Publications by authors named "Grace Yoon"

124 Publications

Evidence for Non-Mendelian Inheritance in Spastic Paraplegia 7.

Mov Disord 2021 Feb 17. Epub 2021 Feb 17.

Department of Human Genetics, McGill University, Montréal, Québec, Canada.

Background: Although the typical inheritance of spastic paraplegia 7 is recessive, several reports have suggested that SPG7 variants may also cause autosomal dominant hereditary spastic paraplegia (HSP).

Objectives: We aimed to conduct an exome-wide genetic analysis on a large Canadian cohort of HSP patients and controls to examine the association of SPG7 and HSP.

Methods: We analyzed 585 HSP patients from 372 families and 1175 controls, including 580 unrelated individuals. Whole-exome sequencing was performed on 400 HSP patients (291 index cases) and all 1175 controls.

Results: The frequency of heterozygous pathogenic/likely pathogenic SPG7 variants (4.8%) among unrelated HSP patients was higher than among unrelated controls (1.7%; OR 2.88, 95% CI 1.24-6.66, P = 0.009). The heterozygous SPG7 p.(Ala510Val) variant was found in 3.7% of index patients versus 0.85% in unrelated controls (OR 4.42, 95% CI 1.49-13.07, P = 0.005). Similar results were obtained after including only genetically-undiagnosed patients. We identified four heterozygous SPG7 variant carriers with an additional pathogenic variant in known HSP genes, compared to zero in controls (OR 19.58, 95% CI 1.05-365.13, P = 0.0031), indicating potential digenic inheritance. We further identified four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2). Of these, there is especially compelling evidence for epistasis between SPG7 and AFG3L2. The p.(Ile705Thr) variant in AFG3L2 is located at the interface between hexamer subunits, in a hotspot of mutations associated with spinocerebellar ataxia type 28 that affect its proteolytic function.

Conclusions: Our results provide evidence for complex inheritance in SPG7-associated HSP, which may include recessive and possibly dominant and digenic/epistasis forms of inheritance. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28528DOI Listing
February 2021

Loss of Aryl Hydrocarbon Receptor Promotes Colon Tumorigenesis in Mice.

Mol Cancer Res 2021 Jan 25. Epub 2021 Jan 25.

Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, Texas.

The mutational genetic landscape of colorectal cancer has been extensively characterized; however, the ability of "cooperation response genes" to modulate the function of cancer "driver" genes remains largely unknown. In this study, we investigate the role of aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, in modulating oncogenic cues in the colon. We show that intestinal epithelial cell-targeted AhR knockout (KO) promotes the expansion and clonogenic capacity of colonic stem/progenitor cells harboring mutations by upregulating Wnt signaling. The loss of AhR in the gut epithelium increased cell proliferation, reduced mouse survival rate, and promoted cecum and colon tumorigenesis in mice. Mechanistically, the antagonism of Wnt signaling induced by haploinsufficiency attenuated the effects of AhR KO on cecum and colon tumorigenesis. IMPLICATIONS: Our findings reveal that AhR signaling plays a protective role in genetically induced colon tumorigenesis at least by suppressing Wnt signaling and provides rationale for the AhR as a therapeutic target for cancer prevention and treatment.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0789DOI Listing
January 2021

De novo variants in POLR3B cause ataxia, spasticity, and demyelinating neuropathy.

Am J Hum Genet 2021 01;108(1):186-193

Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada; Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, M5G 1X8, Canada. Electronic address:

POLR3B encodes the second-largest catalytic subunit of RNA polymerase III, an enzyme involved in transcription. Bi-allelic pathogenic variants in POLR3B are a well-established cause of hypomyelinating leukodystrophy. We describe six unrelated individuals with de novo missense variants in POLR3B and a clinical presentation substantially different from POLR3-related leukodystrophy. These individuals had afferent ataxia, spasticity, variable intellectual disability and epilepsy, and predominantly demyelinating sensory motor peripheral neuropathy. Protein modeling and proteomic analysis revealed a distinct mechanism of pathogenicity; the de novo POLR3B variants caused aberrant association of individual enzyme subunits rather than affecting overall enzyme assembly or stability. We expand the spectrum of disorders associated with pathogenic variants in POLR3B to include a de novo heterozygous POLR3B-related disorder.
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http://dx.doi.org/10.1016/j.ajhg.2020.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820722PMC
January 2021

De Novo variants in EEF2 cause a neurodevelopmental disorder with benign external hydrocephalus.

