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Purpose Within this study, we aimed to discover novel gene–disease associations in patients with no genetic diagnosis after exome/genome sequencing (ES/GS). Methods We followed two approaches: (1) a patient-centered approach, which after routine diagnostic analysis systematically interrogates variants in genes not yet associated to human diseases; and (2) a gene variant centered approach. For the latter, we focused on de novo variants in patients that presented with neurodevelopmental delay (NDD) and/or intellectual disability (ID), which are the most common reasons for genetic testing referrals. Gene–disease association was assessed using our data repository that combines ES/GS data and Human Phenotype Ontology terms from over 33,000 patients. Results We propose six novel gene–disease associations based on 38 patients with variants in the BLOC1S1, IPO8, MMP15, PLK1, RAP1GDS1, and ZNF699 genes. Furthermore, our results support causality of 31 additional candidate genes that had little published evidence and no registered OMIM phenotype (56 patients). The phenotypes included syndromic/nonsyndromic NDD/ID, oral–facial–digital syndrome, cardiomyopathies, malformation syndrome, short stature, skeletal dysplasia, and ciliary dyskinesia. Conclusion Our results demonstrate the value of data repositories which combine clinical and genetic data for discovering and confirming gene–disease associations. Genetic laboratories should be encouraged to pursue such analyses for the benefit of undiagnosed patients and their families.

PURPOSE Missense variants clustering in the BTB domain region of RHOBTB2 cause a developmental and epileptic encephalopathy (DEE) with early-onset seizures and severe intellectual disability. METHODS By international collaboration we assembled individuals with pathogenic RHOBTB2 variants and a variable spectrum of neurodevelopmental disorders (NDDs). By western blotting we investigated the consequences of missense variants in vitro. RESULTS In accordance with previous observations, de novo heterozygous missense variants in the BTB domain region led to a severe DEE in 16 individuals. We now identified also de novo missense variants in the GTPase domain in six individuals with apparently more variable neurodevelopmental phenotypes with or without epilepsy. In contrast to variants in the BTB domain region, variants in the GTPase domain do not impair proteasomal degradation of RHOBTB2 in vitro, indicating different functional consequences.Furthermore, we observed bi-allelic splice-site and truncating variants in nine families with variable neurodevelopmental phenotypes, indicating that complete loss of RHOBTB2 is pathogenic as well. CONCLUSION By identifying phenotype-genotype correlations regarding location and consequences of de novo missense variants in RHOBTB2 and by identifying bi-allelic truncating variants, we further delineate and expand the molecular and clinical spectrum of RHOBTB2 related disorders including both autosomal dominant and recessive NDDs.

Background: Inborn errors of metabolism (IEM) are prevalent autosomal recessive disorders in Saudi Arabia. Socio-economic factors, such as consanguineous marriages, play a role in the high rate of diseases. The government of Saudi Arabia created a newborn screening program (NBS) for the most prevalent disorders to facilitate early intervention and the prevention of severe complications. The study aimed to determine the carried pathogenic allele of the diseases included in the NBS and the most frequently carried phenotype in the Saudi population. Methodology: We performed targeted genetic screening for the genes associated with the IEM in the NBS. We used the results of the whole exome sequencing of 1,314 affected and unaffected individuals from 650 families. The results constitute the King Abdullah International Medical Research Center Genomic Database. Results: According to the data set, four diseases occurred most frequently in the Saudi population: adrenal hyperplasia, propionic acidemia, phenylketonuria, and maple syrup urine disease. In total, 12 pathogenic variants occurred frequently. Conclusion: This study generated an updated list of the most pathogenic variants in the Saudi population, based on the National Guard Hospital dataset. Additional research with larger data sets from the different regions will provide valuable information about the allele distribution in the Saudi population, creating a carrier screening program.

