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Primary pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma is a very rare presentation of MALT lymphoma. The presence of a completely negative autoimmune and inflammatory background makes it a real challenge and very rare presentation (probably the second reported case in the literature). We report a case of primary pulmonary MALT lymphoma with negative autoimmune background, demonstrating as multifocal bulky variceal masses causing significant clinical symptoms., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Family and Community Medicine.)

Human disorders of the enteric nervous system (ENS), e.g., Hirschsprung's disease, are rarely associated with major central nervous system involvement. We describe two families each segregating a different homozygous truncating variant in KIF26A with a unique constellation of severe megacolon that resembles Hirschsprung's disease but lacks aganglionosis as well as brain malformations that range from severe to mild. The intestinal phenotype bears a striking resemblance to that observed in Kif26a -/- mice where KIF26A deficiency was found to cause abnormal GDNF-Ret signaling resulting in failure to establish normal neuronal networks despite myenteric neuronal hyperplasia. Very recently, a range of brain developmental phenotypes were described in patients and mice with KIF26A deficiency and were found to result from abnormal radial migration and increased apoptosis. Our report, therefore, reveals a recognizable autosomal-recessive human KIF26A deficiency phenotype characterized by severe ENS dysfunction and a range of brain malformations., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Au-Kline syndrome (AKS) is a neurodevelopmental disorder associated with multiple malformations and a characteristic facial gestalt. The first individuals ascertained carried de novo loss-of-function (LoF) variants in HNRNPK. Here, we report 32 individuals with AKS (26 previously unpublished), including 13 with de novo missense variants. We propose new clinical diagnostic criteria for AKS that differentiate it from the clinically overlapping Kabuki syndrome and describe a significant phenotypic expansion to include individuals with missense variants who present with subtle facial features and few or no malformations. Many gene-specific DNA methylation (DNAm) signatures have been identified for neurodevelopmental syndromes. Because HNRNPK has roles in chromatin and epigenetic regulation, we hypothesized that pathogenic variants in HNRNPK may be associated with a specific DNAm signature. Here, we report a unique DNAm signature for AKS due to LoF HNRNPK variants, distinct from controls and Kabuki syndrome. This DNAm signature is also identified in some individuals with de novo HNRNPK missense variants, confirming their pathogenicity and the phenotypic expansion of AKS to include more subtle phenotypes. Furthermore, we report that some individuals with missense variants have an "intermediate" DNAm signature that parallels their milder clinical presentation, suggesting the presence of an epi-genotype phenotype correlation. In summary, the AKS DNAm signature may help elucidate the underlying pathophysiology of AKS. This DNAm signature also effectively supported clinical syndrome delineation and is a valuable aid for variant interpretation in individuals where a clinical diagnosis of AKS is unclear, particularly for mild presentations., Competing Interests: Declaration of interests H.T.B. is a consultant for Mahzi therapeutics., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The solute carrier (SLC) superfamily encompasses >400 transmembrane transporters involved in the exchange of amino acids, nutrients, ions, metals, neurotransmitters and metabolites across biological membranes. SLCs are highly expressed in the mammalian brain; defects in nearly 100 unique SLC-encoding genes (OMIM: https://www.omim.org) are associated with rare Mendelian disorders including developmental and epileptic encephalopathy and severe neurodevelopmental disorders. Exome sequencing and family-based rare variant analyses on a cohort with neurodevelopmental disorders identified two siblings with developmental and epileptic encephalopathy and a shared deleterious homozygous splicing variant in SLC38A3. The gene encodes SNAT3, a sodium-coupled neutral amino acid transporter and a principal transporter of the amino acids asparagine, histidine, and glutamine, the latter being the precursor for the neurotransmitters GABA and glutamate. Additional subjects with a similar developmental and epileptic encephalopathy phenotype and biallelic predicted-damaging SLC38A3 variants were ascertained through GeneMatcher and collaborations with research and clinical molecular diagnostic laboratories. Untargeted metabolomic analysis was performed to identify novel metabolic biomarkers. Ten individuals from seven unrelated families from six different countries with deleterious biallelic variants in SLC38A3 were identified. Global developmental delay, intellectual disability, hypotonia, and absent speech were common features while microcephaly, epilepsy, and visual impairment were present in the majority. Epilepsy was drug-resistant in half. Metabolomic analysis revealed perturbations of glutamate, histidine, and nitrogen metabolism in plasma, urine, and CSF of selected subjects, potentially representing biomarkers of disease. Our data support the contention that SLC38A3 is a novel disease gene for developmental and epileptic encephalopathy and illuminate the likely pathophysiology of the disease as perturbations in glutamine homeostasis., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Developmental and epileptic encephalopathy 35 (DEE 35) is a severe neurological condition caused by biallelic variants in ITPA, encoding inosine triphosphate pyrophosphatase, an essential enzyme in purine metabolism. We delineate the genotypic and phenotypic spectrum of DEE 35, analyzing possible predictors for adverse clinical outcomes. We investigated a cohort of 28 new patients and reviewed previously described cases, providing a comprehensive characterization of 40 subjects. Exome sequencing was performed to identify underlying ITPA pathogenic variants. Brain MRI (magnetic resonance imaging) scans were systematically analyzed to delineate the neuroradiological spectrum. Survival curves according to the Kaplan-Meier method and log-rank test were used to investigate outcome predictors in different subgroups of patients. We identified 18 distinct ITPA pathogenic variants, including 14 novel variants, and two deletions. All subjects showed profound developmental delay, microcephaly, and refractory epilepsy followed by neurodevelopmental regression. Brain MRI revision revealed a recurrent pattern of delayed myelination and restricted diffusion of early myelinating structures. Congenital microcephaly and cardiac involvement were statistically significant novel clinical predictors of adverse outcomes. We refined the molecular, clinical, and neuroradiological characterization of ITPase deficiency, and identified new clinical predictors which may have a potentially important impact on diagnosis, counseling, and follow-up of affected individuals., (© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.)

Background: Obesity and diabetes are two chronic metabolic diseases whose prevalence is increasing at an alarming rate globally. A close association between obesity, diabetes, and insulin resistance has been identified, and many studies have pinpointed obesity as a causal risk factor for insulin resistance. However, the mechanism underlying this association is not entirely understood. In the past decade, ceramides have gained attention due to their accumulation in certain tissues and their suggested role in initiating insulin resistance. This study aims to determine the association of specific ceramides and their major metabolizing enzymes with obesity-associated insulin resistance., Methods: The samples comprised subcutaneous adipose tissues collected from three cohorts: lean non-diabetic (controls; n = 20), obese-non-diabetic (n = 66), and obese-diabetic (n = 32). Ceramide levels were quantified using LC-MS/MS and mRNA expression level for different enzymes were estimated using real-time PCR-based RNA expression analysis., Results: C16-ceramide (P = 0.023), C16-dihydro-ceramide (P < 0.005), C18-dihydro-ceramide (P = 0.009) and C24-ceramide (P = 0.040) levels were significantly increased in the obese cohort compared to the control group. However, stratification of the obese group revealed a significant increase in the C16-ceramide levels (P = 0.027) and mRNA over expression of the serine palmitoyl transferases enzyme subunit SPT1 (P < 0.005) in the obese-diabetic cohort compared to the obese-non-diabetic cohort., Conclusions: The present study indicates that C16-ceramide plays a pivotal role in inducing insulin resistance. Overexpression of SPT1 in the obese-diabetic group and its positive correlation with C16-ceramide suggest that C16-ceramide was generated through the de novo pathway., (© 2022. The Author(s).)

