Publications by authors named "Hakon Hakonarson"

688 Publications

A novel MBTPS2 variant associated with BRESHECK syndrome impairs sterol-regulated transcription and the endoplasmic reticulum stress response.

Am J Med Genet A 2021 Oct 15. Epub 2021 Oct 15.

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

Ichthyosis follicularis, atrichia, and photophobia syndrome (IFAP syndrome) is a rare, X-linked disorder caused by pathogenic variants in membrane-bound transcription factor protease, site 2 (MBTPS2). Pathogenic MBTPS2 variants also cause BRESHECK syndrome, characterized by the IFAP triad plus intellectual disability and multiple congenital anomalies. Here we present a patient with ichthyosis, sparse hair, pulmonic stenosis, kidney dysplasia, hypospadias, growth failure, thrombocytopenia, anemia, bone marrow fibrosis, and chronic diarrhea found by research-based exome sequencing to harbor a novel, maternally inherited MBTPS2 missense variant (c.766 G>A; (p.Val256Leu)). In vitro modeling supports variant pathogenicity, with impaired cell growth in cholesterol-depleted media, attenuated activation of the sterol regulatory element-binding protein pathway, and failure to activate the endoplasmic reticulum stress response pathway. Our case expands both the genetic and phenotypic spectrum of BRESHECK syndrome to include a novel MBTPS2 variant and cytopenias, bone marrow fibrosis, and chronic diarrhea.
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http://dx.doi.org/10.1002/ajmg.a.62537DOI Listing
October 2021

Rare neurological manifestations in a Saudi Arabian patient with Ehlers-Danlos syndrome and a novel homozygous variant in the TNXB gene.

Am J Med Genet A 2021 Oct 11. Epub 2021 Oct 11.

Center for Applied Genomics (CAG), The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

We report a 38-year-old Saudi male with Ehlers-Danlos Syndrome (EDS). The patient presented with rare and unusual neurological manifestations, including but not limited to ophthalmoplegia and myopathic pattern on his electromyography. In addition to hand weakness, there was skin hyperextensibility, joint hyperflexibility, and frontal baldness. Next-generation sequencing was performed on target exon sequences, using whole exome sequencing and Burrows-Wheeler Aligner for alignment/base calling. Genome Analysis Toolkit and reference genome Homo sapiens (UCSC hg19) were used for sequence processing and analysis. Variant classification was done according to standard international recommendations. A novel homozygous variant, NM_019105.6: c.8488C>T p.(Gln2830*), was detected in the TNXB gene. This variant is not reported in the literature nor dbSNP or gnomAD databases. Additionally, this variant is predicted to create a premature stop codon and produce a truncated protein or nonsense-mediated mRNA decay. Hence, it is classified as a likely pathogenic variant. The same point variant was found in a heterozygous state in the patient's father and sister. Both presented with milder symptoms associated with Ehlers-Danlos syndromes and heritable connective tissue disorders. Therefore, the patient was diagnosed as a tenascin-X (TNX) deficient type of EDS known as classical-like Ehlers-Danlos syndrome. TNX deficient patients may present with clinical and electrophysiological manifestations that are unusual in EDS like frontal baldness, ophthalmoplegia, and myotonia, which mimic myotonic dystrophy type I. Clinicians should be aware of the potential overlap of symptoms among these two diseases to ensure correct diagnosis is made.
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http://dx.doi.org/10.1002/ajmg.a.62539DOI Listing
October 2021

Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss.

Am J Hum Genet 2021 Oct;108(10):2006-2016

Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany.

Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype.
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http://dx.doi.org/10.1016/j.ajhg.2021.08.003DOI Listing
October 2021

HIF-1α Pulmonary Phenotype Wide Association Study Unveils a Link to Inflammatory Airway Conditions.

Front Genet 2021 21;12:756645. Epub 2021 Sep 21.

Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.

Despite experimental data linking HIF-1α dysfunction to inflammatory airway conditions, the effect of single nucleotide polymorphisms within the gene on these conditions remains poorly understood. In the current study, we complete a phenotype wide association study to assess the link between SNPs with known disease associations and respiratory phenotypes. We report two SNPs of the gene, the intronic rs79865957 and the missense rs41508050. In these positions the A and the T allele are significantly associated with allergic rhinitis and acute bronchitis and bronchiolitis, respectively. These findings further support the role of HIF-1α in inflammatory pulmonary conditions and may serve as a basis to refine our understanding of other HIF-1α associated phenotypes.
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http://dx.doi.org/10.3389/fgene.2021.756645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490729PMC
September 2021

Genetic Variation in on 1p36.13 Is Associated with Common Forms of Human Generalized Epilepsy.

Genes (Basel) 2021 Sep 18;12(9). Epub 2021 Sep 18.

Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

We performed a genome-wide association study (GWAS) to identify genetic variation associated with common forms of idiopathic generalized epilepsy (GE) and focal epilepsy (FE). Using a cohort of 2220 patients and 14,448 controls, we searched for single nucleotide polymorphisms (SNPs) associated with GE, FE and both forms combined. We did not find any SNPs that reached genome-wide statistical significance ( ≤ 5 × 10) when comparing all cases to all controls, and few SNPs of interest comparing FE cases to controls. However, we document multiple linked SNPs in the - genes that reach genome-wide significance and are associated with disease when comparing GE cases alone to controls. genes encode enzymes that deiminate arginine to citrulline in molecular pathways related to epigenetic regulation of histones and autoantibody formation. Although epilepsy genetics and treatment are focused strongly on ion channel and neurotransmitter mechanisms, these results suggest that epigenetic control of gene expression and the formation of autoantibodies may also play roles in epileptogenesis.
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http://dx.doi.org/10.3390/genes12091441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472138PMC
September 2021

A genome-wide association meta-analysis identifies new eosinophilic esophagitis loci.