The leucine-rich glioma-inactivated (LGI) family consists of four highly conserved paralogous genes, LGI1-4, that are highly expressed in mammalian central and/or peripheral nervous systems. LGI1 antibodies are detected in subjects with autoimmune limbic encephalitis and peripheral nerve hyperexcitability syndromes (PNHSs) such as Isaacs and Morvan syndromes. Pathogenic variations of LGI1 and LGI4 are associated with neurological disorders as disease traits including familial temporal lobe epilepsy and neurogenic arthrogryposis multiplex congenita 1 with myelin defects, respectively. No human disease has been reported associated with either LGI2 or LGI3. We implemented exome sequencing and family-based genomics to identify individuals with deleterious variants in LGI3 and utilized GeneMatcher to connect practitioners and researchers worldwide to investigate the clinical and electrophysiological phenotype in affected subjects. We also generated Lgi3-null mice and performed peripheral nerve dissection and immunohistochemistry to examine the juxtaparanode LGI3 microarchitecture. As a result, we identified 16 individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. Deep phenotypic characterization showed LGI3 LoF causes a potentially clinically recognizable PNHS trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability. Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons. Our data demonstrate bi-allelic LoF variants in LGI3 cause a clinically distinguishable disease trait of PNHS, most likely caused by disturbed Kv1 channel distribution in the absence of LGI3.

Despite clear technical superiority of genome sequencing (GS) over other diagnostic methods such as exome sequencing (ES), few studies are available regarding the advantages of its clinical application. We analyzed 1007 consecutive index cases for whom GS was performed in a diagnostic setting over a 2-year period. We reported pathogenic and likely pathogenic (P/LP) variants that explain the patients’ phenotype in 212 of the 1007 cases (21.1%). In 245 additional cases (24.3%), a variant of unknown significance (VUS) related to the phenotype was reported. We especially investigated patients which had had ES with no genetic diagnosis (n = 358). For this group, GS diagnostic yield was 14.5% (52 patients with P/LP out of 358). GS should be especially indicated for ES-negative cases since up to 29.6% of them could benefit from GS testing (14.5% with P/LP, n = 52 and 15.1% with VUS, n = 54). Genetic diagnoses in most of the ES-negative/GS-positive cases were determined by technical superiority of GS, i.e., access to noncoding regions and more uniform coverage. Importantly, we reported 79 noncoding variants, of which, 41 variants were classified as P/LP. Interpretation of noncoding variants remains challenging, and in many cases, complementary methods based on direct enzyme assessment, biomarker testing and RNA analysis are needed for variant classification and diagnosis. We present the largest cohort of patients with GS performed in a clinical setting to date. The results of this study should direct the decision for GS as standard second-line, or even first-line stand-alone test.

BACKGROUND Familial Mediterranean fever is a hereditary inflammatory disorder caused by variants in MEFV. c.2230G>T p.(Ala744Ser) rs61732874 is considered to be an established pathogenic variant in MEFV, but in this study we provide a complete evaluation that suggests this variant is likely benign. METHODS Using an in-house exome database from 924 individuals, we extracted all individuals harboring this variant for clinical, laboratory, and familial evaluation. RESULTS We identified the variant in 58 individuals from 39 families. The allele frequency of this variant in our database is 4.2%. None of the identified individuals match the diagnosis of Familial Mediterranean Fever. Using the American College of Medical Genetics and Genomics guidelines for variant classification, this variant is classified as likely benign and not pathogenic. CONCLUSION Conflicting evidence about variants creates challenges for testing laboratories and impacts patient care. Sharing information drawn mainly from underrepresented populations and clinical phenotyping are important tools for precise curation of genetic variants.

Background Primary Ciliary Dyskinesia (PCD) is also known as immotile-cilia syndrome, an autosomal recessive disorder of ciliary function, leading to mucus retention in the respiratory system in childhood. Our knowledge in the pathophysiological aspect of this devastating disorder is increasing with the advancement of genetic and molecular testing. Case presentation Here in, we report two siblings with a classical clinical and radiological presentation of PCD. Using whole exome sequencing we identified a homozygous truncating variant (c.3402 T > A); p.(Tyr1134*) in the NEK10 gene. Western bolt analysis revealed a decrease in the expression of NEK10 protein in the patient cells. Conclusions NEK10 plays a central role in the post-mitotic process of cilia assembly, regulating ciliary length and functions during physiological and pathological status. This study highlights the challenges of identifying disease-causing variants for a highly heterogeneous disorder and reports on the identification of a novel variant in NEK10 which recently associated with PCD.