The coronavirus pandemic (COVID-19) is disrupting the entire world; its rapid global spread threatens to affect millions of people. Accurate and timely diagnosis of COVID-19 is essential to control the spread and alleviate risk. Due to the promising results achieved by integrating machine learning (ML), particularly deep learning (DL), in automating the multiple disease diagnosis process. In the current study, a model based on deep learning was proposed for the automated diagnosis of COVID-19 using chest X-ray images (CXR) and clinical data of the patient. The aim of this study is to investigate the effects of integrating clinical patient data with the CXR for automated COVID-19 diagnosis. The proposed model used data collected from King Fahad University Hospital, Dammam, KSA, which consists of 270 patient records. The experiments were carried out first with clinical data, second with the CXR, and finally with clinical data and CXR. The fusion technique was used to combine the clinical features and features extracted from images. The study found that integrating clinical data with the CXR improves diagnostic accuracy. Using the clinical data and the CXR, the model achieved an accuracy of 0.970, a recall of 0.986, a precision of 0.978, and an F-score of 0.982. Further validation was performed by comparing the performance of the proposed system with the diagnosis of an expert. Additionally, the results have shown that the proposed system can be used as a tool that can help the doctors in COVID-19 diagnosis.

Pathogenic variants in aminoacyl-tRNA synthetases (ARS1) cause a diverse spectrum of autosomal recessive disorders. Tyrosyl tRNA synthetase (TyrRS) is encoded by YARS1 (cytosolic, OMIM*603,623) and is responsible of coupling tyrosine to its specific tRNA. Next to the enzymatic domain, TyrRS has two additional functional domains (N-Terminal TyrRS Mini and C-terminal EMAP-II-like domain) which confer cytokine-like functions. Mutations in YARS1 have been associated with autosomal-dominant Charcot-Marie-Tooth (CMT) neuropathy type C and a heterogenous group of autosomal recessive, multisystem diseases. We identified 12 individuals from 6 families with the recurrent homozygous missense variant c.1099C > T;p.(Arg367Trp) (NM&#95;003680.3) in YARS1. This variant causes a multisystem disorder with developmental delay, microcephaly, failure to thrive, short stature, muscular hypotonia, ataxia, brain anomalies, microcytic anemia, hepatomegaly, and hypothyroidism. In silico analyses show that the p.(Arg367Trp) does not affect the catalytic domain responsible of enzymatic coupling, but destabilizes the cytokine-like C-terminal domain. The phenotype associated with p.(Arg367Trp) is distinct from the other biallelic pathogenic variants that reside in different functional domains of TyrRS which all show some common, but also divergent clinical signs [(e.g., p.(Phe269Ser)-retinal anomalies, p.(Pro213Leu)/p.(Gly525Arg)-mild ID, p.(Pro167Thr)-high fatality)]. The diverse clinical spectrum of ARS1-associated disorders is related to mutations affecting the various non-canonical domains of ARS1, and impaired protein translation is likely not the exclusive disease-causing mechanism of YARS1- and ARS1-associated neurodevelopmental disorders. KEY MESSAGES: The missense variant p.(Arg367Trp) in YARS1 causes a distinct multisystem disorder. p.(Arg367Trp) affects a non-canonical domain with cytokine-like functions. Phenotypic heterogeneity associates with the different affected YARS1 domains. Impaired protein translation is likely not the exclusive mechanism of ARS1-associated disorders., (© 2021. The Author(s).)

Purpose: N-terminal acetyltransferases modify proteins by adding an acetyl moiety to the first amino acid and are vital for protein and cell function. The NatB complex acetylates 20% of the human proteome and is composed of the catalytic subunit NAA20 and the auxiliary subunit NAA25. In five individuals with overlapping phenotypes, we identified recessive homozygous missense variants in NAA20., Methods: Two different NAA20 variants were identified in affected individuals in two consanguineous families by exome and genome sequencing. Biochemical studies were employed to assess the impact of the NAA20 variants on NatB complex formation and catalytic activity., Results: Two homozygous variants, NAA20 p.Met54Val and p.Ala80Val (GenBank: NM&#95;016100.4, c.160A>G and c.239C>T), segregated with affected individuals in two unrelated families presenting with developmental delay, intellectual disability, and microcephaly. Both NAA20-M54V and NAA20-A80V were impaired in their capacity to form a NatB complex with NAA25, and in vitro acetylation assays revealed reduced catalytic activities toward different NatB substrates. Thus, both NAA20 variants are impaired in their ability to perform cellular NatB-mediated N-terminal acetylation., Conclusion: We present here a report of pathogenic NAA20 variants causing human disease and data supporting an essential role for NatB-mediated N-terminal acetylation in human development and physiology., (© 2021. The Author(s).)

Background: Molecular autopsy refers to DNA-based identification of the cause of death. Despite recent attempts to broaden its scope, the term remains typically reserved to sudden unexplained death in young adults. In this study, we aim to showcase the utility of molecular autopsy in defining lethal variants in humans., Methods: We describe our experience with a cohort of 481 cases in whom the cause of premature death was investigated using DNA from the index or relatives (molecular autopsy by proxy). Molecular autopsy tool was typically exome sequencing although some were investigated using targeted approaches in the earlier stages of the study; these include positional mapping, targeted gene sequencing, chromosomal microarray, and gene panels., Results: The study includes 449 cases from consanguineous families and 141 lacked family history (simplex). The age range was embryos to 18 years. A likely causal variant (pathogenic/likely pathogenic) was identified in 63.8% (307/481), a much higher yield compared to the general diagnostic yield (43%) from the same population. The predominance of recessive lethal alleles allowed us to implement molecular autopsy by proxy in 55 couples, and the yield was similarly high (63.6%). We also note the occurrence of biallelic lethal forms of typically non-lethal dominant disorders, sometimes representing a novel bona fide biallelic recessive disease trait. Forty-six disease genes with no OMIM phenotype were identified in the course of this study. The presented data support the candidacy of two other previously reported novel disease genes (FAAH2 and MSN). The focus on lethal phenotypes revealed many examples of interesting phenotypic expansion as well as remarkable variability in clinical presentation. Furthermore, important insights into population genetics and variant interpretation are highlighted based on the results., Conclusions: Molecular autopsy, broadly defined, proved to be a helpful clinical approach that provides unique insights into lethal variants and the clinical annotation of the human genome., (© 2021. The Author(s).)

