.5 years (range, 0-39), and at molecular diagnosis was 5 years (range, 0-40). Patients mostly originated from the southwest region of Colombia (19/26, 73%). Pathogenic variants in PTPN11 are the most common cause of NS in Colombian individuals followed by SHOC2 and SOS1 variants. The prevalence of cardiomyopathy was low in this population compared to other populations. Further research is needed with a larger sample size and including different regions of Colombia to correlate our findings. This study provides new information about time to diagnosis of NS in Colombia, genotypes, and provides important information to help develop guidelines for diagnosis and management of this disease in the region.

Autosomal dominant variants in LDB3 (also known as ZASP), encoding the PDZ-LIM domain-binding factor, have been linked to a late onset phenotype of cardiomyopathy and myofibrillar myopathy in humans. However, despite knockout mice displaying a much more severe phenotype with premature death, bi-allelic variants in LDB3 have not yet been reported. Here we identify biallelic loss-of-function variants in five unrelated cardiomyopathy families by next generation sequencing. In the first family we identified compound heterozygous LOF variants in LDB3 in a fetus with bilateral talipes and mild left cardiac ventricular enlargement. Ultra-structural examination revealed highly irregular Z-disc formation, and RNA analysis demonstrated little/no expression of LDB3 protein with a functional C-terminal LIM domain in muscle tissue from the affected fetus. In a second family a homozygous LDB3 nonsense variant was identified in a young girl with severe early onset dilated cardiomyopathy with left ventricular non compaction; the same homozygous nonsense variant was identified in a third unrelated female infant with dilated cardiomyopathy. We further identified homozygous LDB3 frameshift variants in two unrelated probands diagnosed with cardiomegaly and severely reduced left ventricular ejection fraction. Our findings demonstrate that recessive LDB3 variants can lead to an early-onset severe human phenotype of cardiomyopathy and myopathy, reminiscent of the knockout mouse phenotype, and supporting a loss of function mechanism.

Zinc-finger nuclease (ZFN)-based in vivo genome editing is a novel treatment that can potentially provide lifelong protein replacement with single intravenous administration. Three first-in-human open-label ascending single-dose phase 1/2 studies were performed in parallel (starting November 2017) primarily to assess safety and tolerability of ZFN in vivo editing therapy in mucopolysaccharidosis I (MPS I) (n = 3), MPS II (n = 9), and hemophilia B (n = 1). Treatment was well tolerated with no serious treatment-related adverse events. At the 1e13 vg/kg dose, evidence of genome editing was detected through albumin-transgene fusion transcripts in liver for MPS II (n = 2) and MPS I (n = 1) subjects. The MPS I subject also had a transient increase in leukocyte iduronidase activity to the lower normal range. At the 5e13 vg/kg dose, one MPS II subject had a transient increase in plasma iduronate-2-sulfatase approaching normal levels and one MPS I subject approached mid-normal levels of leukocyte iduronidase activity with no evidence of genome editing. The hemophilia B subject was not able to decrease use of factor IX concentrate; genome editing could not be assessed. Overall, ZFN in vivo editing therapy had a favorable safety profile with evidence of targeted genome editing in liver, but no long-term enzyme expression in blood.

Nearly half of all human proteins are acetylated at their N-termini by the NatA N-terminal acetyltransferase complex. NAA10 is evolutionarily conserved as the catalytic subunit of NatA in complex with NAA15, but may also have NatA-independent functions. Several NAA10 variants are associated with genetic disorders. The phenotypic spectrum includes developmental delay, intellectual disability, and cardiac abnormalities. Here, we have identified the previously undescribed NAA10 c.303C>A and c.303C>G p.(N101K) variants in two unrelated girls. These girls have developmental delay, but they both also display hemihypertrophy a feature normally not observed or registered among these cases. Functional studies revealed that NAA10 p.(N101K) is completely impaired in its ability to bind NAA15 and to form an enzymatically active NatA complex. In contrast, the integrity of NAA10 p.(N101K) as a monomeric acetyltransferase is intact. Thus, this NAA10 variant may represent the best example of the impact of NatA mediated N-terminal acetylation, isolated from other potential NAA10-mediated cellular functions and may provide important insights into the phenotypes observed in individuals expressing pathogenic NAA10 variants.