Ral (Ras-like) GTPases play an important role in the control of cell migration and have been implicated in Ras-mediated tumorigenicity. Recently, variants in RALA were also described as a cause of intellectual disability and developmental delay, indicating the relevance of this pathway to neuropediatric diseases. Here, we report the identification of bi-allelic variants in RALGAPA1 (encoding Ral GTPase activating protein catalytic alpha subunit 1) in four unrelated individuals with profound neurodevelopmental disability, muscular hypotonia, feeding abnormalities, recurrent fever episodes, and infantile spasms . Dysplasia of corpus callosum with focal thinning of the posterior part and characteristic facial features appeared to be unifying findings. RalGAPA1 was absent in the fibroblasts derived from two affected individuals suggesting a loss-of-function effect of the RALGAPA1 variants. Consequently, RalA activity was increased in these cell lines, which is in keeping with the idea that RalGAPA1 deficiency causes a constitutive activation of RalA. Additionally, levels of RalGAPB, a scaffolding subunit of the RalGAP complex, were dramatically reduced, indicating a dysfunctional RalGAP complex. Moreover, RalGAPA1 deficiency clearly increased cell-surface levels of lipid raft components in detached fibroblasts, which might indicate that anchorage-dependence of cell growth signaling is disturbed. Our findings indicate that the dysregulation of the RalA pathway has an important impact on neuronal function and brain development. In light of the partially overlapping phenotype between RALA- and RALGAPA1-associated diseases, it appears likely that dysregulation of the RalA signaling pathway leads to a distinct group of genetic syndromes that we suggest could be named RALopathies.

Purpose: The mediator (MED) multisubunit-complex modulates the activity of the transcriptional machinery, and genetic defects in different MED subunits (17, 20, 27) have been implicated in neurologic diseases. In this study, we identified a recurrent homozygous variant in MED11 (c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families. Methods: To investigate the genetic cause of the disease, exome or genome sequencing were performed in 5 unrelated families identified via different research networks and Matchmaker Exchange. Deep clinical and brain imaging evaluations were performed by clinical pediatric neurologists and neuroradiologists. The functional effect of the candidate variant on both MED11 RNA and protein was assessed using reverse transcriptase polymerase chain reaction and western blotting using fibroblast cell lines derived from 1 affected individual and controls and through computational approaches. Knockouts in zebrafish were generated using clustered regularly interspaced short palindromic repeats/Cas9. Results: The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death. Functional studies on patient-derived fibroblasts did not show a loss of protein function but rather disruption of the C-terminal of MED11, likely impairing binding to other MED subunits. A zebrafish knockout model recapitulates key clinical phenotypes. Conclusion: Loss of the C-terminal ofMED subunit 11 may affect its binding efficiency to otherMED subunits, thus implicating the MED-complex stability in brain development and neurodegeneration.

Biallelic changes in the ZNFX1 gene have been recently reported to cause severe familial immunodeficiency. Through a search of our bio/databank with information from genetic testing of >55 000 individuals, we identified nine additional patients from seven families with six novel homozygous ZNFX1 variants. Consistent with the previously described phenotype, our patients suffered from monocytosis, thrombocytopenia, hepatosplenomegaly, recurrent infections, and lymphadenopathy. The two most severely affected probands also had renal involvement and clinical presentations compatible with hemophagocytic lymphohistiocytosis. The disease was less lethal among our patients than previously reported. We identified two missense changes, two variants predicted to result in complete protein loss through nonsense-mediated decay, and two frameshift changes that likely introduce a truncation. Our findings (i) independently confirm the role of ZNFX1 in primary genetic immunodeficiency, (ii) expand the genetic and clinical spectrum of ZNFX1-related disease, and (iii) illustrate the utility of large, well-curated, and continually updated genotype-phenotype databases in resolving molecular diagnoses of patients with initially negative genetic testing findings.