Background: Pulmonary embolism (PE) is a common life-threatening medical emergency that needs prompt diagnosis and management. Providing urgent care is a key determinant of quality in the emergency department (ED) and time-based targets have been implemented to reduce length of stay and overcrowding. The study aimed to determine factors that are associated with having a time-to-disposition of less than 4 h in patients with suspected PE who underwent computed tomography pulmonary angiography (CT-PA) to confirm the diagnosis., Methods: After obtaining approval from the ethics committee, we conducted a retrospective observational study by examining CT-PA scans that was performed to rule out PE in all adult patients presenting at the ED between January 2018 and December 2019. Demographic information and clinical information, as well as arrival and disposition times were collected from electronic health records. Multivariable regression analysis was used to identify the independent factors associated with meeting the 4-h target in the ED., Results: In total, the study involved 232 patients (76 men and 156 women). The median length of stay in the ED was 5.2 h and the 4-h target was achieved in 37% of patients. Multivariable logistic regression analysis revealed that a positive CT-PA scan for PE was independently associated with meeting the four-hour target in the ED (odds ratio [OR]: 2.2; 95% CI: 1.1-4.8). Furthermore, Hemoptysis was the only clinical symptom that served as an independent factor associated with meeting the 4-h target in the ED (OR: 10.4; 95% CI: 1.2-90.8)., Conclusion: Despite the lower number of staff and higher volume of patients on weekends, patients who presented on weekends had shorter stays and were more likely to meet the 4-h target. Careful clinical assessment, prior to requesting a CT-PA scan, is crucial, since negative CT-PA scans may be associated with failure to meet the 4-h target., (© 2021. The Author(s).)

The purpose of this study is to describe a Mendelian disorder of DNA damage repair. Phenotypic delineation of two families, one new and one previously published, with overlapping dysmorphic and neurodevelopmental features was undertaken. Functional characterization of DNA damage repair in fibroblasts obtained from the index individuals in each of the two families was pursued. We present new evidence of a distinct disorder caused by biallelic truncating variants in ZNF668 comprising microcephaly, growth deficiency, severe global developmental delay, brain malformation, and distinct facial dysmorphism. DNA damage repair defect was observed in fibroblasts of affected individuals. ZNF668 deficiency in humans results in a recognizable autosomal recessive disorder, which we propose to name ZNF668-related ZMAND (ZNF668-related brain malformation, microcephaly, abnormal growth, neurodevelopmental delay, and dysmorphism). Our results add to the growing list of Mendelian disorders of the DNA damage repair machinery., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To investigate the effect of PLXNA1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and to functionally characterize the zebrafish homologs plxna1a and plxna1b during development., Methods: We assembled ten patients from seven families with biallelic or de novo PLXNA1 variants. We describe genotype-phenotype correlations, investigated the variants by structural modeling, and used Morpholino knockdown experiments in zebrafish to characterize the embryonic role of plxna1a and plxna1b., Results: Shared phenotypic features among patients include global developmental delay (9/10), brain anomalies (6/10), and eye anomalies (7/10). Notably, seizures were predominantly reported in patients with monoallelic variants. Structural modeling of missense variants in PLXNA1 suggests distortion in the native protein. Our zebrafish studies enforce an embryonic role of plxna1a and plxna1b in the development of the central nervous system and the eye., Conclusion: We propose that different biallelic and monoallelic variants in PLXNA1 result in a novel neurodevelopmental syndrome mainly comprising developmental delay, brain, and eye anomalies. We hypothesize that biallelic variants in the extracellular Plexin-A1 domains lead to impaired dimerization or lack of receptor molecules, whereas monoallelic variants in the intracellular Plexin-A1 domains might impair downstream signaling through a dominant-negative effect., (© 2021. The Author(s).)

BACKGROUND Cerebral palsy may be accompanied by gastrointestinal disorders. Percutaneous endoscopic gastrostomy (PEG) tube placement is an increasingly performed procedure in these patients. While PEG tube feeding can result in weight gain and a decrease in aspiration episodes, this insertion of a PEG tube is not without complications. Specifically, intestinal volvulus following PEG tube insertion is an exceedingly rare complication. CASE REPORT A 34-year-old man with cerebral palsy was brought to the emergency department with a history of recurrent vomiting. He had a history of PEG tube insertion 2 months prior to his presentation. The physical examination was non-contributory. Abdominal computed tomography was suggestive of an intestinal volvulus around the PEG tube. Subsequently, the patient underwent an exploratory laparotomy, which confirmed the diagnosis and enabled successful management. Unexpectedly, the patient suffered cardiac arrest 5 days following the operation. Cardiopulmonary resuscitation was performed with pharmacological intervention and defibrillation in accordance with the advanced cardiac life support guidelines. He recovered successfully and was discharged after a 4-day observation. CONCLUSIONS Clinicians should have a high index of suspicion for small bowel volvulus in patients who had a PEG tube inserted, along with intestinal obstruction. Furthermore, caregivers should be educated to recognize the early signs of intestinal obstruction and seek medical attention, since a delay can result in fatal outcomes.

Background: Computers have become a fundamental part of clinical radiology departments. Radiologists tend to spend long hours in front of computers, reading and analyzing medical images. This prolonged use of computers is associated with digital eye strain. Therefore, this study aimed to estimate the prevalence of digital eye strain among radiologists and determine its contributory factors., Methods: An online survey was sent to radiologists practicing in hospitals in the Eastern Province of Saudi Arabia. The survey addressed demographic information, workload and workstation environment, personal eye care, and evaluation of digital eye strain symptoms as well as the strategies employed to reduce these symptoms. Results were analyzed descriptively using Chi-square tests and logistic regression analyses., Results: The survey was completed by 198 participants (111 men and 87 women), including residents (40.9%), senior registrars (27.3%), and consultants (27.3%). Most participants (71.2%) were aged below 40 years. Most participants tend to spend 7-9 hours daily reviewing medical images. Overall, 50 participants (25.3%) take a break from work once daily only. A total of 53 participants (26.8%) reported undergoing an eye examination within the past year and 100 participants (50.5%) reported experiencing digital eye strain. Multivariate logistic regression analysis revealed that female sex (odds ratio [OR] = 3.9; 95% confidence interval [95% CI]: 1.6-10.0) and the practice of taking breaks once a day (OR = 15.1; 95% CI: 2.4-94.1) or twice a day (OR = 5.5; 95% CI: 1.1-28.4) only were associated with higher rates of digital eye strain symptoms., Conclusion: Digital eye strain is a prevalent condition among radiologists regardless of their subspecialty. It is more commonly seen among radiology residents. Being a female and not taking frequent breaks were associated with higher rates of digital eye strain., (Copyright © 2020 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