Acrodysostosis refers to a rare heterogeneous group of bone dysplasias that share skeletal features, hormone resistance, and intellectual disability. Two genes have been associated with acrodysostosis with or without hormone resistance (PRKAR1A and PDE4D). Severe intellectual disability has been reported with acrodysostosis but brain malformations and ichthyosis have not been reported in these syndromes. Here we describe a female patient with acrodysostosis, intellectual disability, cerebellar hypoplasia, and lamellar ichthyosis. The patient has an evolving distinctive facial phenotype and childhood onset ataxia. X-rays showed generalized osteopenia, shortening of middle and distal phalanges, and abnormal distal epiphysis of the ulna and radius. Brain magnetic resonance imaging showed cerebellar atrophy without other brainstem abnormalities. Genetic workup included nondiagnostic chromosomal microarray and skeletal dysplasia molecular panels. These clinical findings are different from any recognized form of acrodysostosis syndrome. Whole exome sequencing did not identify rare or predicted pathogenic variants in genes associated with known acrodysostosis, lamellar ichthyosis, and other overlapping disorders. A broader search for rare alleles absent in healthy population databases and controls identified two heterozygous truncating alleles in FBNL7 and PPM1M genes, and one missense allele in the NPEPPS gene. Identification of additional patients is required to delineate the mechanism of this unique disorder.

Heterozygous de novo or inherited gain-of-function mutations in the MTOR gene cause Smith-Kingsmore Syndrome (SKS). SKS is a rare autosomal dominant condition, and individuals with SKS display macrocephaly/megalencephaly, developmental delay, intellectual disability, and seizures. A few dozen individuals are reported in the literature. Here, we report a cohort of 28 individuals with SKS that represent 9 new MTOR pathogenic variants, including p.R1480_C1483del or Δ(R1480-C1483). We conducted a detailed natural history study on these patients and found prevalent pathophysiological deficits among SKS individuals, in addition to the common neurodevelopmental symptoms. The new symptoms include sleep-wake disturbance, hyperphagia, and hyperactivity, which are indicative of homeostatic imbalance. To better characterize SKS variants, we developed MTOR mutant cellular models and performed biochemical and cellular circadian rhythm assays to study the variants. We showed that these SKS alleles display a range of MTOR activities under nutrient-deficient basal conditions and respond to MTOR inhibitors differently. For example, Δ(R1480-C1483) is more active than the classic SKS variant C1483F and less responsive to MTOR inhibition by rapamycin. Further, we showed that optimal MTOR activity, important for metabolic and protein homeostasis, is required for normal circadian function. These data can help guide treatment strategies. As SKS is caused by gain of function mutations in MTOR, we used rapamycin to treat several patients. While higher doses caused delayed sleep-wake phase disorder, lower doses improved not only sleep but also aggression and repetitive behaviors. Thus, our study expands both the clinical and molecular spectrum of SKS and offers treatment options guided by molecular and sleep/wake data to improve both cognitive and non-cognitive homeostatic functions.

Gaucher disease (GD) is an autosomal recessive inherited lysosomal storage disease that often presents in early childhood and is associated with damage to multiple organ systems. Many challenges associated with GD diagnosis and management arise from the considerable heterogeneity of disease presentations and natural history. Phenotypic classification has traditionally been based on the absence (in type 1 GD) or presence (in types 2 and 3 GD) of neurological involvement of varying severity. However, patient management and prediction of prognosis may be best served by a dynamic, evolving definition of individual phenotype rather than by a rigid system of classification. Patients may experience considerable delays in diagnosis, which can potentially be reduced by effective screening programs; however, program implementation can involve ethical and practical challenges. Variation in the clinical course of GD and an uncertain prognosis also complicate decisions concerning treatment initiation, with differing stakeholder perspectives around efficacy and acceptable cost/benefit ratio. We review the challenges faced by physicians in the diagnosis and management of GD in pediatric patients. We also consider future directions and goals, including acceleration of accurate diagnosis, improvements in the understanding of disease heterogeneity (natural history, response to treatment, and prognosis), the need for new treatments to address unmet needs for all forms of GD, and refinement of the tools for monitoring disease progression and treatment efficacy, such as specific biomarkers.