Background Dihydrolipoamide dehydrogenase deficiency (DLDD) is a rare metabolic disorder inherited in an autosomal recessive manner. This heterogeneous disease has a variable clinical presentation, onset, and biochemical markers. Materials and methods We retrospectively reviewed the clinical and molecular diagnosis of eight cases with DLDD from four referral centers in Saudi Arabia. Results Remarkably, we found hepatic involvement ranging from acute hepatic failure to chronic hepatitis in five patients. In addition, neurological disorders in the form of seizures, developmental delay, ataxia, hypotonia and psychomotor symptoms were found in five patients, two of them with a combination of hepatic and neurological symptoms. In addition, only one patient had recurrent episodes of hypoglycemia. While most patients had the hepatic form of homozygous variant c.685G > T in the DLD gene, one patient was found to have a novel variant c.623C > T that had neurological and hepatic symptoms. Conclusions We describe the largest reported DLDD cohort in the Saudi population. Clinical, biochemical, radiological, and molecular characterization was reviewed and no clear genotype-phenotype correlation was found in this cohort.

Medical artificial intelligence (MAI) is artificial intelligence (AI) applied to the healthcare field. AI can be applied to many different aspects of genetics, such as variant classification. With little or no prior experience in AI coding, we share our experience with variant classification using the Variant Artificial Intelligence Easy Scoring (VARIES), an open-access platform, and the Automatic Machine Learning (AutoML) of the Google Cloud Platform.We investigated exome sequencing data from a sample of 1410 individuals. The majority (80%) were used for training and 20% for testing. The user-friendly Google Cloud Platform was used to create the VARIES model, and the TRIPOD checklist to develop and validate the prediction model for the development of the VARIES system.The learning rate of the training dataset reached optimal results at an early stage of iteration, with a loss value near zero in approximately 4 min. For the testing dataset, the results for F1 (micro average) was 0.64, F1 (macro average) 0.34, micro-average area under the curve AUC (one-over-rest) 0.81 and the macro-average AUC (one-over-rest) 0.73. The overall performance characteristics of the VARIES model suggest the classifier has a high predictive ability.We present a systematic guideline to create a genomic AI prediction tool with high predictive power, using a graphical user interface provided by Google Cloud Platform, with no prior experience in creating the software programs required.

Secondary findings (SF) are defined as genetic conditions discovered unintentionally during an evaluation of raw data for another disease. We aimed to identify the rate of secondary genetic findings in the Saudi population in the 59 genes of the American College of Medical Genetics and Genomics (ACMG) list. In our study, the raw data of 1254 individuals, generated from exome sequencing for clinical purposes, were studied. Variants detected in the 59 genes on the ACMG list of secondary findings were investigated. Pathogenicity classifications were assigned to those variants based on the ACMG scoring system. We identified 2409 variants in the 59 gene list, 45 variants were classified as pathogenic/likely pathogenic variants according to the ACMG classification. The LDLR gene had the greatest number of pathogenic/likely pathogenic variants 12%. Cardiovascular genetic diseases had the highest frequency of disorders detected as secondary findings. In this study, the overall rate of positive cases identified with secondary findings in the Saudi population was 8%. The different in our current study and the previous studies in Saudi Arabia can be explained by the differences between the sequencing method, the criteria used for variant classification, the availability of newer evidence at the time of the publication, and the fact that we identified Saudi novel variants never reported in other populations.

Intellectual disability poses a huge burden on the health care system, and it is one of the most common referral reasons to the genetic and child neurology clinic. Intellectual disability (ID) is genetically heterogeneous, and it is associated with several other neurological conditions. Exome sequencing is a robust genetic tool and has revolutionized the process of molecular diagnosis and novel gene discovery. Besides its diagnostic clinical value, novel gene discovery is prime in reverse genetics, when human mutations help to understand the function of a gene and may aid in better understanding of the human brain and nervous system. Using WES, we identified a biallelic truncating variant in DNAJA1 gene (c.511C>T p.(Gln171*) in a multiplex Saudi consanguineous family. The main phenotype shared between the siblings was intellectual disability and seizure disorder.