J Allergy Clin Immunol 2021 Sep 25. Epub 2021 Sep 25.

Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pa; Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa; Divisions of Human Genetics and Pulmonary Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pa; Faculty of Medicine, University of Iceland, Reykjavik, Iceland. Electronic address:

Background: Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder of the esophagus marked by eosinophilic infiltration. Cumulative evidence indicates that the risk of EoE involves the complex interplay of both genetic and environmental factors. Because only a few genetic loci have been identified in EoE, the genetic underpinning of EoE remains largely elusive.

Objective: We sought to identify genetic loci associated with EoE.

Methods: Four EoE cohorts were genotyped using the Illumina single nucleotide polymorphism array platform, totaling 1,930 cases and 13,634 controls of European ancestry. Genotype imputation was performed with the Michigan Imputation Server using the Trans-Omics for Precision Medicine reference panel including whole-genome sequencing data from more than 100,000 individuals. Meta-analysis was conducted to identify potential novel genetic loci associated with EoE.

Results: Our study identified 11 new genome-wide significant loci, of which 6 are common variant loci, including 5q31.1 (rs2106984, P = 4.16 × 10; odds ratio [OR], 1.26, RAD50), 15q22.2 (rs2279293, P = 1.23 × 10; OR, 0.69, RORA), and 15q23 (rs56062135, P = 2.91 × 10; OR, 1.29, SMAD3), which have been previously associated with allergic conditions. Interestingly, a low-frequency synonymous mutation within the MATN2 gene was identified as the most significant single nucleotide polymorphism at the 8q22.1 locus. We also identified 5 sex-specific loci in the EoE cases, including an inflammatory bowel disease-associated locus at 9p24.1 (rs62541556, P = 4.4 × 10; OR, 1.11, JAK2).

Conclusions: Our findings demonstrate shared genetic underpinnings between EoE and other immune-mediated diseases and provide novel candidate genes for therapeutic target identification and prioritization.
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http://dx.doi.org/10.1016/j.jaci.2021.08.018DOI Listing
September 2021

Effect of micro-osteoperforations on the gene expression profile of the periodontal ligament of orthodontically moved human teeth.

Clin Oral Investig 2021 Sep 9. Epub 2021 Sep 9.

Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Levy Building 246, 240 South 40th Street, Philadelphia, PA, 19104 47, USA.

Objectives: This study aimed to evaluate the effect of micro-osteoperforations (MOPs) on the gene expression profile of the periodontal ligament (PDL) of orthodontically moved teeth.

Materials And Methods: Fifteen participants were randomly assigned into two groups: tooth movement only (Tr1, n = 7) and tooth movement supplemented with MOPs (Tr2, n = 8). In each subject, orthodontic tooth movement (OTM) was performed on premolar in one side, while no force was applied on contralateral premolar (Unt, n = 15). Seven days after loading, premolars were extracted for orthodontic reasons. RNA extraction from PDL and subsequent RNA-sequencing were performed. False discovery rates (Padj < 0.05) and log2 fold change (+ / - 1.5) thresholds were used to identify sets of differentially expressed genes (DEGs) among the groups. DEGs were analyzed with gene ontology enrichment, KEGG, and network analysis.

Results: Three hundred thirty-one DEGs were found between Tr1 and Unt, and 356 between Tr2 and Unt. Although, there were no significantly DEGs between Tr2 and Tr1, DEGs identified exclusively in Tr1 vs. Unt were different from those identified exclusively in Tr2 vs. Unt. In Tr1, genes were related to bone metabolism processes, such as osteoclast and osteoblast differentiation. In Tr2, genes were associated to inflammation processes, like inflammatory and immune responses, and cellular response to tumor necrosis factor.

Conclusions: MOPs do not significantly alter the PDL gene expression profile of orthodontically moved human teeth. This study provides for the first time evidence on the whole PDL gene expression profiles associated to OTM in humans. Novel biomarkers for OTM are suggested for additional research. Clinical relevance The identified biomarkers provide new insights into the molecular mechanisms that would occur when OTM is supplemented with MOPs. These markers are expected to be useful in the near future for the application of personalized strategies related to the OTM.
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http://dx.doi.org/10.1007/s00784-021-04178-yDOI Listing
September 2021

Discovery of Novel Host Molecular Factors Underlying HBV/HCV Infection.

Front Cell Dev Biol 2021 12;9:690882. Epub 2021 Aug 12.

Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China.

Hepatitis is an inflammatory condition of the liver, which is frequently caused by the infection of hepatitis B virus (HBV) or hepatitis C virus (HCV). Hepatitis can lead to the development of chronic complications including cancer, making it a major public health burden. Co-infection of HBV and HCV can result in faster disease progression. Therefore, it is important to identify shared genetic susceptibility loci for HBV and HCV infection to further understand the underlying mechanism. Through a meta-analysis based on genome-wide association summary statistics of HBV and HCV infection, we found one novel locus in the Asian population and two novel loci in the European population. By functional annotation based on multi-omics data, we identified the likely target genes at each novel locus, such as and , which play a critical role in autophagy and immune response to virus. By re-analyzing a microarray dataset from Hmgb1 mice and RNA-seq data from mouse liver tissue overexpressing , we found that differential expression of autophagy and immune and metabolic gene pathways underlie these conditions. Our study reveals novel common susceptibility loci to HBV and HCV infection, supporting their role in linking autophagy signaling and immune response.
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http://dx.doi.org/10.3389/fcell.2021.690882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397444PMC
August 2021

Genetic association of primary nonresponse to anti-TNFα therapy in patients with inflammatory bowel disease.