Hum Mol Genet 2021 Feb;29(24):3892-3899

Department of Human Genetics, Radboud University Medical Center and Donders Institute for Brain, Cognition and Behavior, 6525 GA Nijmegen, The Netherlands.

Eukaryotic translation elongation factor 2 (eEF2) is a key regulatory factor in gene expression that catalyzes the elongation stage of translation. A functionally impaired eEF2, due to a heterozygous missense variant in the EEF2 gene, was previously reported in one family with spinocerebellar ataxia-26 (SCA26), an autosomal dominant adult-onset pure cerebellar ataxia. Clinical exome sequencing identified de novo EEF2 variants in three unrelated children presenting with a neurodevelopmental disorder (NDD). Individuals shared a mild phenotype comprising motor delay and relative macrocephaly associated with ventriculomegaly. Populational data and bioinformatic analysis underscored the pathogenicity of all de novo missense variants. The eEF2 yeast model strains demonstrated that patient-derived variants affect cellular growth, sensitivity to translation inhibitors and translational fidelity. Consequently, we propose that pathogenic variants in the EEF2 gene, so far exclusively associated with late-onset SCA26, can cause a broader spectrum of neurologic disorders, including childhood-onset NDDs and benign external hydrocephalus.
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http://dx.doi.org/10.1093/hmg/ddaa270DOI Listing
February 2021

Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects.

Am J Hum Genet 2020 12 23;107(6):1170-1177. Epub 2020 Nov 23.

Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address:

KDM4B is a lysine-specific demethylase with a preferential activity on H3K9 tri/di-methylation (H3K9me3/2)-modified histones. H3K9 tri/di-demethylation is an important epigenetic mechanism responsible for silencing of gene expression in animal development and cancer. However, the role of KDM4B on human development is still poorly characterized. Through international data sharing, we gathered a cohort of nine individuals with mono-allelic de novo or inherited variants in KDM4B. All individuals presented with dysmorphic features and global developmental delay (GDD) with language and motor skills most affected. Three individuals had a history of seizures, and four had anomalies on brain imaging ranging from agenesis of the corpus callosum with hydrocephalus to cystic formations, abnormal hippocampi, and polymicrogyria. In mice, lysine demethylase 4B is expressed during brain development with high levels in the hippocampus, a region important for learning and memory. To understand how KDM4B variants can lead to GDD in humans, we assessed the effect of KDM4B disruption on brain anatomy and behavior through an in vivo heterozygous mouse model (Kdm4b), focusing on neuroanatomical changes. In mutant mice, the total brain volume was significantly reduced with decreased size of the hippocampal dentate gyrus, partial agenesis of the corpus callosum, and ventriculomegaly. This report demonstrates that variants in KDM4B are associated with GDD/ intellectual disability and neuroanatomical defects. Our findings suggest that KDM4B variation leads to a chromatinopathy, broadening the spectrum of this group of Mendelian disorders caused by alterations in epigenetic machinery.
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http://dx.doi.org/10.1016/j.ajhg.2020.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820620PMC
December 2020

Channelopathies Are a Frequent Cause of Genetic Ataxias Associated with Cerebellar Atrophy.

Mov Disord Clin Pract 2020 Nov 29;7(8):940-949. Epub 2020 Sep 29.

Division of Clinical and Metabolic Genetics, Department of Paediatrics The Hospital for Sick Children, University of Toronto Toronto Ontario Canada.