Background: Whole exome sequencing (WES) is widely used as a first-tier diagnostic test. The diagnostic yield for WES is estimated at approximately 50%, leaving the requesting clinician with 50% ambiguous or negative results in cases where the diseases-causing variants could not be identified. Methods: We retrospectively assessed the results of all WES tests requested from 2015 to 2018 at our institution. We included participants with a negative test result, irrespective of the phenotype. Complete data collection, medical-record extraction, and additional analysis were done for qualifying cases. Results: The cohort included 151 participants with a negative WES result. Of the sample, 18% (n=27) were discharged from the genetic clinic, and only three cases required additional genetic testing prior to discharge. The decision to discharge a patient was based on several factors, including a mild phenotype (i.e. a phenotype that can be resolved and doesn’t require surgical, rehabilitation or medical intervention), a confirmed multifactorial condition, or the patient is developing according to the milestones for his age group and has a negative family history. The discharge rate and the period of being followed at the clinic improved over time. In 2015, none was discharged, and in 2016, nearly 100% of the negative cases were discharged in 6-12 months. In 2017, 65% of the cases were discharged in less than six months, and all cases tested in 2018, were discharged from the clinic in less than three months.Conclusion: Informative negative WES results lower the cost of additional testing, reduce the number of follow-up consultations, and result in the reassurance or discharge the patient. The informative negative WES results (18%) can be combined with the hit rate of the WES (50%) in consanguineous population, increasing the clinical utility of WES testing to 68%.

Summary The ubiquitin-proteasome system facilitates the degradation of unstable or damaged proteins. UBR1–7, which are members of hundreds of E3 ubiquitin ligases, recognize and regulate the half-life of specific proteins on the basis of their N-terminal sequences (“N-end rule”). In seven individuals with intellectual disability, epilepsy, ptosis, hypothyroidism, and genital anomalies, we uncovered bi-allelic variants in UBR7. Their phenotype differs significantly from that of Johanson-Blizzard syndrome (JBS), which is caused by bi-allelic variants in UBR1, notably by the presence of epilepsy and the absence of exocrine pancreatic insufficiency and hypoplasia of nasal alae. While the mechanistic etiology of JBS remains uncertain, mutation of both Ubr1 and Ubr2 in the mouse or of the C. elegans UBR5 ortholog results in Notch signaling defects. Consistent with a potential role in Notch signaling, C. elegans ubr-7 expression partially overlaps with that of ubr-5, including in neurons, as well as the distal tip cell that plays a crucial role in signaling to germline stem cells via the Notch signaling pathway. Analysis of ubr-5 and ubr-7 single mutants and double mutants revealed genetic interactions with the Notch receptor gene glp-1 that influenced development and embryo formation. Collectively, our findings further implicate the UBR protein family and the Notch signaling pathway in a neurodevelopmental syndrome with epilepsy, ptosis, and hypothyroidism that differs from JBS. Further studies exploring a potential role in histone regulation are warranted given clinical overlap with KAT6B disorders and the interaction of UBR7 and UBR5 with histones.

INTRODUCTION Currently, next-generation sequencing (NGS) technology is more accessible and available to detect the genetic causation of diseases. Though NGS technology benefited some clinical phenotypes, for some clinical diagnoses such as seizures and epileptic disorders, adaptation occurred slowly. The genetic diagnosis was mainly based on epilepsy gene panels and not on whole exome and/or genome sequencing. METHOD We retrospectively analyzed 420 index cases, referred for NGS over a period of 18 months, to investigate the challenges in diagnosing epilepsy. RESULT Of the 420 cases, 65 (15%) were referred due to epilepsy with one third having a positive family history. The result of the NGS was 14 positive cases (21.5%), 16 inconclusive cases (24%), and 35 (53%) negative cases. No gene has been detected twice in the inconclusive and positive groups. Comparative genomic hybridization has been performed for all 30 NGS negative cases and four cases with pathogenic variants (deletion in 15q11.213.1, deletion of 2p16.3, deletion in Xq22.1, and deletion in 17p13.3) were identified. CONCLUSION These findings have implications for our understanding of the approach to genetic testing and counseling of patients affected with seizures and epilepsy disorders. The overall diagnostic yield of exome/genome sequencing in our cohort was 23%. The main characteristic is genetic heterogeneity, supporting NGS technology as a suitable testing approach for seizures and epilepsy disorders. Genetic counseling for newly identified disease-causing variants depends on the pedigree interpretation, within the context of disease penetrance and variable expressivity.