Pharmacogenet Genomics 2021 Aug 18. Epub 2021 Aug 18.

Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina Department of Medicine, University of Chicago, Chicago, Illinois Departments of Medicine (Medical Genetics) and Genome Sciences, Universtiy of Washington Medical Center, Seattle, Washington Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee The Center for Applied Genomics, The Children's Hospital of Philadelphia Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati US Department of Veterans Affairs Medical Center, Cincinnati, Ohio Office of Research Computing and Analytics, Marshfield Clinic Research Institute Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, Wisconsin, USA.

Objectives: Primary nonresponse (PNR) to antitumor necrosis factor-α (TNFα) biologics is a serious concern in patients with inflammatory bowel disease (IBD). We aimed to identify the genetic variants associated with PNR.

Patients And Methods: Patients were recruited from outpatient GI clinics and PNR was determined using both clinical and endoscopic findings. A case-control genome-wide association study was performed in 589 IBD patients and associations were replicated in an independent cohort of 293 patients. Effect of the associated variant on gene expression and TNFα secretion was assessed by cell-based assays. Pleiotropic effects were investigated by Phenome-wide association study (PheWAS).

Results: We identified rs34767465 as associated with PNR to anti-TNFα therapy (odds ratio: 2.07, 95% CI, 1.46-2.94, P = 2.43 × 10-7, [replication odds ratio: 1.8, 95% CI, 1.04-3.16, P = 0.03]). rs34767465 is a multiple-tissue expression quantitative trait loci for FAM114A2. Using RNA-sequencing and protein quantification from HapMap lymphoblastoid cell lines (LCLs), we found a significant decrease in FAM114A2 mRNA and protein expression in both heterozygous and homozygous genotypes when compared to wild type LCLs. TNFα secretion was significantly higher in THP-1 cells [differentiated into macrophages] with FAM114A2 knockdown versus controls. Immunoblotting experiments showed that depletion of FAM114A2 impaired autophagy-related pathway genes suggesting autophagy-mediated TNFα secretion as a potential mechanism. PheWAS showed rs34767465 was associated with comorbid conditions found in IBD patients (derangement of joints [P = 3.7 × 10-4], pigmentary iris degeneration [P = 5.9 × 10-4], diverticulum of esophagus [P = 7 × 10-4]).

Conclusions: We identified a variant rs34767465 associated with PNR to anti-TNFα biologics, which increases TNFα secretion through mechanism related to autophagy. rs34767465 may also explain the comorbidities associated with IBD.
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http://dx.doi.org/10.1097/FPC.0000000000000445DOI Listing
August 2021

Insights into non-autoimmune type 1 diabetes with 13 novel loci in low polygenic risk score patients.

Sci Rep 2021 08 6;11(1):16013. Epub 2021 Aug 6.

The Center for Applied Genomics, Children's Hospital of Philadelphia, 3615 Civic Center Blvd, Abramson Building, Philadelphia, PA, 19104, USA.

With polygenic risk score (PRS) for autoimmune type 1 diabetes (T1D), this study identified T1D cases with low T1D PRS and searched for susceptibility loci in these cases. Our hypothesis is that genetic effects (likely mediated by relatively rare genetic variants) of non-mainstream (or non-autoimmune) T1D might have been diluted in the previous studies on T1D cases in general. Two cohorts for the PRS modeling and testing respectively were included. The first cohort consisted of 3302 T1D cases and 6181 controls, and the independent second cohort consisted of 3297 T1D cases and 6169 controls. Cases with low T1D PRS were identified using PRSice-2 and compared to controls with low T1D PRS by genome-wide association (GWA) test. Thirteen novel genetic loci with high imputation quality (Quality Score r > 0.91) were identified of SNPs/SNVs associated with low PRS T1D at genome-wide significance (P ≤ 5.0 × E-08), in addition to 4 established T1D loci, 3 reported loci by our previous study, as well as 9 potential novel loci represented by rare SNVs, but with relatively low imputation quality (Quality Score r < 0.90). For the 13 novel loci, 9 regions have been reported of association with obesity related traits by previous GWA studies. Three loci encoding long intergenic non-protein coding RNAs (lncRNA), and 2 loci involved in N-linked glycosylation are also highlighted in this study.
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http://dx.doi.org/10.1038/s41598-021-94994-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346538PMC
August 2021

Genome-Wide Association Studies of Conotruncal Heart Defects with Normally Related Great Vessels in the United States.

Genes (Basel) 2021 07 1;12(7). Epub 2021 Jul 1.

Department of Epidemiology, Human Genetics and Environmental Sciences, UTHealth School of Public Health, Houston, TX 77030, USA.