Background: Cerebellar atrophy is a nonspecific imaging finding observed in a number of neurological disorders. Genetic ataxias associated with cerebellar atrophy are a heterogeneous group of conditions, rendering the approach to diagnosis challenging.

Objectives: To define the spectrum of genetic ataxias associated with cerebellar atrophy in a Canadian cohort and the diagnostic yield of exome sequencing for this group of conditions.

Methods: A total of 92 participants from 66 families with cerebellar atrophy were recruited for this multicenter prospective cohort study. Exome sequencing was performed for all participants between 2011 and 2017 as part of 1 of 2 national research programs, Finding of Rare Genetic Disease Genes or Enhanced Care for Rare Genetic Diseases in Canada.

Results: A genetic diagnosis was established in 53% of families (35/66). Pathogenic variants were found in 21 known genes, providing a diagnosis for 31/35 families (89%), and in 4 novel genes, accounting for 4/35 families (11%). Of the families, 31/66 (47%) remained without a genetic diagnosis. The most common diagnoses were channelopathies, which were established in 9/35 families (26%). Additional clinical findings provided useful clues to specific diagnoses.

Conclusions: We report on the high frequency of channelopathies as a cause of genetic ataxias associated with cerebellar atrophy and the utility of exome sequencing for this group of conditions.
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http://dx.doi.org/10.1002/mdc3.13086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604675PMC
November 2020

Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.

Authors:
Félixe Pelletier Stefanie Perrier Ferdy K Cayami Amytice Mirchi Stephan Saikali Luan T Tran Nicole Ulrick Kether Guerrero Emmanouil Rampakakis Rosalina M L van Spaendonk Sakkubai Naidu Daniela Pohl William T Gibson Michelle Demos Cyril Goizet Ingrid Tejera-Martin Ana Potic Brent L Fogel Bernard Brais Michel Sylvain Guillaume Sébire Charles Marques Lourenço Joshua L Bonkowsky Coriene Catsman-Berrevoets Pedro S Pinto Sandya Tirupathi Petter Strømme Ton de Grauw Dorota Gieruszczak-Bialek Ingeborg Krägeloh-Mann Hanna Mierzewska Heike Philippi Julia Rankin Tahir Atik Brenda Banwell William S Benko Astrid Blaschek Annette Bley Eugen Boltshauser Drago Bratkovic Klara Brozova Icíar Cimas Christopher Clough Bernard Corenblum Argirios Dinopoulos Gail Dolan Flavio Faletra Raymond Fernandez Janice Fletcher Maria Eugenia Garcia Garcia Paolo Gasparini Janina Gburek-Augustat Dolores Gonzalez Moron Aline Hamati Inga Harting Christoph Hertzberg Alan Hill Grace M Hobson A Micheil Innes Marcelo Kauffman Susan M Kirwin Gerhard Kluger Petra Kolditz Urania Kotzaeridou Roberta La Piana Eriskay Liston William McClintock Meriel McEntagart Fiona McKenzie Serge Melançon Anjum Misbahuddin Mohnish Suri Fernando I Monton Sebastien Moutton Raymond P J Murphy Miriam Nickel Hüseyin Onay Simona Orcesi Ferda Özkınay Steffi Patzer Helio Pedro Sandra Pekic Mercedes Pineda Marfa Amy Pizzino Barbara Plecko Bwee Tien Poll-The Vera Popovic Dietz Rating Marie-France Rioux Norberto Rodriguez Espinosa Anne Ronan John R Ostergaard Elsa Rossignol Rocio Sanchez-Carpintero Anna Schossig Nesrin Senbil Laura K Sønderberg Roos Cathy A Stevens Matthis Synofzik László Sztriha Daniel Tibussek Dagmar Timmann Davide Tonduti Bart P van de Warrenburg Maria Vázquez-López Sunita Venkateswaran Pontus Wasling Evangeline Wassmer Richard I Webster Gert Wiegand Grace Yoon Joost Rotteveel Raphael Schiffmann Marjo S van der Knaap Adeline Vanderver Gabriel Á Martos-Moreno Constantin Polychronakos Nicole I Wolf Geneviève Bernard

J Clin Endocrinol Metab 2021 Jan;106(2):e660-e674

Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.