Whole-exome sequencing (WES) and whole-genome sequencing (WGS) are used to diagnose genetic and inherited disorders. However, few studies comparing the detection rates of WES and WGS in clinical settings have been performed. Variant call format files were generated and raw data analysis was performed in cases in which the final molecular results showed discrepancies. We classified the possible explanations for the discrepancies into three categories: the time interval between the two tests, the technical limitations of WES, and the impact of the sequencing system type. This cohort comprised 108 patients with negative array comparative genomic hybridization and negative or inconclusive WES results before WGS was performed. Ten (9%) patients had positive WGS results. However, after reanalysis the WGS hit rate decreased to 7% (7 cases). In four cases the variants were identified by WES but missed for different reasons. Only 3 cases (3%) were positive by WGS but completely unidentified by WES. In this study, we showed that 30% of the positive cases identified by WGS could be identified by reanalyzing the WES raw data, and WGS achieved an only 7% higher detection rate. Therefore, until the cost of WGS approximates that of WES, reanalyzing WES raw data is recommended before performing WGS.

We report the first case of nonimmune hydrops fetalis (NIHF) associated with a recessive, in-frame deletion of V205 in the G protein–coupled receptor, Calcitonin Receptor-Like Receptor (hCALCRL). Homozygosity results in fetal demise from hydrops fetalis, while heterozygosity in females is associated with spontaneous miscarriage and subfertility. Using molecular dynamic modeling and in vitro biochemical assays, we show that the hCLR(V205del) mutant results in misfolding of the first extracellular loop, reducing association with its requisite receptor chaperone, receptor activity modifying protein (RAMP), translocation to the plasma membrane and signaling. Using three independent genetic mouse models we establish that the adrenomedullin–CLR–RAMP2 axis is both necessary and sufficient for driving lymphatic vascular proliferation. Genetic ablation of either lymphatic endothelial Calcrl or nonendothelial Ramp2 leads to severe NIHF with embryonic demise and placental pathologies, similar to that observed in humans. Our results highlight a novel candidate gene for human congenital NIHF and provide structure–function insights of this signaling axis for human physiology.

Propionic acidemia is an inborn error of metabolism that is inherited in an autosomal recessive manner. It is characterized by a deficient propionyl-CoA carboxylase due to mutations in either of its beta or alpha subunits. In the literature, there is a clear association between propionic acidemia and epilepsy. In this cohort, we retrospectively reviewed the data of 14 propionic acidemia patients in Saudi Arabia and compared the findings to those of former studies. Six of the 14 (43%) patients developed epileptic seizure, mainly focal seizures. All patients were responsive to conventional antiepileptic drugs as their seizures are controlled. The predominant electroencephalographic (EEG) findings were diffuse slowing in 43% and multifocal epileptiform discharges in 14% of the patients. In 1 patient, burst suppression pattern was detected, a pattern never before reported in patients with propionic acidemia. Brain magnetic resonance imaging (MRI) findings mainly consisted of signal changes of the basal ganglia (36%), generalized brain atrophy (43%), and delayed myelination (43%).The most common genotype in our series is the homozygous missense mutation in the PCCA gene (c.425G>A; p. Gly142Asp). However, there is no clear genotype–seizure correlation. We conclude that seizure is not an uncommon finding in patients with propionic acidemia and not difficult to control. Additional studies are needed to further elaborate on genotype–seizure correlation.