BACKGROUND Gangliocytic paraganglioma is an extremely rare tumor, with only 263 reported cases. This tumor has heterogeneous clinical presentation, with gastrointestinal bleeding being the most common. However, jaundice is a relatively unusual presentation, seen in less than 5% of all cases. CASE REPORT We report the case of a 32-year-old man who presented with abdominal pain and jaundice. He reported having similar episodes of this pain recently, but they were milder in severity. On examination, there was a tenderness in the right upper quadrant with a positive Murphy sign. Laboratory investigation revealed total bilirubin of 3.6 mg/dL with a direct bilirubin of 3.0 mg/dL, alkaline phosphatase of 323 IU/L, and g-glutamyltransferase level of 1153 IU/L, giving the impression of obstructive jaundice. The abdominal ultrasound examination revealed a normal common bile duct diameter with no thickening or pericholecystic fluid noted. Subsequently, the patient underwent endoscopic retrograde cholangiopancreatography, which revealed a mass in the second part of the duodenum. Histopathological examination of biopsy specimens obtained by fine-needle biopsy revealed an unencapsulated submucosal lesion with epithelioid, spindle, and ganglion cells. The spindle cells expressed positive immunohistochemical staining for S100, synaptophysin, and chromogranin. These findings were consistent with the diagnosis of gangliocytic paraganglioma. Surgical resection of the tumor was advised. However, the patient refused the operation despite the recommendation of the oncology team. CONCLUSIONS Gangliocytic paraganglioma is a very rare tumor that may present with a clinical picture mimicking a biliary disease. Clinicians should have a high index of suspicion for duodenal lesions in patients presenting with obstructive jaundice with no evidence of biliary stones.

TP73 belongs to the TP53 family of transcription factors and has therefore been well studied in cancer research. Studies in mice, however, have revealed non-oncogenic activities related to multiciliogenesis. Utilizing whole-exome sequencing analysis in a cohort of individuals with a mucociliary clearance disorder and cortical malformation, we identified homozygous loss-of-function variants in TP73 in seven individuals from five unrelated families. All affected individuals exhibit a chronic airway disease as well as a brain malformation consistent with lissencephaly. We performed high-speed video microscopy, immunofluorescence analyses, and transmission electron microscopy in respiratory epithelial cells after spheroid or air liquid interface culture to analyze ciliary function, ciliary length, and number of multiciliated cells (MCCs). The respiratory epithelial cells studied display reduced ciliary length and basal bodies mislocalized within the cytoplasm. The number of MCCs is severely reduced, consistent with a reduced number of cells expressing the transcription factors crucial for multiciliogenesis (FOXJ1, RFX2). Our data demonstrate that autosomal-recessive deleterious variants in the TP53 family member TP73 cause a mucociliary clearance disorder due to a defect in MCC differentiation., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Autophagy is the major intracellular degradation route in mammalian cells. Systemic ablation of core autophagy-related ( ATG ) genes in mice leads to embryonic or perinatal lethality, and conditional models show neurodegeneration. Impaired autophagy has been associated with a range of complex human diseases, yet congenital autophagy disorders are rare., Methods: We performed a genetic, clinical, and neuroimaging analysis involving five families. Mechanistic investigations were conducted with the use of patient-derived fibroblasts, skeletal muscle-biopsy specimens, mouse embryonic fibroblasts, and yeast., Results: We found deleterious, recessive variants in human ATG7 , a core autophagy-related gene encoding a protein that is indispensable to classical degradative autophagy. Twelve patients from five families with distinct ATG7 variants had complex neurodevelopmental disorders with brain, muscle, and endocrine involvement. Patients had abnormalities of the cerebellum and corpus callosum and various degrees of facial dysmorphism. These patients have survived with impaired autophagic flux arising from a diminishment or absence of ATG7 protein. Although autophagic sequestration was markedly reduced, evidence of basal autophagy was readily identified in fibroblasts and skeletal muscle with loss of ATG7. Complementation of different model systems by deleterious ATG7 variants resulted in poor or absent autophagic function as compared with the reintroduction of wild-type ATG7 ., Conclusions: We identified several patients with a neurodevelopmental disorder who have survived with a severe loss or complete absence of ATG7, an essential effector enzyme for autophagy without a known functional paralogue. (Funded by the Wellcome Centre for Mitochondrial Research and others.)., (Copyright © 2021 Massachusetts Medical Society.)

BCAS3 microtubule-associated cell migration factor (BCAS3) is a large, highly conserved cytoskeletal protein previously proposed to be critical in angiogenesis and implicated in human embryogenesis and tumorigenesis. Here, we established BCAS3 loss-of-function variants as causative for a neurodevelopmental disorder. We report 15 individuals from eight unrelated families with germline bi-allelic loss-of-function variants in BCAS3. All probands share a global developmental delay accompanied by pyramidal tract involvement, microcephaly, short stature, strabismus, dysmorphic facial features, and seizures. The human phenotype is less severe compared with the Bcas3 knockout mouse model and cannot be explained by angiogenic defects alone. Consistent with being loss-of-function alleles, we observed absence of BCAS3 in probands' primary fibroblasts. By comparing the transcriptomic and proteomic data based on probands' fibroblasts with those of the knockout mouse model, we identified similar dysregulated pathways resulting from over-representation analysis, while the dysregulation of some proposed key interactors could not be confirmed. Together with the results from a tissue-specific Drosophila loss-of-function model, we demonstrate a vital role for BCAS3 in neural tissue development., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may not elicit lifelong protective immunity and reinfection could occur. Liver function impairment is a common manifestation of coronavirus disease 2019 (COVID-19). However, acute hepatic failure in the setting of COVID-19 is very rare., Case Presentation: We report the case of a 47-year-old woman who presented with acute abdominal pain and vomiting. Abdominal examination revealed a soft and lax abdomen with mild tenderness in the right upper quadrant. The patient recovered from COVID-19 2 months previously with negative results on reverse transcription-polymerase chain reaction (RT-PCR). Laboratory investigations revealed markedly elevated transaminases with normal results on viral hepatitis serology panel and undetectable blood paracetamol level. Prior to admission, the patient underwent RT-PCR for SARS-CoV-2, which revealed a positive result. The patient experienced rapid deterioration in the neurological status with a remarkable increase in the liver enzyme levels. Despite aggressive resuscitation, the patient suffered irreversible cardiac arrest and died., Conclusion: Fulminant hepatic failure is a rare manifestation in patients with re-positive RT-PCR tests for SARS-CoV-2. Clinicians should maintain a high index of suspicion for hepatic injury with active monitoring of liver enzymes.

Purpose: To identify novel genes associated with intellectual disability (ID) in four unrelated families., Methods: Here, through exome sequencing and international collaboration, we report eight individuals from four unrelated families of diverse geographic origin with biallelic loss-of-function variants in UBE4A., Results: Eight evaluated individuals presented with syndromic intellectual disability and global developmental delay. Other clinical features included hypotonia, short stature, seizures, and behavior disorder. Characteristic features were appreciated in some individuals but not all; in some cases, features became more apparent with age. We demonstrated that UBE4A loss-of-function variants reduced RNA expression and protein levels in clinical samples. Mice generated to mimic patient-specific Ube4a loss-of-function variant exhibited muscular and neurological/behavioral abnormalities, some of which are suggestive of the clinical abnormalities seen in the affected individuals., Conclusion: These data indicate that biallelic loss-of-function variants in UBE4A cause a novel intellectual disability syndrome, suggesting that UBE4A enzyme activity is required for normal development and neurological function.