Conotruncal defects with normally related great vessels (CTD-NRGVs) occur in both patients with and without 22q11.2 deletion syndrome (22q11.2DS), but it is unclear to what extent the genetically complex etiologies of these heart defects may overlap across these two groups, potentially involving variation within and/or outside of the 22q11.2 region. To explore this potential overlap, we conducted genome-wide SNP-level, gene-level, and gene set analyses using common variants, separately in each of five cohorts, including two with 22q11.2DS ( = 1472 total cases) and three without 22q11.2DS ( = 935 total cases). Results from the SNP-level analyses were combined in meta-analyses, and summary statistics from these analyses were also used in gene and gene set analyses. Across all these analyses, no association was significant after correction for multiple comparisons. However, several SNPs, genes, and gene sets with suggestive evidence of association were identified. For common inherited variants, we did not identify strong evidence for shared genomic mechanisms for CTD-NRGVs across individuals with and without 22q11.2 deletions. Nevertheless, several of our top gene-level and gene set results have been linked to cardiogenesis and may represent candidates for future work.
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http://dx.doi.org/10.3390/genes12071030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306129PMC
July 2021

Genetic architecture of type 1 diabetes with low genetic risk score informed by 41 unreported loci.

Commun Biol 2021 07 23;4(1):908. Epub 2021 Jul 23.

The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Type 1 diabetes (T1D) patients with low genetic risk scores (GRS) may be non-autoimmune or autoimmune mediated by other genetic loci. The T1D-GRS2 provides us an opportunity to look into the genetic architecture of these patients. A total of 18,949 European individuals were included in this study, including 6599 T1D cases and 12,323 controls. 957 (14.5%) T1D patients were identified with low GRS (GRS < 8.43). The genome-wide association study on these patients identified 41 unreported loci. Two loci with common variants and 39 loci with rare variants were identified in this study. This study identified common SNPs associated with both low GRS T1D and expression levels of the interferon-α-induced MNDA gene, indicating the role of viral infection in T1D. Interestingly, 16 of the 41 unreported loci have been linked to autism spectrum disorder (ASD) by previous studies, suggesting that genes residing at these loci may underlie both T1D and autism.
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http://dx.doi.org/10.1038/s42003-021-02368-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302754PMC
July 2021

Cleft palate morphology, genetic etiology, and risk of mortality in infants with Robin sequence.

Am J Med Genet A 2021 Jul 22. Epub 2021 Jul 22.

Division of Craniofacial Medicine, Seattle Children's Hospital, Seattle, WA, USA.

Robin sequence (RS) has many genetic and nongenetic causes, including isolated Robin sequence (iRS), Stickler syndrome (SS), and other syndromes (SyndRS). The purpose of this study was to determine if the presence and type of cleft palate varies between etiologic groups. A secondary endpoint was to determine the relationship of etiologic group, cleft type, and mortality. Retrospective chart review of patients with RS at two high-volume craniofacial centers. 295 patients with RS identified. CP was identified in 97% with iRS, 95% with SS, and 70% of those with SyndRS (p < .0001). U-shaped CP was seen in 86% of iRS, 82% with SS, but only 27% with SyndRS (p < .0001). At one institution, 12 children (6%) with RS died, all from the SyndRS group (p < .0001). All died due to medical comorbidities related to their syndrome. Only 25% of children who died had a U-shaped CP. The most common palatal morphology among those who died was an intact palate. U-shaped CP was most strongly associated with iRS and SS, and with a lower risk of mortality. RS with submucous CP, cleft lip and palate or intact palate was strongly suggestive of an underlying genetic syndrome and higher risk of mortality.
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http://dx.doi.org/10.1002/ajmg.a.62430DOI Listing
July 2021

Deep learning prediction of attention-deficit hyperactivity disorder in African Americans by copy number variation.

Exp Biol Med (Maywood) 2021 Jul 7:15353702211018970. Epub 2021 Jul 7.

Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

Current understanding of the underlying molecular network and mechanism for attention-deficit hyperactivity disorder (ADHD) is lacking and incomplete. Previous studies suggest that genomic structural variations play an important role in the pathogenesis of ADHD. For effective modeling, deep learning approaches have become a method of choice, with ability to predict the impact of genetic variations involving complicated mechanisms. In this study, we examined copy number variation in whole genome sequencing from 116 African Americans ADHD children and 408 African American controls. We divided the human genome into 150 regions, and the variation intensity in each region was applied as feature vectors for deep learning modeling to classify ADHD patients. The accuracy of deep learning for predicting ADHD diagnosis is consistently around 78% in a two-fold shuffle test, compared with ∼50% by traditional k-mean clustering methods. Additional whole genome sequencing data from 351 European Americans children, including 89 ADHD cases and 262 controls, were applied as independent validation using feature vectors obtained from the African American ethnicity analysis. The accuracy of ADHD labeling was lower in this setting (∼70-75%) but still above the results from traditional methods. The regions with highest weight overlapped with the previously reported ADHD-associated copy number variation regions, including genes such as and , key drivers of metabotropic glutamate receptor signaling. A notable discovery is that structural variations in non-coding genomic (intronic/intergenic) regions show prediction weights that can be as high as prediction weight from variations in coding regions, results that were unexpected.
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http://dx.doi.org/10.1177/15353702211018970DOI Listing
July 2021

Association Between a Common, Benign Genotype and Unnecessary Bone Marrow Biopsies Among African American Patients.

JAMA Intern Med 2021 Aug;181(8):1100-1105

Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.

Importance: Up to two-thirds of African American individuals carry the benign rs2814778-CC genotype that lowers total white blood cell (WBC) count.

Objective: To examine whether the rs2814778-CC genotype is associated with an increased likelihood of receiving a bone marrow biopsy (BMB) for an isolated low WBC count.

Design, Setting, And Participants: This retrospective genetic association study assessed African American patients younger than 90 years who underwent a BMB at Vanderbilt University Medical Center, Mount Sinai Health System, or Children's Hospital of Philadelphia from January 1, 1998, to December 31, 2020.