Summary We report seven affected individuals from six families with a recurrent, de novo variant in the ARPC4 gene (c.472C>T [p.Arg158Cys (GenBank: NM_005718.4)]). Core features in affected individuals include microcephaly, mild motor delays, and significant speech impairment. ARPC4 is a core subunit of the actin-related protein (ARP2/3) complex, which catalyzes the formation of F-actin networks. We show that the recurrent ARPC4 missense change is associated with a decreased amount of F-actin in cells from two affected individuals. Taken together, our results implicate heterozygous ARPC4 missense variants as a cause of neurodevelopmental disorders and microcephaly., We report a neurodevelopmental disorder with microcephaly in seven affected individuals with the same de novo variant in the ARPC4 gene. The recurrent variant in ARPC4, a subunit of the complex that catalyzes F-actin network formation, is associated with decreased F-actin in cells from affected individuals.

RASopathies are a group of developmental disorders caused by pathogenic variants in the RAS-MAPK pathway. Cardiomyopathy is a major feature of this group of disorders, specifically hypertrophic cardiomyopathy (HCM). HCM can be the first presenting feature in individuals with RASopathies. We conducted a retrospective study of all individuals who have had a cardiomyopathy gene panel ordered through our institution to determine the prevalence of pathogenic or likely pathogenic variants in RAS pathway genes in individuals with cardiomyopathy. We evaluated variants in the following genes: BRAF, CBL, HRAS, KRAS, MAP2K1, MAP2K2, NF1, NRAS, PTPN11, RAF1, SHOC2, and SOS1. We reviewed 74 cases with cardiomyopathy, including 32 with HCM, 24 with dilated cardiomyopathy (DCM), nine with both left ventricular noncompaction (LVNC) and DCM, four with LVNC only, two with arrhythmogenic right ventricular cardiomyopathy (ARVC) and three with unspecified cardiomyopathy. We identified four patients (5.41%) with pathogenic or likely pathogenic variants in HRAS, PTPN11 and RAF1 (two individuals). Indication for testing for all four individuals was HCM. The prevalence of pathogenic or likely pathogenic variants in RASopathy genes in our HCM patient cohort is 12.5% (4/32). We conclude that the RASopathy genes should be included on multi-gene panels for cardiomyopathy to increase diagnostic yield for individuals with HCM.

Contains fulltext : 245031.pdf (Publisher’s version ) (Closed access) PURPOSE: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants. METHODS: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing. RESULTS: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies. CONCLUSION: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.

There is a shortage of genetics providers worldwide and access is limited to large academic centers. Telemedicine programs can facilitate access to genetic services to patients living in remote locations. The goal of this study was to improve access to genetic services in the Dominican Republic by creating a partnership model between a pediatrician and geneticist. This approach has been used within the United States but not in the setting of two different countries, healthcare system, and cultures. Patients were referred to the Centro de Obstetricia y Ginecologia program if a syndromic or genetic etiology was suspected by their local provider. Pediatrician first evaluated all patients prior to telemedicine appointment to review family and medical history. All genetic visits were scheduled within 2 weeks of referral in collaboration with telehealth program at Cincinnati Children's Hospital Medical Center. A total of 66 individuals were evaluated during a period of 5 years. Fifty-seven individuals underwent genetic studies, and a molecular diagnosis was made in 39 individuals. Exome sequencing was the most common first line test when differential diagnosis was broad (n = 40). The most common inheritance was autosomal recessive in 15 individuals, followed by 13 individuals with autosomal dominant disorders, 7 individuals X-linked disorders, and 4 individuals with chromosomal abnormalities. This study provides data to support utility of geneticist and pediatrician partnership to provide outreach telemedicine diagnostics and management services for rare diseases in an international setting.