Background: Family medicine physicians may encounter a wide variety of conditions, including acute and urgent cases. Considering the limited access to diagnostic investigations in primary care practice, chest X-ray remains the imaging modality of choice. The current study assessed the competency of family medicine residents in the interpretation of chest X-rays for emergency conditions and to compare it with that of diagnostic radiology residents, general practitioners, and medical interns., Methods: An online survey was distributed to 600 physicians, including family medicine residents, medical interns, general practitioners, and diagnostic radiology residents. The study included some background information such as gender, years in practice, training type, interest in pulmonary medicine and diagnostic radiology, and having adequate training on the interpretation of chest X-rays. The survey had 10 chest X-ray cases with brief clinical information. Participants were asked to choose the most likely diagnosis and to rate their degree of confidence in the interpretation of the chest X-ray for each case., Results: The survey was completed by 205 physicians (response rate = 34.2%). The overall diagnostic accuracy was 63.1% with a significant difference between family medicine and radiology residents (58.0% vs. 90.5%; P < 0.001). The COVID-19 pneumonia (85.4%) and pneumoperitoneum (80.5%) cases had the highest diagnostic accuracy scores. There was a significant correlation between the diagnostic confidence and accuracy (r s  = 0.39; P < 0.001). Multivariable regression analysis revealed that being diagnostic radiology residents (odds ratio [OR]: 13.0; 95% confidence interval [CI]: 2.5-67.7) and having higher diagnostic confidence (OR: 2.2; 95% CI: 1.3-3.8) were the only independent predictors of achieving high diagnostic accuracy., Conclusion: The competency of family medicine residents in the interpretation of chest X-ray for emergency conditions was far from optimal. The introduction of radiology training courses on emergency conditions seems imperative. Alternatively, the use of tele-radiology in primary healthcare centers should be considered.

Background: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy that is strongly associated with chronic liver disease. Isolated hepatic tuberculosis is an uncommon type of tuberculosis. Concomitant occurrence of both conditions is extremely rare., Case Presentation: We report the case of a 47-year-old man who presented with fever and abdominal pain for 3 months prior to presentation. He reported a history of anorexia and significant weight loss. Abdominal examination revealed a tender, enlarged liver. Abdominal computed tomography (CT) demonstrated a solid heterogeneous hepatic mass with peripheral arterial enhancement, but no venous washout, conferring a radiological impression of suspected cholangiocarcinoma. However, a CT-guided biopsy of the lesion resulted in the diagnosis of concomitant HCC and isolated hepatic tuberculosis., Conclusion: A rapid increase in tumor size should draw attention to the possibility of a concomitant infectious process. Clinicians must have a high index of suspicion for tuberculosis, especially in patients from endemic areas, in order to initiate early and proper treatment.

Autism spectrum disorder (ASD) is a constellation of neurodevelopmental disorders with high phenotypic and genetic heterogeneity, complicating the discovery of causative genes. Through a forward genetics approach selecting for defective vocalization in mice, we identified Kdm5a as a candidate ASD gene. To validate our discovery, we generated a Kdm5a knockout mouse model ( Kdm5a -/- ) and confirmed that inactivating Kdm5a disrupts vocalization. In addition, Kdm5a -/- mice displayed repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis. Loss of KDM5A also resulted in dysregulation of the hippocampal transcriptome. To determine if KDM5A mutations cause ASD in humans, we screened whole exome sequencing and microarray data from a clinical cohort. We identified pathogenic KDM5A variants in nine patients with ASD and lack of speech. Our findings illustrate the power and efficacy of forward genetics in identifying ASD genes and highlight the importance of KDM5A in normal brain development and function., Competing Interests: LE, IT, NN, JR, SL, KK, XL, PA, MT, AG, AH, PZ, HA, AR, KH, MA, CW, BD, RL, MC, MF, RR, RA, EE, RM, HH, AL, BB, MC No competing interests declared, (© 2020, El Hayek et al.)

Recently, the genetic cause of HIDEA syndrome (hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities) was identified as biallelic pathogenic variants in P4HTM, which encodes an atypical member of the prolyl 4-hydroxylases (P4Hs) family of enzymes. We report seven patients from four new families in whom HIDEA was only diagnosed after whole-exome sequencing (WES) revealed novel disease-causing variants in P4HTM. We note the variable phenotypic expressivity of the syndrome except for cognitive impairment/developmental delay, and hypotonia, which seem to be consistent findings. One patient only presented with hypotonia, developmental delay, and abnormal eye movements, which highlights the challenge in diagnosing milder cases with this new syndrome. Other notable features include mild facial dysmorphism, obesity, and brain dysmyelination and atrophy. We conclude that HIDEA is a highly variable syndrome and suspect that a large fraction of patients will be diagnosed via reverse phenotyping after recessive P4HTM variants are identified by agnostic genomic sequencing assays., (© 2020 Wiley Periodicals LLC.)

Major Facilitator Superfamily Domain containing 2a (MFSD2A) is an essential endothelial lipid transporter at the blood-brain barrier. Biallelic variants affecting function in MFSD2A cause autosomal recessive primary microcephaly 15 (MCPH15, OMIM# 616486). We sought to expand our knowledge of the phenotypic spectrum of MCPH15 and demonstrate the underlying mechanism of inactivation of the MFSD2A transporter. We carried out detailed analysis of the clinical and neuroradiological features of a series of 27 MCPH15 cases, including eight new individuals from seven unrelated families. Genetic investigation was performed through exome sequencing (ES). Structural insights on the human Mfsd2a model and in-vitro biochemical assays were used to investigate the functional impact of the identified variants. All patients had primary microcephaly and severe developmental delay. Brain MRI showed variable degrees of white matter reduction, ventricular enlargement, callosal hypodysgenesis, and pontine and vermian hypoplasia. ES led to the identification of six novel biallelic MFSD2A variants (NG&#95;053084.1, NM&#95;032793.5: c.556+1G>A, c.748G>T; p.(Val250Phe), c.750&#95;753del; p.(Cys251SerfsTer3), c.977G>A; p.(Arg326His), c.1386&#95;1435del; p.(Gln462HisfsTer17), and c.1478C>T; p.(Pro493Leu)) and two recurrent variants (NM&#95;032793.5: c.593C>T; p.(Thr198Met) and c.476C>T; p.(Thr159Met)). All these variants and the previously reported NM&#95;032793.5: c.490C>A; p.(Pro164Thr) resulted in either reduced MFSD2A expression and/or transport activity. Our study further delineates the phenotypic spectrum of MCPH15, refining its clinical and neuroradiological characterization and supporting that MFSD2A deficiency causes early prenatal brain developmental disruption. We also show that poor MFSD2A expression despite normal transporter activity is a relevant pathomechanism in MCPH15.