Exposure: The rs2814778-CC genotype.

Main Outcomes And Measures: The proportion of individuals with the CC genotype who underwent BMB for an isolated low WBC count and had a normal biopsy result compared with the proportion of individuals with the CC genotype who underwent BMB for other indications and had a normal biopsy result.

Results: Among 399 individuals who underwent a BMB (mean [SD] age, 41.8 [22.5] years, 234 [59%] female), 277 (69%) had the CC genotype. A total of 35 patients (9%) had clinical histories of isolated low WBC counts, and 364 (91%) had other histories. Of those with a clinical history of isolated low WBC count, 34 of 35 (97%) had the CC genotype vs 243 of 364 (67%) of those without a low WBC count history. Among those with the CC genotype, 33 of 34 (97%) had normal results for biopsies performed for isolated low WBC counts compared with 134 of 243 individuals (55%) with biopsies performed for other histories (P < .001).

Conclusions And Relevance: In this genetic association study, among patients of African American race who had a BMB with a clinical history of isolated low WBC counts, the rs2814778-CC genotype was highly prevalent, and 97% of these BMBs identified no hematologic abnormality. Accounting for the rs2814778-CC genotype in clinical decision-making could avoid unnecessary BMB procedures.
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http://dx.doi.org/10.1001/jamainternmed.2021.3108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239990PMC
August 2021

A unified framework identifies new links between plasma lipids and diseases from electronic medical records across large-scale cohorts.

Nat Genet 2021 07 17;53(7):972-981. Epub 2021 Jun 17.

Department of Genetics and Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Plasma lipids are known heritable risk factors for cardiovascular disease, but increasing evidence also supports shared genetics with diseases of other organ systems. We devised a comprehensive three-phase framework to identify new lipid-associated genes and study the relationships among lipids, genotypes, gene expression and hundreds of complex human diseases from the Electronic Medical Records and Genomics (347 traits) and the UK Biobank (549 traits). Aside from 67 new lipid-associated genes with strong replication, we found evidence for pleiotropic SNPs/genes between lipids and diseases across the phenome. These include discordant pleiotropy in the HLA region between lipids and multiple sclerosis and putative causal paths between triglycerides and gout, among several others. Our findings give insights into the genetic basis of the relationship between plasma lipids and diseases on a phenome-wide scale and can provide context for future prevention and treatment strategies.
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http://dx.doi.org/10.1038/s41588-021-00879-yDOI Listing
July 2021

Expanding the genetic landscape of oral-facial-digital syndrome with two novel genes.

Am J Med Genet A 2021 08 15;185(8):2409-2416. Epub 2021 Jun 15.

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

Oral-facial-digital syndromes (OFDS) are a heterogeneous and rare group of Mendelian disorders characterized by developmental abnormalities of the oral cavity, face, and digits caused by dysfunction of the primary cilium, a mechanosensory organelle that exists atop most cell types that facilitates organ patterning and growth. OFDS is inherited both in an X-linked dominant, X-linked recessive, and autosomal recessive manner. Importantly, though many of the causal genes for OFDS have been identified, up to 40% of OFD syndromes are of unknown genetic basis. Here we describe three children with classical presentations of OFDS including lingual hamartomas, polydactyly, and characteristic facial features found by exome sequencing to harbor variants in causal genes not previously associated with OFDS. We describe a female with hypothalamic hamartoma, urogenital sinus, polysyndactyly, and multiple lingual hamartomas consistent with OFDVI with biallelic pathogenic variants in CEP164, a gene associated with ciliopathy-spectrum disease, but never before with OFDS. We additionally describe two unrelated probands with postaxial polydactyly, multiple lingual hamartomas, and dysmorphic features both found to be homozygous for an identical TOPORS missense variant, c.29 C>A; (p.Pro10Gln). Heterozygous TOPORS pathogenic gene variants are associated with autosomal dominant retinitis pigmentosa, but never before with syndromic ciliopathy. Of note, both probands are of Dominican ancestry, suggesting a possible founder allele.
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http://dx.doi.org/10.1002/ajmg.a.62337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361718PMC
August 2021

A Mendelian Randomization Approach Using 3-HMG-Coenzyme-A Reductase Gene Variation to Evaluate the Association of Statin-Induced Low-Density Lipoprotein Cholesterol Lowering With Noncardiovascular Disease Phenotypes.

JAMA Netw Open 2021 Jun 1;4(6):e2112820. Epub 2021 Jun 1.

Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.

Importance: Observational studies suggest that statins, which inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, may be associated with beneficial effects in many noncardiovascular diseases.

Objective: To construct a weighted HMG-CoA reductase (HMGCR) gene genetic risk score (GRS) using variants in the HMGCR gene affecting low-density lipoprotein cholesterol as an instrumental variable for mendelian randomization analyses to test associations with candidate noncardiovascular phenotypes previously associated with statin use in observational studies.

Design, Setting, And Participants: This cohort study included 53 385 unrelated adults of European ancestry with genome-wide genotypes available from BioVU (a practice-based biobank, used for discovery) and 30 444 unrelated adults with European ancestry available in the Electronic Medical Records and Genomics (eMERGE; a research consortium that conducts genetic research using electronic medical records, used for replication). The study was conducted from February 6, 2015, through April 31, 2019; data analysis was performed from August 26, 2019, through December 22, 2020.

Interventions: An HMGCR GRS was calculated.