Context: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date.

Objective: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy.

Design: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated.

Setting: This was a multicenter retrospective study using information collected from 3 predominant centers.

Patients: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included.

Main Outcome Measures: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts.

Results: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients.

Conclusions: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.
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http://dx.doi.org/10.1210/clinem/dgaa700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823228PMC
January 2021

Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia.

Brain 2020 10;143(10):2929-2944

Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0-49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2-5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1-46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an 'AP-4 deficiency syndrome'. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.
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http://dx.doi.org/10.1093/brain/awz307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780481PMC
October 2020

Loss of aryl hydrocarbon receptor potentiates FoxM1 signaling to enhance self-renewal of colonic stem and progenitor cells.

EMBO J 2020 Oct 10;39(19):e104319. Epub 2020 Aug 10.

Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX, USA.

The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that senses xenobiotics, diet, and gut microbial-derived metabolites, is increasingly recognized as a key regulator of intestinal biology. However, its effects on the function of colonic stem and progenitor cells remain largely unexplored. Here, we observed that inducible deletion of AhR in Lgr5 stem cells increases the percentage of colonic stem cells and enhances organoid initiating capacity and growth of sorted stem and progenitor cells, while AhR activation has the opposite effect. Moreover, intestinal-specific AhR knockout increases basal stem cell and crypt injury-induced cell proliferation and promotes colon tumorigenesis in a preclinical colitis-associated tumor model by upregulating FoxM1 signaling. Mechanistically, AhR transcriptionally suppresses FoxM1 expression. Activation of AhR in human organoids recapitulates phenotypes observed in mice, such as reduction in the percentage of colonic stem cells, promotion of stem cell differentiation, and attenuation of FoxM1 signaling. These findings indicate that the AhR-FoxM1 axis, at least in part, mediates colonic stem/progenitor cell behavior.
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http://dx.doi.org/10.15252/embj.2019104319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527924PMC
October 2020

FLVCR1-related disease as a rare cause of retinitis pigmentosa and hereditary sensory autonomic neuropathy.

Eur J Med Genet 2020 Nov 19;63(11):104037. Epub 2020 Aug 19.

Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, Toronto, Canada; Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada; Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Canada. Electronic address:

FLVCR1 encodes for a transmembrane heme exporter protein and it is known to cause a rare form of syndromic retinitis pigmentosa: posterior column ataxia with retinitis pigmentosa. Recently, the FLVCR1-associated phenotype has been expanded with sporadic reports of hereditary sensory-autonomic neuropathy or non-syndromic retinitis pigmentosa. Here, we report a 23-year- old female with early onset hypomyelinating sensory-autonomic neuropathy and retinitis pigmentosa. Both features were present since childhood. The patient developed signs of advanced retinitis pigmentosa by the age of 10 years leading to legal blindness after the age of 18. Following candidate gene panel testing, which was negative, whole exome sequencing revealed compound heterozygous pathogenic FLVCR1 variants: NM_014053.3: c.3G > T; p.(Met1?) and NM_014053.3: c.730G > A; p.(Gly244Ser), the latter variant is novel. In this report we highlight the association of retinitis pigmentosa with hypomyelinating sensory-autonomic neuropathy, which could be underdiagnosed due to variable severity. To summarize, the phenotypic heterogeneity of FLVCR1 variants is broad and should include retinitis pigmentosa along with range of neurological features.
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http://dx.doi.org/10.1016/j.ejmg.2020.104037DOI Listing
November 2020

Distinct Regulatory Programs Control the Latent Regenerative Potential of Dermal Fibroblasts during Wound Healing.

Cell Stem Cell 2020 09 4;27(3):396-412.e6. Epub 2020 Aug 4.

Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada; Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada. Electronic address:

Dermal fibroblasts exhibit considerable heterogeneity during homeostasis and in response to injury. Defining lineage origins of reparative fibroblasts and regulatory programs that drive fibrosis or, conversely, promote regeneration will be essential for improving healing outcomes. Using complementary fate-mapping approaches, we show that hair follicle mesenchymal progenitors make limited contributions to wound repair. In contrast, extrafollicular progenitors marked by the quiescence-associated factor Hic1 generated the bulk of reparative fibroblasts and exhibited functional divergence, mediating regeneration in the center of the wound neodermis and scar formation in the periphery. Single-cell RNA-seq revealed unique transcriptional, regulatory, and epithelial-mesenchymal crosstalk signatures that enabled mesenchymal competence for regeneration. Integration with scATAC-seq highlighted changes in chromatin accessibility within regeneration-associated loci. Finally, pharmacological modulation of RUNX1 and retinoic acid signaling or genetic deletion of Hic1 within wound-activated fibroblasts was sufficient to modulate healing outcomes, suggesting that reparative fibroblasts have latent but modifiable regenerative capacity.
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http://dx.doi.org/10.1016/j.stem.2020.07.008DOI Listing
September 2020

Assessing non-Mendelian inheritance in inherited axonopathies.

Genet Med 2020 Dec 3;22(12):2114-2119. Epub 2020 Aug 3.

Dr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.

Purpose: Inherited axonopathies (IA) are rare, clinically and genetically heterogeneous diseases that lead to length-dependent degeneration of the long axons in central (hereditary spastic paraplegia [HSP]) and peripheral (Charcot-Marie-Tooth type 2 [CMT2]) nervous systems. Mendelian high-penetrance alleles in over 100 different genes have been shown to cause IA; however, about 50% of IA cases do not receive a genetic diagnosis. A more comprehensive spectrum of causative genes and alleles is warranted, including causative and risk alleles, as well as oligogenic multilocus inheritance.

Methods: Through international collaboration, IA exome studies are beginning to be sufficiently powered to perform a pilot rare variant burden analysis. After extensive quality control, our cohort contained 343 CMT cases, 515 HSP cases, and 935 non-neurological controls. We assessed the cumulative mutational burden across disease genes, explored the evidence for multilocus inheritance, and performed an exome-wide rare variant burden analysis.

Results: We replicated the previously described mutational burden in a much larger cohort of CMT cases, and observed the same effect in HSP cases. We identified a preliminary risk allele for CMT in the EXOC4 gene (p value= 6.9 × 10-6, odds ratio [OR] = 2.1) and explored the possibility of multilocus inheritance in IA.

Conclusion: Our results support the continuing emergence of complex inheritance mechanisms in historically Mendelian disorders.
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http://dx.doi.org/10.1038/s41436-020-0924-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710562PMC
December 2020

De Novo Variants in the ATPase Module of MORC2 Cause a Neurodevelopmental Disorder with Growth Retardation and Variable Craniofacial Dysmorphism.

Am J Hum Genet 2020 08 20;107(2):352-363. Epub 2020 Jul 20.

GeneDx, Inc., Gaithersburg, MD 20877, USA.

MORC2 encodes an ATPase that plays a role in chromatin remodeling, DNA repair, and transcriptional regulation. Heterozygous variants in MORC2 have been reported in individuals with autosomal-dominant Charcot-Marie-Tooth disease type 2Z and spinal muscular atrophy, and the onset of symptoms ranges from infancy to the second decade of life. Here, we present a cohort of 20 individuals referred for exome sequencing who harbor pathogenic variants in the ATPase module of MORC2. Individuals presented with a similar phenotype consisting of developmental delay, intellectual disability, growth retardation, microcephaly, and variable craniofacial dysmorphism. Weakness, hyporeflexia, and electrophysiologic abnormalities suggestive of neuropathy were frequently observed but were not the predominant feature. Five of 18 individuals for whom brain imaging was available had lesions reminiscent of those observed in Leigh syndrome, and five of six individuals who had dilated eye exams had retinal pigmentary abnormalities. Functional assays revealed that these MORC2 variants result in hyperactivation of epigenetic silencing by the HUSH complex, supporting their pathogenicity. The described set of morphological, growth, developmental, and neurological findings and medical concerns expands the spectrum of genetic disorders resulting from pathogenic variants in MORC2.
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http://dx.doi.org/10.1016/j.ajhg.2020.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413887PMC
August 2020

Positron Emission Tomography Imaging of Infection Using a Nitro-Prodrug Analogue of 2-[F]F--Aminobenzoic Acid.