Purpose: Computed tomography pulmonary angiography (CT-PA) is the diagnostic modality used for pulmonary embolism (PE). This study aimed to estimate the positive CT-PA rate and identify the predictors of positive CT-PA results., Methods: A retrospective observational study was conducted by examining the CT-PA data for ruling out PE in all adult patients who visited the King Fahd Hospital of Imam Abdulrahman Bin Faisal University. The data regarding background demographic information, clinical information, and CT-PA findings were collected from electronic health records. Data were analyzed descriptively using the chi-squared test. Multivariate regression analysis was used to identify the predictors of positive CT-PA results., Results: In total, 548 patients (209 male, 339 female) who underwent CT-PA scans were included. The positive CT-PA rate was 18.8%. The Charlson Comorbidity Index was not significantly associated with positive CT-PA results (p = 0.456). Multivariate logistic regression analysis revealed that smoking (odds ratio [OR] 4.96; 95% confidence interval [95% CI] 2.05-12.02) was an independent factor associated with positive CT-PA results. The CT-PA scans performed in winter and spring were 43% (OR 0.43; 95% CI 0.22-0.84) and 52% (OR 0.52; 95% CI 0.28-0.97) less likely to show positive results compared with those performed in autumn, respectively., Conclusion: The positive CT-PA rate varied significantly between seasons. Smoking was a predictor of positive CT-PA results. These findings may assist in developing interventions for improving the utilization of CT-PA scans to avoid unnecessary exposure of patients to radiation., Clinical Trial Registration: N/A.

Background: Pulmonary embolism (PE) is a common life-threatening condition with non-specific clinical presentations. The diagnosis of PE depends highly on imaging studies, which may also provide prognostic information. This study aimed to describe the clinical and imaging profiles of patients with PE, emphasizing the differences between central and peripheral PE., Methods: After ethics review board approval, this retrospective observational study examined the non-negative results in adult patients who underwent computed tomography pulmonary angiography (CT-PA) at our hospital between May 2016 and December 2019. Demographic and clinical information and imaging findings were collected from the electronic medical records., Results: The study included 85 cases that were identified after re-interpreting the 103 non-negative CT-PA scans. Six cases were excluded for incomplete data and 12 cases were false-positive. Central PE was found in 63.5% of the cases. Obesity was the most common risk factor seen in 37.6% of the cases. Furthermore, 9.4% of the patients had sickle cell disease, which tended to be associated with peripheral PE. There was no difference between the peripheral and central PE in most clinical and imaging parameters evaluated (P > 0.05). However, patients with isolated subsegmental PE were more likely to develop hemoptysis (P = 0.04)., Conclusion: This study suggests that patients with obesity and sickle cell disease constitute an important proportion of all PE cases. Furthermore, the clinical and imaging profiles in patients with peripheral PE are similar to those in patients with central PE. Future research should focus on the clinical value of peripheral PE in patients with sickle cell disease.

Background: The practice of clinical radiology has become more sedentary in the era of the Picture Archiving and Communication System. Physical inactivity is a well-known risk factor for various chronic diseases. This study aimed to determine the frequency and pattern of physical exercises among radiologists in the Eastern Province of Saudi Arabia and the association between physical exercises and the prevalence of work-related musculoskeletal symptoms., Methods: An online survey was sent to radiologists in all hospitals (academic, public, and private) in the major cities of the Eastern Province of Saudi Arabia. It covered information about demographic characteristics and the frequency and pattern of physical exercises. It also included an evaluation of work-related musculoskeletal symptoms using the Nordic Musculoskeletal Questionnaire. This survey of 263 radiologists was conducted in April 2019. The study outcome was the presence of disabling musculoskeletal symptoms in any body region which restricted the performance of normal activities within the last 12 months. The study results were analyzed descriptively using the Chi-square test., Results: The survey was completed by 198 participants (111 men and 87 women) with a response rate of 75.3%. Most participants (71.2%) were less than 40 years. Eighty-three men (74.8%) did a physical exercise at least weekly, compared to 45 (51.7%) women. Men were more likely to engage in various physical exercises than women. Overall, 60.9% of participants who did not do any physical exercise regularly (less than monthly) reported having disabling neck pain. This figure was found lower among participants who did physical exercises monthly (45.8%) or at least weekly (32.8%). A similar pattern was observed with shoulder pain, with 45.7% found in participants who did not exercise and only 25.8% in those engaging in physical activities at least weekly., Conclusions: Physical inactivity is common among radiologists, especially female ones, in the Eastern Province of Saudi Arabia. The physical inactivity was significantly associated with work-related musculoskeletal symptoms. Gender-specific health promotion programs are needed to mitigate the negative health outcomes due to the sedentary nature of the radiology current practice., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Gamma-aminobutyric acid (GABA) and glutamate are the most abundant amino acid neurotransmitters in the brain. GABA, an inhibitory neurotransmitter, is synthesized by glutamic acid decarboxylase (GAD). Its predominant isoform GAD67, contributes up to ∼90% of base-level GABA in the CNS, and is encoded by the GAD1 gene. Disruption of GAD1 results in an imbalance of inhibitory and excitatory neurotransmitters, and as Gad1-/- mice die neonatally of severe cleft palate, it has not been possible to determine any potential neurological dysfunction. Furthermore, little is known about the consequence of GAD1 disruption in humans. Here we present six affected individuals from six unrelated families, carrying bi-allelic GAD1 variants, presenting with developmental and epileptic encephalopathy, characterized by early-infantile onset epilepsy and hypotonia with additional variable non-CNS manifestations such as skeletal abnormalities, dysmorphic features and cleft palate. Our findings highlight an important role for GAD1 in seizure induction, neuronal and extraneuronal development, and introduce GAD1 as a new gene associated with developmental and epileptic encephalopathy., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: At least 50% of patients with suspected Mendelian disorders remain undiagnosed after whole-exome sequencing (WES), and the extent to which non-coding variants that are not captured by WES contribute to this fraction is unclear. Whole transcriptome sequencing is a promising supplement to WES, although empirical data on the contribution of RNA analysis to the diagnosis of Mendelian diseases on a large scale are scarce., Results: Here, we describe our experience with transcript-deleterious variants (TDVs) based on a cohort of 5647 families with suspected Mendelian diseases. We first interrogate all families for which the respective Mendelian phenotype could be mapped to a single locus to obtain an unbiased estimate of the contribution of TDVs at 18.9%. We examine the entire cohort and find that TDVs account for 15% of all "solved" cases. We compare the results of RT-PCR to in silico prediction. Definitive results from RT-PCR are obtained from blood-derived RNA for the overwhelming majority of variants (84.1%), and only a small minority (2.6%) fail analysis on all available RNA sources (blood-, skin fibroblast-, and urine renal epithelial cells-derived), which has important implications for the clinical application of RNA-seq. We also show that RNA analysis can establish the diagnosis in 13.5% of 155 patients who had received "negative" clinical WES reports. Finally, our data suggest a role for TDVs in modulating penetrance even in otherwise highly penetrant Mendelian disorders., Conclusions: Our results provide much needed empirical data for the impending implementation of diagnostic RNA-seq in conjunction with genome sequencing.