Main Outcomes And Measures: The association between the HMGCR GRS and the presence or absence of 22 noncardiovascular phenotypes previously associated with statin use in clinical studies.

Results: Of the 53 385 individuals in BioVU, 29 958 (56.1%) were women; mean (SD) age was 59.9 (15.6) years. The finding between the HMGCR GRS and the noncardiovascular phenotypes of interest in this cohort was significant only for type 2 diabetes. An HMGCR GRS equivalent to a 10-mg/dL decrease in the low-density lipoprotein cholesterol level was associated with an increased risk of type 2 diabetes (odds ratio [OR], 1.09; 95% CI, 1.04-1.15; P = 5.58 × 10-4). The HMGCR GRS was not associated with other phenotypes; the closest were increased risk of Parkinson disease (OR, 1.30; 95% CI, 1.07-1.58; P = .007) and kidney failure (OR, 1.18; 95% CI, 1.05-1.34; P = .008). Of the 30 444 individuals in eMERGE, 16 736 (55.0%) were women; mean (SD) age was 68.7 (15.4) years. The association between the HMGCR GRS and type 2 diabetes was replicated in this cohort (OR, 1.09; 95% CI, 1.01-1.17; P = .02); however, the HMGCR GRS was not associated with Parkinson disease (OR, 0.93; 95% CI, 0.75-1.16; P = .53) and kidney failure (OR, 1.18; 95% CI, 0.98-1.41; P = .08) in the eMERGE cohort.

Conclusions And Relevance: A mendelian randomization approach using variants in the HMGCR gene replicated the association between statin use and increased type 2 diabetes risk but provided no strong evidence for pleiotropic effects of statin-induced decrease of the low-density lipoprotein cholesterol level on other diseases.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.12820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185593PMC
June 2021

Novel EDGE encoding method enhances ability to identify genetic interactions.

PLoS Genet 2021 06 4;17(6):e1009534. Epub 2021 Jun 4.

Department of Genetics, Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

Assumptions are made about the genetic model of single nucleotide polymorphisms (SNPs) when choosing a traditional genetic encoding: additive, dominant, and recessive. Furthermore, SNPs across the genome are unlikely to demonstrate identical genetic models. However, running SNP-SNP interaction analyses with every combination of encodings raises the multiple testing burden. Here, we present a novel and flexible encoding for genetic interactions, the elastic data-driven genetic encoding (EDGE), in which SNPs are assigned a heterozygous value based on the genetic model they demonstrate in a dataset prior to interaction testing. We assessed the power of EDGE to detect genetic interactions using 29 combinations of simulated genetic models and found it outperformed the traditional encoding methods across 10%, 30%, and 50% minor allele frequencies (MAFs). Further, EDGE maintained a low false-positive rate, while additive and dominant encodings demonstrated inflation. We evaluated EDGE and the traditional encodings with genetic data from the Electronic Medical Records and Genomics (eMERGE) Network for five phenotypes: age-related macular degeneration (AMD), age-related cataract, glaucoma, type 2 diabetes (T2D), and resistant hypertension. A multi-encoding genome-wide association study (GWAS) for each phenotype was performed using the traditional encodings, and the top results of the multi-encoding GWAS were considered for SNP-SNP interaction using the traditional encodings and EDGE. EDGE identified a novel SNP-SNP interaction for age-related cataract that no other method identified: rs7787286 (MAF: 0.041; intergenic region of chromosome 7)-rs4695885 (MAF: 0.34; intergenic region of chromosome 4) with a Bonferroni LRT p of 0.018. A SNP-SNP interaction was found in data from the UK Biobank within 25 kb of these SNPs using the recessive encoding: rs60374751 (MAF: 0.030) and rs6843594 (MAF: 0.34) (Bonferroni LRT p: 0.026). We recommend using EDGE to flexibly detect interactions between SNPs exhibiting diverse action.
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http://dx.doi.org/10.1371/journal.pgen.1009534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208534PMC
June 2021

Elevation of Circulating LIGHT (TNFSF14) and Interleukin-18 Levels in Sepsis-Induced Multi-Organ Injuries.

medRxiv 2021 May 27. Epub 2021 May 27.

Objective: The cytokines, LIGHT (TNFSF14) and Interleukin-18 (IL-18), are two important therapeutic targets due to their central roles in the function of activated T cells and inflammatory injury. LIGHT was recently shown to play a major role in COVID19 induced acute respiratory distress syndrome (ARDS), reducing mortality and hospital stay. This study aims to investigate the associations of LIGHT and IL-18 with non-COVID19 related ARDS, acute hypoxic respiratory failure (AHRF) or acute kidney injury (AKI), secondary to viral or bacterial sepsis.

Research Design And Methods: A cohort of 280 subjects diagnosed with sepsis, including 91 cases with sepsis triggered by viral infections, were investigated in this study and compared to healthy controls. Serum LIGHT, IL-18, and 59 other biomarkers (cytokines, chemokines and acute-phase reactants) were measured and associated with symptom severity.

Results: ARDS was observed in 36% of the patients, with 29% of the total patient cohort developing multi-organ failure (failure of two or more organs). We observed significantly increased LIGHT level (>2SD above mean of healthy subjects) in both bacterial sepsis patients (P=1.80E-05) and patients with sepsis from viral infections (P=1.78E-03). In bacterial sepsis, increased LIGHT level associated with ARDS, AKI and higher Apache III scores, findings also supported by correlations of LIGHT with other biomarkers of organ failures, suggesting LIGHT may be an inflammatory driver. IL-18 levels were highly variable across individuals, and consistently correlated with Apache III scores, mortality, and AKI, in both bacterial and viral sepsis.