ACS Infect Dis 2020 08 31;6(8):2249-2259. Epub 2020 Jul 31.

Chronus Pharmaceuticals, 25 Health Sciences Drive, Stony Brook, New York 11790, United States.

Deep-seated bacterial infections caused by pathogens such as are difficult to diagnose and treat and are thus a major threat to human health. In previous work we demonstrated that positron emission tomography (PET) imaging with 2-[F]F--aminobenzoic acid (2-[F]F-PABA) could noninvasively identify, localize, and monitor infection with excellent sensitivity and specificity in a rodent soft tissue infection model. However, 2-[F]F-PABA is rapidly N-acetylated and eliminated, and in an attempt to improve radiotracer accumulation in bacteria we adopted a prodrug strategy in which the acid was protected by an ester and the amine was replaced with a nitro group. Metabolite analysis indicated that the nitro group of ethyl 2-[F]fluoro-4-nitrobenzoate (2-[F]F-ENB) is converted to the corresponding amine by bacteria-specific nitroreductases while the ester is hydrolyzed into the acid. PET/CT imaging of 2-[F]F-ENB and the corresponding acid 2-[F]F-NB in a rat soft tissue infection model demonstrated colocalization of the radiotracer with the bioluminescent signal arising from Xen29, and demonstrated that the tracer could differentiate infection from sterile inflammation. Significantly, the accumulation of both 2-[F]F-ENB and 2-[F]F-NB at the site of infection was 17-fold higher than at the site of sterile inflammation compared to 8-fold difference observed for 2-[F]F-PABA, supporting the proposal that the active radiotracer is 2-[F]F-NB. Collectively, these data suggest that 2-[F]F-ENB and 2-[F]F-NB have the potential for translation to humans as a rapid, noninvasive diagnostic tool to identify and localize infections.
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http://dx.doi.org/10.1021/acsinfecdis.0c00374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429255PMC
August 2020

Macrophages and Associated Ligands in the Aged Injured Nerve: A Defective Dynamic That Contributes to Reduced Axonal Regrowth.

Front Aging Neurosci 2020 12;12:174. Epub 2020 Jun 12.

Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.

The regenerative capacity of injured peripheral nerves is diminished with aging. To identify factors that contribute to this impairment, we compared the immune cell response in young vs. aged animals following nerve injury. First, we confirmed that macrophage accumulation is delayed in aged injured nerves which is due to defects in monocyte migration as a result of defects in site-specific recruitment signals in the aged nerve. Interestingly, impairment in both macrophage accumulation and functional recovery could be overcome by transplanting bone marrow from aged animals into young mice. That is, upon exposure to a youthful environment, monocytes/macrophages originating from the aged bone marrow behaved similarly to young cells. Transcriptional profiling of aged macrophages following nerve injury revealed that both pro- and anti-inflammatory genes were largely downregulated in aged compared to young macrophages. One ligand of particular interest was macrophage-associated secreted protein (MCP1), which exhibited a potent role in regulating aged axonal regrowth . Given that macrophage-derived MCP1 is significantly diminished in the aged injured nerve, our data suggest that age-associated defects in MCP1 signaling could contribute to the regenerative deficits that occur in the aged nervous system.
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http://dx.doi.org/10.3389/fnagi.2020.00174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304384PMC
June 2020

Engaging South Asian youth and families: A clinical review.