Neural tube defects (NTDs) are among the most common birth defects in humans and yet their molecular etiology remains poorly understood. NTDs are believed to result from the complex interaction of environmental factors with a multitude of genetic risk factors in a classical multifactorial disease model. Mendelian forms of NTDs in which single variants are sufficient to cause the disease are extremely rare. We report a monozygotic twin with severe NTDs (occipital encephalocele and myelomeningocele) and a shared de novo, likely truncating, variant in SMARCC1. RTPCR analysis suggests the potential null nature of the variant attributed to nonsense-mediated decay. SMARCC1 is extremely constrained in humans and encodes a highly conserved core chromatin remodeler, BAF155. Mice that are heterozygous for a null allele or homozygous for a hypomorphic allele develop severe NTDs in the form of exencephaly. This is the first report of SMARCC1 mutation in humans, and it shows a critical and conserved requirement for intact BAF chromatin remodeling complex in neurulation. Ann Neurol 2018;83:433-436.

Background: Dilated cardiomyopathy (DCM) is a progressive, lethal disorder that has heterogeneous genetic background. It has been linked to mutations in Nebulin-related-anchoring protein (NRAP) gene. NRAP expressed mainly in striated and cardiac muscles, and it plays substantial role in the sarcomeric contraction cycle and myofibrillogenesis. Case Presentation: A 17-month-old baby girl presented at the age of 13 months with symptoms of heart failure. She was diagnosed as a case of dilated cardiomyopathy. Using whole exome sequencing, diagnosis is confirmed due to homozygous NRAP variant c.400-407 del p.(Cys134 Serfs*12), which create premature stop codon. Conclusion: This case report supports preceding reports that biallelic deletion mutations in NRAP gene cause an autosomal recessive DCM with low penetrance genetic risk factor. However, the age of presentation can vary from early infancy up to adulthood.

Background Aicardi-Goutieres syndrome is a rare genetic neurological disorder with variable clinical manifestations. Molecular detection of specific mutations is required to confirm the diagnosis. The aim of this study was to review the clinical and molecular diagnostic findings in 24 individuals with Aicardi-Goutieres syndrome who presented during childhood in an Arab population. Materials and Methods We reviewed the records of 24 patients from six tertiary hospitals in different Arab countries. All included patients had a molecular diagnosis of Aicardi-Goutieres syndrome. Results Six individuals with Aicardi-Goutieres syndrome (25%) had a neonatal presentation, whereas the remaining patients presented during the first year of life. Patients presented with developmental delay (24 cases, 100%); spasticity (24 cases, 100%); speech delay (23 cases, 95.8%); profound intellectual disability (21 cases, 87.5%); truncal hypotonia (21 cases, 87.5%); seizures (eighteen cases, 75%); and epileptic encephalopathy (15 cases, 62.5%). Neuroimaging showed white matter abnormalities (22 cases, 91.7%), cerebral atrophy (75%), and small, multifocal calcifications in the lentiform nuclei and deep cerebral white matter (54.2%). Homozygous mutations were identified in RNASEH2B (54.2%), RNASEH2A (20.8%), RNASEH2C (8.3%), SAMHD1 (8.3%), TREX1 (4.2%), and heterozygous mutations in IFIH1 (4.2%), with c.356A>G (p.Asp119Gly) in RNASEH2B being the most frequent mutation. Three novel mutations c.987delT and c.625 + 1G>A in SAMHD1 gene and c.961G>T in the IFIHI1 gene were identified. Conclusions This is the largest molecularly confirmed Aicardi-Goutieres syndrome cohort from Arabia. By presenting these clinical and molecular findings, we hope to raise awareness of Aicardi-Goutieres syndrome and to demonstrate the importance of specialist referral and molecular diagnosis.

Inflammatory bowel diseases (IBDs) are idiopathic autoimmune diseases that are characterized by inflammation of both the small and large intestine. Although IBD is common in the general population, the pathophysiology remains ambiguous. Clear understanding of IBD pathophysiology would be a major step toward curative treatment in the future. Hyperhomocysteinemia has been associated with multiple autoimmune diseases including IBD, but homocystinuria has not been associated with IBD before. We report a 9-year-old girl with Crohn’s disease and homocystinuria. Her gastrointestinal symptoms improved significantly upon classical homocystinuria treatment, and her last colonoscopy showed a pronounced remission. This case supports the inflammatory role of homocysteine in the gastrointestinal tract and the association between hyperhomocysteinemia and IBD manifestations.