Conclusions: For the first time, we demonstrate independent effects of LIGHT and IL-18 in septic organ failures. LIGHT levels are significantly elevated in non-COVID19 sepsis patients with ARDS and/or multi-organ failures suggesting that anti-LIGHT therapy may be effective therapy in a subset of patients with sepsis. Given the large variance of plasma IL-18 among septic subjects, targeting this pathway raises opportunities that require a precision application.
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http://dx.doi.org/10.1101/2021.05.25.21257799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168398PMC
May 2021

Pathogenic variants in , a chromatin remodeler, cause a range of syndromic neurodevelopmental features.

Sci Adv 2021 May 12;7(20). Epub 2021 May 12.

Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ, USA.

Intellectual disability encompasses a wide spectrum of neurodevelopmental disorders, with many linked genetic loci. However, the underlying molecular mechanism for more than 50% of the patients remains elusive. We describe pathogenic variants in , encoding the ATPase motor of the ISWI chromatin remodeler, as a cause of a previously unidentified neurodevelopmental disorder, identifying 12 individuals with de novo or dominantly segregating rare heterozygous variants. Accompanying phenotypes include mild developmental delay, frequent postnatal short stature and microcephaly, and recurrent dysmorphic features. Loss of function of the SMARCA5 ortholog led to smaller body size, reduced sensory dendrite complexity, and tiling defects in larvae. In adult flies, Iswi neural knockdown caused decreased brain size, aberrant mushroom body morphology, and abnormal locomotor function. loss of function was rescued by wild-type but not mutant SMARCA5. Our results demonstrate that pathogenic variants cause a neurodevelopmental syndrome with mild facial dysmorphia.
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http://dx.doi.org/10.1126/sciadv.abf2066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115915PMC
May 2021

Serum levels of the IgA isotype switch factor TGF-β1 are elevated in patients with COVID-19.

FEBS Lett 2021 07 21;595(13):1819-1824. Epub 2021 May 21.

Shenzhen Key Laboratory of Allergy & Immunology, State Key Laboratory of Respiratory Disease for Allergy at Shenzhen University, Shenzhen University School of Medicine, China.

We previously observed enhanced immunoglobulin A (IgA) responses in severe COVID-19, which might confer damaging effects. Given the important role of IgA in immune and inflammatory responses, the aim of this study was to investigate the dynamic response of the IgA isotype switch factor TGF-β1 in COVID-19 patients. We observed, in a total of 153 COVID-19 patients, that the serum levels of TGF-β1 were increased significantly at the early and middle stages of COVID-19, and correlated with the levels of SARS-CoV-2-specific IgA, as well as with the APACHE II score in patients with severe disease. In view of the genetic association of the TGF-β1 activator THBS3 with severe COVID-19 identified by the COVID-19 Host Genetics Initiative, this study suggests TGF-β1 may play a key role in COVID-19.
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http://dx.doi.org/10.1002/1873-3468.14104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209884PMC
July 2021

A new syndrome of moyamoya disease, kidney dysplasia, aminotransferase elevation, and skin disease associated with de novo variants in RNF213.

Am J Med Genet A 2021 07 7;185(7):2168-2174. Epub 2021 May 7.

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

Ring-finger protein 213 (RNF213) encodes a protein of unknown function believed to play a role in cellular metabolism and angiogenesis. Gene variants are associated with susceptibility to moyamoya disease. Here, we describe two children with moyamoya disease who also demonstrated kidney disease, elevated aminotransferases, and recurrent skin lesions found by exome sequencing to have de novo missense variants in RNF213. These cases highlight the ability of RNF213 to cause Mendelian moyamoya disease in addition to acting as a genetic susceptibility locus. The cases also suggest a new, multi-organ RNF213-spectrum disease characterized by liver, skin, and kidney pathology in addition to severe moyamoya disease caused by heterozygous, de novo C-terminal RNF213 missense variants.
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http://dx.doi.org/10.1002/ajmg.a.62215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360119PMC
July 2021

Metabolomic profiling of anaerobic and aerobic energy metabolic pathways in chronic obstructive pulmonary disease.

Exp Biol Med (Maywood) 2021 Jul 6;246(14):1586-1596. Epub 2021 May 6.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.

While there is no cure for chronic obstructive pulmonary disease (COPD), its progressive nature and the formidable challenge to manage its symptoms warrant a more extensive study of the pathogenesis and related mechanisms. A new emphasis on COPD study is the change of energy metabolism. For the first time, this study investigated the anaerobic and aerobic energy metabolic pathways in COPD using the metabolomic approach. Metabolomic analysis was used to investigate energy metabolites in 140 COPD patients. The significance of energy metabolism in COPD was comprehensively explored by the Global Initiative for Chronic Obstructive Lung Disease-GOLD grading, acute exacerbation vs. stable phase (either clinical stability or four-week stable phase), age group, smoking index, lung function, and COPD Assessment Test (CAT) score. Through comprehensive evaluation, we found that COPD patients have a significant imbalance in the aerobic and anaerobic energy metabolisms in resting state, and a high tendency of anaerobic energy supply mechanism that correlates positively with disease progression. This study highlighted the significance of anaerobic and low-efficiency energy supply pathways in lung injury and linked it to the energy-inflammation-lung ventilatory function and the motion limitation mechanism in COPD patients, which implies a novel therapeutic direction for this devastating disease.
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http://dx.doi.org/10.1177/15353702211008808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326443PMC
July 2021

ANKRD11 variants: KBG syndrome and beyond.