Int J Soc Psychiatry 2020 09 25;66(6):584-592. Epub 2020 May 25.

Department of Health Law, Policy & Management, Boston University School of Public Health, Boston, MA, USA.

Objective: South Asians (SAs), a rapidly growing minority group in the United States are underrepresented in mental health research. They represent a unique sub-group of Asian immigrants in that their journey to the United States in the last 50 years was driven by the pursuit of academic and career opportunities. Our goal is to provide a topical overview of factors contributing to the mental health challenges of South Asian American (SAA) youth and to describe culturally sensitive approaches that would provide effective treatment for SAA youth and their families.

Methods: We conducted a review of published literature in PubMed and PsycInfo search engines using the key words South Asian immigrants, South Asian Americans, psychological, psychiatric, mental health treatment, therapy and interventions.

Results: The challenges faced by these highly educated families are distinctive in that there is a struggle to maintain ethnic identity based on collectivism while embracing American ideals of individualism. These opposing values along with model minority expectations put SAs at high risk for mental health concerns and acculturative family distancing. Furthermore, mental health stigma impedes help-seeking. Mental health practitioners must navigate the different value systems of the parent-child dyad without ostracizing either generation and deliver effective care. Hence, culturally adapted family therapy and community-based approaches may be particularly relevant in SA youth.

Conclusion: Our article outlines common family attitudes and issues pertinent to mental health in youth and discusses useful clinical approaches to dealing with SAA youth and their families.
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http://dx.doi.org/10.1177/0020764020922881DOI Listing
September 2020

Pearls & Oy-sters: Fatal brain edema is a rare complication of severe CACNA1A-related disorder.

Neurology 2020 04 13;94(14):631-634. Epub 2020 Mar 13.

From the Division of Clinical and Metabolic Genetics (L.G., G.Y.) and Division of Neurology (L.G., E.W.Y.T., S.P.M., G.Y.), Department of Paediatrics, and Division of Pathology, Department of Paediatric Laboratory Medicine (C.H.), The Hospital for Sick Children, University of Toronto, Canada.

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http://dx.doi.org/10.1212/WNL.0000000000009223DOI Listing
April 2020

Clinical spectrum of POLR3-related leukodystrophy caused by biallelic pathogenic variants.

Neurol Genet 2019 Dec 30;5(6):e369. Epub 2019 Oct 30.