Multiple myeloma is the most common hematological malignancy in Gaucher disease type 1 (GD1). There is a lack of outcome data and consensus regarding screening of gammopathies. This study explores utility of screening in Porto Alegre, Brazil, and Cincinnati, Ohio. A retrospective analysis of clinical information and laboratory data from GD1 patients was performed. Over 19 years, 68 individuals with GD1 (31 males, 37 females) underwent screening, and 20 (29.4%) had abnormalities. Twelve (17.6%) had polyclonal gammopathy (mean age 24.2 years, p = .02), seven (10%) had monoclonal gammopathy of uncertain significance (MGUS; mean age 52.7 years, p = .009). One had multiple myeloma (age 61 years). Risk factors for MGUS included male gender (p = .05), p.N409S allele (p = .032). MGUS developed in six of 62 treated and two of four untreated individuals. Of those with MGUS receiving treatment, four were on enzyme replacement therapy (ERT) and one on substrate reduction therapy (SRT). Gammopathy normalized in 13 treated individuals (10 polyclonal, three MGUS) and remained abnormal in two treated individuals (two polyclonal, two MGUS). Gammopathy relapse was seen in one individual with MGUS and three with polyclonal gammopathy. This study describes screening for gammopathies and identifies risk factors in individuals with GD1.

Contains fulltext : 238254.pdf (Publisher’s version ) (Closed access) PURPOSE: To investigate monoallelic CLPB variants. Pathogenic variants in many genes cause congenital neutropenia. While most patients exhibit isolated hematological involvement, biallelic CLPB variants underlie a neurological phenotype ranging from nonprogressive intellectual disability to prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, 3-methylglutaconic aciduria, and neutropenia. CLPB was recently shown to be a mitochondrial refoldase; however, the exact function remains elusive. METHODS: We investigated six unrelated probands from four countries in three continents, with neutropenia and a phenotype dominated by epilepsy, developmental issues, and 3-methylglutaconic aciduria with next-generation sequencing. RESULTS: In each individual, we identified one of four different de novo monoallelic missense variants in CLPB. We show that these variants disturb refoldase and to a lesser extent ATPase activity of CLPB in a dominant-negative manner. Complexome profiling in fibroblasts showed CLPB at very high molecular mass comigrating with the prohibitins. In control fibroblasts, HAX1 migrated predominantly as monomer while in patient samples multiple HAX1 peaks were observed at higher molecular masses comigrating with CLPB thus suggesting a longer-lasting interaction between CLPB and HAX1. CONCLUSION: Both biallelic as well as specific monoallelic CLPB variants result in a phenotypic spectrum centered around neurodevelopmental delay, seizures, and neutropenia presumably mediated via HAX1.

South America comprises of heterogeneous topographies, populations, and health care systems. Therefore, it is not surprising to see differences among the countries regarding expertise, education, and practices of ophthalmic genetics for patients with rare eye diseases. Nevertheless, common challenges such as limited genetics training in medical schools and among ophthalmologists, scarcity of diagnostic tools for phenotyping, and expensive genetic testing not covered by the public healthcare systems, are seen in all of them. Here, we provide a detailed report of the current status of ophthalmic genetics, described by the personal views of local ophthalmologists from Brazil, Colombia, Argentina, and Chile. By reporting our strengths and weaknesses as a region, we intend to highlight the need for guidelines on how to manage these patients aligned with public health policies. Our region contributes to research worldwide, with thousands of well diagnosed patients from a number of unique and genetically diverse populations. The constant expansion of ophthalmic genetics and molecular diagnostics requires us to join forces to collaborate across South America and with other countries to improve access to next-generation diagnostics and ultimately improve patient care.