In mammals, a subset of arginine tRNA isoacceptors are methylated in the anticodon loop by the METTL2 methyltransferase to form the 3-methylcytosine (m3C) modification. However, the mechanism by which METTL2 identifies specific tRNA arginine species for m3C formation as well as the biological role of m3C in mammals is unknown. Here, we show that human METTL2 forms a complex with DALR anticodon binding domain containing 3 (DALRD3) protein to recognize particular arginine tRNAs destined for m3C modification. DALRD3-deficient human cells exhibit nearly complete loss of the m3C modification in tRNA-Arg species. Notably, we identify a homozygous nonsense mutation in the DALRD3 gene that impairs m3C formation in human patients exhibiting developmental delay and early-onset epileptic encephalopathy. These findings uncover an unexpected function for the DALRD3 protein in the targeting of distinct arginine tRNAs for m3C modification and suggest a crucial biological role for DALRD3-dependent tRNA modification in proper neurological development.

BACKGROUND Splenosis is a benign condition involving the auto-transplantation of splenic tissue at various locations, resulting from splenic injury or splenectomy. CASE REPORT A 40-year-old male, with a history of remote exploratory laparotomy with splenectomy secondary to blunt abdominal trauma, presented with symptoms consistent with acute appendicitis, which was subsequently confirmed by computed tomography scan of the abdomen that further demonstrated the presence of multiple abdominal nodules, one of which was adjacent to the appendix. A laparoscopic appendectomy was then performed along with resection of the nodule located in the mesoappendix, which was confirmed to be a splenic tissue based on histopathological examination. CONCLUSIONS Abdominal splenosis is not an uncommon condition in patients with a history of splenic injury. However, the involvement of the mesoappendix, which may or may not contribute to acute inflammation of the appendix, is very rare.

Arthrogryposis multiplex congenita (AMC) is an important birth defect with a significant genetic contribution. Many syndromic forms of AMC have been described, but remain unsolved at the molecular level. In this report, we describe a novel syndromic form of AMC in two multiplex consanguineous families from Saudi Arabia and Oman. The phenotype is highly consistent, and comprises neurogenic arthrogryposis, microcephaly, brain malformation (absent corpus callosum), optic atrophy, limb fractures, profound global developmental delay, and early lethality. Whole-exome sequencing revealed a different homozygous truncating variant in SCYL2 in each of the two families. SCYL2 is a component of clathrin-coated vesicles, and deficiency of its mouse ortholog results in a severe neurological phenotype that largely recapitulates the phenotype observed in our patients. Our results suggest that severe neurogenic arthrogryposis with brain malformation is the human phenotypic consequence of SCYL2 loss of function mutations.

The gene IL6ST encodes GP130, the common signal transducer of the IL-6 cytokine family consisting of 10 cytokines. Previous studies have identified cytokine-selective IL6ST defects that preserve LIF signaling. We describe three unrelated families with at least five affected individuals who presented with lethal Stüve-Wiedemann-like syndrome characterized by skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response. We identified essential loss-of-function variants in IL6ST (a homozygous nonsense variant and a homozygous intronic splice variant with exon skipping). Functional tests showed absent cellular responses to GP130-dependent cytokines including IL-6, IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF). Genetic reconstitution of GP130 by lentiviral transduction in patient-derived cells reversed the signaling defect. This study identifies a new genetic syndrome caused by the complete lack of signaling of a whole family of GP130-dependent cytokines in humans and highlights the importance of the LIF signaling pathway in pre- and perinatal development., Competing Interests: Disclosures: Dr. Chen reported grants from Celgene during the conduct of the study and grants from Celgene outside the submitted work. Dr. Devey is an employee and stockholder of Celgene and is a former employee and stockholder of GlaxoSmithKline. Dr. Shanmugasundaram is an employee and stockholder of Celgene and a stockholder of Pfizer. Celgene has now become a wholly-owned subsidiary of Bristol-Myers Squibb. Dr. Aschenbrenner reported grants from UCB Pharma GmbH and grants from Eli Lilly and Company outside the submitted work. Dr. Uhlig reported grants from Celgene during the conduct of the study, grants from UCB Pharma, grants from Eli Lilly, personal fees from AbbVie, personal fees from Pfizer, and "other" from Regeneron outside the submitted work. No other disclosures were reported., (© 2020 Chen et al.)

MEDNIK syndrome (mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma) is an autosomal-recessive disorder caused by bi-allelic mutations in AP1S1, encoding the small σ subunit of the AP-1 complex. Central to the pathogenesis of MEDNIK syndrome is abnormal AP-1-mediated trafficking of copper transporters; this abnormal trafficking results in a hybrid phenotype combining the copper-deficiency-related characteristics of Menkes disease and the copper-toxicity-related characteristics of Wilson disease. We describe three individuals from two unrelated families in whom a MEDNIK-like phenotype segregates with two homozygous null variants in AP1B1, encoding the large β subunit of the AP-1 complex. Similar to individuals with MEDNIK syndrome, the affected individuals we report display abnormal copper metabolism, evidenced by low plasma copper and ceruloplasmin, but lack evidence of copper toxicity in the liver. Functional characterization of fibroblasts derived from affected individuals closely resembles the abnormal ATP7A trafficking described in MEDNIK syndrome both at baseline and in response to copper treatment. Taken together, our results expand the list of inborn errors of copper metabolism., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

We report four unrelated children with homozygous loss-of-function variants in TASP1 and an overlapping phenotype comprising developmental delay with hypotonia and microcephaly, feeding difficulties with failure-to-thrive, recurrent respiratory infections, cardiovascular malformations, cryptorchidism, happy demeanor, and distinctive facial features. Two children had a homozygous founder deletion encompassing exons 5-11 of TASP1, the third had a homozygous missense variant, c.701 C>T (p.Thr234Met), affecting the active site of the encoded enzyme, and the fourth had a homozygous nonsense variant, c.199 C>T (p.Arg67*). TASP1 encodes taspase 1 (TASP1), which is responsible for cleaving, thus activating, the lysine methyltransferases KMT2A and KMT2D, which are essential for histone methylation and transcription regulation. The consistency of the phenotype, the critical biological function of TASP1, the deleterious nature of the TASP1 variants, and the overlapping features with Wiedemann-Steiner and Kabuki syndromes respectively caused by pathogenic variants in KMT2A and KMT2D all support that TASP1 is a disease-related gene., (© 2019 Wiley Periodicals, Inc.)