Clin Genet 2021 08 14;100(2):187-200. Epub 2021 May 14.

Centro Fondazione Mariani per il Bambino Fragile ASST-Lariana Sant'Anna Hospital, Department of Pediatrics, San Fermo della Battaglia (Como), Italy.

Mutations affecting the transcriptional regulator Ankyrin Repeat Domain 11 (ANKRD11) are mainly associated with the multisystem developmental disorder known as KBG syndrome, but have also been identified in individuals with Cornelia de Lange syndrome (CdLS) and other developmental disorders caused by variants affecting different chromatin regulators. The extensive functional overlap of these proteins results in shared phenotypical features, which complicate the assessment of the clinical diagnosis. Additionally, re-evaluation of individuals at a later age occasionally reveals that the initial phenotype has evolved toward clinical features more reminiscent of a developmental disorder different from the one that was initially diagnosed. For this reason, variants in ANKRD11 can be ascribed to a broader class of disorders that fall within the category of the so-called chromatinopathies. In this work, we report on the clinical characterization of 23 individuals with variants in ANKRD11. The subjects present primarily with developmental delay, intellectual disability and dysmorphic features, and all but two received an initial clinical diagnosis of either KBG syndrome or CdLS. The number and the severity of the clinical signs are overlapping but variable and result in a broad spectrum of phenotypes, which could be partially accounted for by the presence of additional molecular diagnoses and distinct pathogenic mechanisms.
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http://dx.doi.org/10.1111/cge.13977DOI Listing
August 2021

Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.

J Exp Med 2021 07 5;218(7). Epub 2021 May 5.

Department of Genetics, University of Alabama at Birmingham, Birmingham, AL.

The pioneer transcription factor (TF) PU.1 controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing nonpioneer TFs to enter otherwise inaccessible genomic sites. PU.1 deficiency fatally arrests lymphopoiesis and myelopoiesis in mice, but human congenital PU.1 disorders have not previously been described. We studied six unrelated agammaglobulinemic patients, each harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1. Affected patients lacked circulating B cells and possessed few conventional dendritic cells. Introducing disease-similar SPI1 mutations into human hematopoietic stem and progenitor cells impaired early in vitro B cell and myeloid cell differentiation. Patient SPI1 mutations encoded destabilized PU.1 proteins unable to nuclear localize or bind target DNA. In PU.1-haploinsufficient pro-B cell lines, euchromatin was less accessible to nonpioneer TFs critical for B cell development, and gene expression patterns associated with the pro- to pre-B cell transition were undermined. Our findings molecularly describe a novel form of agammaglobulinemia and underscore PU.1's critical, dose-dependent role as a hematopoietic euchromatin gatekeeper.
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http://dx.doi.org/10.1084/jem.20201750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105723PMC
July 2021

Combined application of genetic and polygenic risk scores for type 1 diabetes risk prediction.

Diabetes Obes Metab 2021 08 3;23(8):2001-2003. Epub 2021 Jun 3.

Centre for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

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http://dx.doi.org/10.1111/dom.14419DOI Listing
August 2021

Genetic correlations between COVID-19 and a variety of traits and diseases.

Innovation (N Y) 2021 May 29;2(2):100112. Epub 2021 Apr 29.

The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

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http://dx.doi.org/10.1016/j.xinn.2021.100112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081576PMC
May 2021

Genomic considerations for FHIR®; eMERGE implementation lessons.

J Biomed Inform 2021 06 28;118:103795. Epub 2021 Apr 28.

Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Structured representation of clinical genetic results is necessary for advancing precision medicine. The Electronic Medical Records and Genomics (eMERGE) Network's Phase III program initially used a commercially developed XML message format for standardized and structured representation of genetic results for electronic health record (EHR) integration. In a desire to move towards a standard representation, the network created a new standardized format based upon Health Level Seven Fast Healthcare Interoperability Resources (HL7® FHIR®), to represent clinical genomics results. These new standards improve the utility of HL7® FHIR® as an international healthcare interoperability standard for management of genetic data from patients. This work advances the establishment of standards that are being designed for broad adoption in the current health information technology landscape.
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http://dx.doi.org/10.1016/j.jbi.2021.103795DOI Listing
June 2021

Inducible knockout of Clec16a in mice results in sensory neurodegeneration.

Sci Rep 2021 04 29;11(1):9319. Epub 2021 Apr 29.

The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.

CLEC16A has been shown to play a role in autophagy/mitophagy processes. Additionally, genetic variants in CLEC16A have been implicated in multiple autoimmune diseases. We generated an inducible whole-body knockout, Clec16a mice, to investigate the loss of function of CLEC16A. The mice exhibited a neuronal phenotype including tremors and impaired gait that rapidly progressed to dystonic postures. Nerve conduction studies and pathological analysis revealed loss of sensory axons that are associated with this phenotype. Activated microglia and astrocytes were found in regions of the CNS. Several mitochondrial-related proteins were up- or down-regulated. Upregulation of interferon stimulated gene 15 (IGS15) were observed in neuronal tissues. CLEC16A expression inversely related to IGS15 expression. ISG15 may be the link between CLEC16A and downstream autoimmune, inflammatory processes. Our results demonstrate that a whole-body, inducible knockout of Clec16a in mice results in an inflammatory neurodegenerative phenotype resembling spinocerebellar ataxia.
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http://dx.doi.org/10.1038/s41598-021-88895-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084945PMC
April 2021
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