CHARGE syndrome (OMIM 214800) is a condition characterized by multisystem involvement with CHD7 pathogenic mutations leading to disease in the majority of patients. Discovery of the molecular cause of CHARGE unmasked a larger phenotypic spectrum than was previously appreciated. Within our interdisciplinary CHARGE syndrome program, we sought to characterize our CHD7-positive CHARGE cohort without coloboma or choanal atresia, highlighting complications and outcomes. We describe 18 individuals with CHD7-confirmed diagnosis from 15 families. The most sensitive finding in the cohort was temporal bone malformations, present in 13/15 individuals. Individuals had an average of 1.6 major features and 3.3 minor features defined by the Blake et al. guidelines. Despite lack of major features or major malformations, the majority of individuals continued to have difficulties with pneumonia, aspiration, secretion management and motility issues that greatly impacted their lives. Our findings illustrate the need for molecular testing and timely recognition given that the major co-morbidities are frequently experienced by patients with the mildest clinical spectrum of CHARGE syndrome.

Signal transduction through the RAF-MEK-ERK pathway, the first described mitogen-associated protein kinase (MAPK) cascade, mediates multiple cellular processes and participates in early and late developmental programs. Aberrant signaling through this cascade contributes to oncogenesis and underlies the RASopathies, a family of cancer-prone disorders. Here, we report that de novo missense variants in MAPK1, encoding the mitogen-activated protein kinase 1 (i.e., extracellular signal-regulated protein kinase 2, ERK2), cause a neurodevelopmental disease within the RASopathy phenotypic spectrum, reminiscent of Noonan syndrome in some subjects. Pathogenic variants promote increased phosphorylation of the kinase, which enhances translocation to the nucleus and boosts MAPK signaling in vitro and in vivo. Two variant classes are identified, one of which directly disrupts binding to MKP3, a dual-specificity protein phosphatase negatively regulating ERK function. Importantly, signal dysregulation driven by pathogenic MAPK1 variants is stimulus reliant and retains dependence on MEK activity. Our data support a model in which the identified pathogenic variants operate with counteracting effects on MAPK1 function by differentially impacting the ability of the kinase to interact with regulators and substrates, which likely explains the minor role of these variants as driver events contributing to oncogenesis. After nearly 20 years from the discovery of the first gene implicated in Noonan syndrome, PTPN11, the last tier of the MAPK cascade joins the group of genes mutated in RASopathies. Sin financiación 11.025 JCR (2020) Q1, 11/176 Genetics & Heredity 6.661 SJR (2020) Q1, 11/340 Genetics No data IDR 2020 UEM

Pre-eclampsia is a multisystem disorder characterized by new-onset hypertension and proteinuria during pregnancy. Pre-eclampsia remains a major cause of maternal death in low-income countries. Vitamin D has a very diverse biological role in cardiovascular diseases. This study will evaluate the association of vitamin D levels and relevance to pre-eclampsia.We conducted a case-control study of women recruited from the GenPE (Genetics and Pre-eclampsia) Colombian registry. This is a multicenter case-control study conducted in eight Colombian cities. 25-Hydroxyvitamin D (25(OH)D) concentration was measured using liquid-chromatography-tandem mass spectrometry from 1013 women with pre-eclampsia and 1015 mothers without pre-eclampsia (controls).Fifty-two percent of women with pre-eclampsia were vitamin D deficient. The 25(OH)D concentrations were significantly lower in the pre-eclampsia (mean 29.99 ng/mL; 95% CI: 29.40-30.58 ng/mL) group compared to controls (mean 33.7 ng/mL; 95% CI: 33.20-34.30 ng/mL). In the unadjusted model, maternal vitamin D deficiency, defined by maternal 25(OH)D concentration30 ng/mL, was associated with an increased probability of suffering from pre-eclampsia (OR 2.10; 95% CI, 1.75-2.51). After adjusting for covariates, a similarly increased probability of having pre-eclampsia was observed (OR 2.18; 95% CI, 1.80-2.64) among women with vitamin D deficiency, relative to controls.Although the results suggest that low maternal concentrations of 25(OH)D increase pre-eclampsia risk, this evidence may not be indicative of a causal association. Future studies are needed to confirm a definite causal relationship between concentrations of vitamin D and the risk of pre-eclampsia, by means of powered clinical trials.