Objectives: Chest computed tomography is commonly used in patients with primary spontaneous pneumothorax to detect the presence of pulmonary blebs or bullae. The aim of this study is to calculate the accuracy of chest computed tomography to detect surgically resectable blebs or bullae in patients with primary spontaneous pneumothorax., Methods: This is a retrospective study includes all patients with primary spontaneous pneumothorax who underwent chest computed tomography evaluation for their disease over the period from January 2005 to December 2015. Patients who underwent surgical exploration were sub-grouped to calculate the sensitivity and the specificity of the chest computed tomography to detect surgically resectable pulmonary blebs or bullae., Results: A total of 143 patients were included in the study. Among them, 120 patients underwent surgical exploration with the finding of 95.7% sensitivity and 42.3% specificity for the chest computed tomography in detection of surgically resectable pulmonary blebs or bullae., Conclusion: The sensitivity of the chest computed tomography scan is high in detecting surgically resectable pulmonary blebs or bullae. However, the specificity is low. This may lead to overdiagnosis of the patients to have pulmonary blebs and bullae. Therefore, the routine use of chest computed tomography scan before the surgical exploration in patients with primary spontaneous pneumothorax should depend on the clinical judgment.

Primary congenital glaucoma is a trabecular meshwork dysgenesis with resultant increased intraocular pressure and ocular damage. CYP1B1 mutations remain the most common identifiable genetic cause. However, important questions about the penetrance of CYP1B1-related congenital glaucoma remain unanswered. Furthermore, mutations in other genes have been described although their exact contribution and potential genetic interaction, if any, with CYP1B1 mutations are not fully explored. In this study, we employed modern genomic approaches to re-examine CYP1B1-related congenital glaucoma. A cohort of 193 patients (136 families) diagnosed with congenital glaucoma. We identified biallelic CYP1B1 mutations in 80.8% (87.5 and 66.1% in familial and sporadic cases, respectively, p < 0.0086). The large family size of the study population allowed us to systematically examine penetrance of all identified alleles. With the exception of c.1103G>A (p.R368H), previously reported pathogenic mutations were highly penetrant (91.2%). We conclude from the very low penetrance and genetic epidemiological analyses that c.1103G>A (p.R368H) is unlikely to be a disease-causing recessive mutation in congenital glaucoma as previously reported. All cases that lacked biallelic CYP1B1 mutations underwent whole exome sequencing. No mutations in LTBP2, MYOC or TEK were encountered. On the other hand, mutations were identified in genes linked to other ophthalmic phenotypes, some inclusive of glaucoma, highlighting conditions that might phenotypically overlap with primary congenital glaucoma (SLC4A4, SLC4A11, CPAMD8, and KERA). We also encountered candidate causal variants in genes not previously linked to human diseases: BCO2, TULP2, and DGKQ. Our results both expand and refine the genetic spectrum of congenital glaucoma with important clinical implications.

Purpose: Genetic testing in pediatric cholestasis can be very informative but genetic causes have not been fully characterized., Methods: Exome sequencing and positional mapping in seven families with cholestatic liver disease and negative clinical testing for known disease genes., Results: KIF12, which encodes a microtubule motor protein with a tentative role in cell polarity, was found to harbor three homozygous likely deleterious variants in three families with sclerosing cholangitis. KIF12 expression is dependent on HNF-1β, deficiency which is known to cause bile duct dysmorphogenesis associated with loss of KIF12 expression. In another extended family, we mapped an apparently novel syndrome of sclerosing cholangitis, short stature, hypothyroidism, and abnormal tongue pigmentation in two cousins to a homozygous variant in PPM1F (POPX2), a regulator of kinesin-mediated ciliary transport. In the fifth family, a syndrome of normal gamma glutamyltransferase (GGT) cholestasis and hearing loss was found to segregate with a homozygous truncating variant in USP53, which encodes an interactor with TJP2. In the sixth family, we mapped a novel syndrome of transient neonatal cholestasis, intellectual disability, and short stature to a homozygous variant in LSR, an important regulator of liver development. In the last family of three affected siblings, a novel syndrome of intractable itching, hypercholanemia, short stature, and intellectual disability was mapped to a single locus that contains a homozygous truncating variant in WDR83OS (C19orf56), known to interact with ATP13A2 and BSEP., Conclusion: Our results expand the genetic heterogeneity of pediatric cholestatic liver disease and highlight the vulnerability of bile homeostasis to a wide range of molecular perturbations.

Purpose: Establishing links between Mendelian phenotypes and genes enables the proper interpretation of variants therein. Autozygome, a rich source of homozygous variants, has been successfully utilized for the high throughput identification of novel autosomal recessive disease genes. Here, we highlight the utility of the autozygome for the high throughput confirmation of previously published tentative links to diseases., Methods: Autozygome and exome analysis of patients with suspected Mendelian phenotypes. All variants were classified according to the American College of Medical Genetics and Genomics guidelines., Results: We highlight 30 published candidate genes (ACTL6B, ADAM22, AGTPBP1, APC, C12orf4, C3orf17 (NEPRO), CENPF, CNPY3, COL27A1, DMBX1, FUT8, GOLGA2, KIAA0556, LENG8, MCIDAS, MTMR9, MYH11, QRSL1, RUBCN, SLC25A42, SLC9A1, TBXT, TFG, THUMPD1, TRAF3IP2, UFC1, UFM1, WDR81, XRCC2, ZAK) in which we identified homozygous likely deleterious variants in patients with compatible phenotypes. We also identified homozygous likely deleterious variants in 18 published candidate genes (ABCA2, ARL6IP1, ATP8A2, CDK9, CNKSR1, DGAT1, DMXL2, GEMIN4, HCN2, HCRT, MYO9A, PARS2, PLOD3, PREPL, SCLT1, STX3, TXNRD2, WIPI2) although the associated phenotypes are sufficiently different from the original reports that they represent phenotypic expansion or potentially distinct allelic disorders., Conclusions: Our results should facilitate the timely relabeling of these candidate disease genes in relevant databases to improve the yield of clinical genomic sequencing.

Neurodevelopmental disorders (NDD) are genetically and phenotypically heterogeneous conditions due to defects in genes involved in development and function of the nervous system. Individuals with NDD, in addition to their primary neurodevelopmental phenotype, may also have accompanying syndromic features that can be very helpful diagnostically especially those with recognizable facial appearance. In this study, we describe ten similarly affected individuals from six unrelated families of different ethnic origins having bi-allelic truncating variants in TMEM94, which encodes for an uncharacterized transmembrane nuclear protein that is highly conserved across mammals. The affected individuals manifested with global developmental delay/intellectual disability, and dysmorphic facial features including triangular face, deep set eyes, broad nasal root and tip and anteverted nostrils, thick arched eye brows, hypertrichosis, pointed chin, and hypertelorism. Birthweight in the upper normal range was observed in most, and all but one had congenital heart defects (CHD). Gene expression analysis in available cells from affected individuals showed reduced expression of TMEM94. Global transcriptome profiling using microarray and RNA sequencing revealed several dysregulated genes essential for cell growth, proliferation and survival that are predicted to have an impact on cardiotoxicity hematological system and neurodevelopment. Loss of Tmem94 in mouse model generated by CRISPR/Cas9 was embryonic lethal and led to craniofacial and cardiac abnormalities and abnormal neuronal migration pattern, suggesting that this gene is important in craniofacial, cardiovascular, and nervous system development. Our study suggests the genetic etiology of a recognizable dysmorphic syndrome with NDD and CHD and highlights the role of TMEM94 in early development., (Published by Elsevier Inc.)