Gaucher disease (GD) is an autosomal-recessive lysosomal storage disease caused by a deficiency of the enzyme, glucocerebrocidase, resulting in accumulation of lipid-laden storage cells in multiple organs such as bone marrow, liver, spleen, and lungs. Type 1 Gaucher disease is the most common form of this condition in which the brain and spinal cord (the central nervous system) are not affected. The Gaucher disease severity scoring system (GD-DS3) is typically used to assess disease severity accounting for skeletal, hematologic, and visceral disease. In addition to being time consuming for the clinician to calculate the scores, some of the assessments are subjective and may falsely increase or decrease disease severity. The purpose of this study was to determine if there is a correlation between liver stiffness values obtained from MR elastography (MRE) and the GD-DS3 score. An IRB approved, HIPAA compliant retrospective study was performed. All patients with type 1 GD imaged with MRE between 2011 and 2016 were included in this study. Clinical and imaging data was collected. Two pediatric radiologists analyzed MR images from abdomen and thigh studies independently to determine bone marrow involvement using a semi-quantitative scoring system with one reviewer analyzing a subset of studies to determine inter-observer reliability. The collected data was used to calculate a GD-DS3 score for all patients. GD-DS3 scores were compared with liver MRE stiffness values. Clinical MRE scores were plotted against GD-DS3 severity scores for 31 patients (15 males, 16 females; median age 27years, age range: 4-67years). The median GD-DS3 score was 4 (range: 1-10.1) and median MRE value was 2.43kPa (range: 1.30-5.20kPa). A significant positive correlation was found between MRE and GD-DS3 scores; Pearson's correlation coefficient value of r=0.47, p

Unfortunately the funding information was not given. Funding is as follows: This work was funded by the ERA PerMed project PerMiM (Austrian Science Fund FWF, I4704-B) to S.B.W. This study was supported by a “Sonata Bis 5” grant of the National Science Center Poland (2015/18/E/NZ1/00673) to S.Z. and D.M.

Gaucher disease (GD) is caused by mutations on the GBA1 gene leading to deficiency in acid β-glucosidase (GCase) and subsequent accumulation of its substrates, glucosylceramide (GlcC) and glucosylsphingosine (GlcS). GlcS in plasma has been proposed as a highly sensitive and specific biomarker for the diagnosis of GD and for monitoring disease progression and response to therapy. Here we report a novel robust and accurate hydrophilic interaction liquid chromatography tandem mass spectrometric method (HILIC-MS/MS) for the direct measurement of glucosylsphingosine (GlcS) in dried plasma spots (DPS). The method was also capable of resolving the isomeric pair, glucosylsphingosine and galactosylsphingosine, the latter of which was proposed as a promising biomarker for Krabbe disease. The method was fully validated and applied to the analysis of 19 GD patients and carriers. The GlcS levels in 9 GD type I patients who have been on enzyme replacement therapy (ERT) were reduced to a mean of 31.0 nM, much lower compared to a pre-treated specimen at a level of 85.8 nM, but still significantly elevated compared to healthy controls. GlcS concentrations in three treated type III GD patients were much lower compared to an untreated patient. In our preclinical GD studies, 4L;C* mice (subacute nGD model) exhibited comparable levels of plasma GlcS, but had much higher GlcS accumulation in the brain than those of 9V/null mice (chronic neuropathic GD model). Our method for the measurement of GlcS in DPS proved to be a very convenient approach for sample collection, storage and shipping nationwide and internationally.