Department of Neurology and Neurosurgery (L.G., L.T.T., K.G., G.B.), McGill University, Montreal, Canada; Department of Pediatrics (L.G., L.T.T., K.G., G.B.), McGill University, Montreal, Canada; Division of Clinical and Metabolic Genetics and Division of Neurology (L.G., G.Y.), The Hospital for Sick Children, University of Toronto, Toronto, Canada; Department of Child Neurology (F.K.C., M.S.V.D.K., N.I.W.), Emma Children's Hospital, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, and Amsterdam Neuroscience, Amsterdam, The Netherlands; Department of Clinical Genetics (F.K.C., R.M.V.S.), VU University Medical Center, Amsterdam, The Netherlands; Department of Human Genetics (F.K.C.), Center for Biomedical Research, Diponegoro University, Semarang, Indonesia; Department of Pediatrics (L.S.), Faculty of Medicine, University of Szeged, Szeged, Hungary; Child Health and Human Development Program (L.T.T., K.G., G.B.), Research Institute of the McGill University Health Center, Montreal, Canada; Division of Medical Genetics, Department of Specialized Medicine (L.T.T., K.G., G.B.), McGill University Health Center, Montreal, Canada; Centre de Référence Neurogénétique (F.H., C.G.), Service de Génétique, CHU Bordeaux, Bordeaux, France; Department of Pediatrics (E.L.F.), Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China; Developmental Neurology Department (S.D.A.), Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy; Neuroscience and Neurorehabilitation Department (G.V.), Bambino Gesu Children's Hospital, Rome, Italy; Center for Pediatric Genomic Medicine (I.T.), Children's Mercy Hospitals and Clinics, Kansas City, MO; University of Missouri-Kansas City School of Medicine (I.T.), Kansas City, MO; Department of Pathology and Laboratory Medicine (I.T.), Children's Mercy Hospitals, Kansas City, MO; Department of Pediatrics (D.M.N.), Section of Medical Genetics, Ochsner for Children, New Orleans, LA; GeneDx (R.P.), Gaithersburg, MD; Division of Neurology (K.S.L.), Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ; Department of Pediatric Neurology (E.W.), Birmingham Children's Hospital, Birmingham, United Kingdom; Department of Medical Genetics (T.P.), Telemark Hospital, Skien, Norway; Department of Paediatric Neurology (P.F.), St Georges University Hospital NHS Foundation Trust, London, United Kingdom; Clinical Genetics Service (M.M.), St George's University Hospitals NHS Foundation Trust, London, United Kingdom; Clinical Genetics Department (J.R.), Royal Devon and Exeter Hospital NHS Trust, Exeter, United Kingdom; Department of Neurology and Neurosurgery (R.W.), The Children's Hospital at Westmead, Westmead, New South Wales, Australia; Center of Developmental Neurology (H.P.), Frankfurt, Germany; Department of Neurology (B.V.D.W.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Neurology (D.T.), Essen University Hospital, University of Duisburg-Essen, Essen, Germany; Department of Clinical Genetics (A.D., C.S.), Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom; Wellcome Sanger Institute (DDD Study), Wellcome Genome Campus, Cambridge, United Kingdom; Department of Pediatrics (N.T.), Division of Child Neurology, University of Texas Health Science Center, Houston, TX, United States of America; Movement Disorders Center and Neurogenetics Research Program (M.C.K.), Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ; Program in Neuroscience (M.C.K.), Arizona State University, Tempe, AZ, United States of America; Division of Neurology (S.S.), Department of Pediatrics, Lady Hardinge Medical College and Associated Kalawati Saran Children's Hospital, New Delhi, India; Division of Neurology (A.V.), Children's Hospital of Philadelphia, Philadelphia, PA; Department of Neurology (A.V.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America; Department of Child Neurology (D.T.), Neurological Institute C. Besta Foundation IRCCS, Milan, Italy; Department of Functional Genomics (M.S.V.D.K.), VU University, Amsterdam, The Netherlands; Unit of Neuromuscular and Neurodegenerative Disorders (E.B.), Laboratory of Molecular Medicine, Bambino Gesu Children's Hospital, Rome, Italy; Laboratoire MRGM, INSERM U1211, University Bordeaux, Bordeaux, France; Université de Bordeaux (S.F.), INSERM U1212, CNRS 5320, Bordeaux, France; and Department of Human Genetics (G.B.), McGill University, Montreal, Canada.

Objective: To determine the clinical, radiologic, and molecular characteristics of RNA polymerase III-related leukodystrophy (POLR3-HLD) caused by biallelic pathogenic variants.

Methods: A cross-sectional observational study involving 25 centers worldwide was conducted. Clinical and molecular information was collected on 23 unreported and previously reported patients with POLR3-HLD and biallelic pathogenic variants in . Brain MRI studies were reviewed.

Results: Fourteen female and 9 male patients aged 7 days to 23 years were included in the study. Most participants presented early in life (birth to 6 years), and motor deterioration was seen during childhood. A notable proportion of patients required a wheelchair before adolescence, suggesting a more severe phenotype than previously described in POLR3-HLD. Dental, ocular, and endocrine features were not invariably present (70%, 50%, and 50%, respectively). Five patients (22%) had a combination of hypomyelinating leukodystrophy and abnormal craniofacial development, including 1 individual with clear Treacher Collins syndrome (TCS) features. Brain MRI revealed hypomyelination in all cases, often with areas of pronounced T2 hyperintensity corresponding to T1 hypointensity of the white matter. Twenty-nine different pathogenic variants (including 12 new disease-causing variants) in were identified.

Conclusions: This study provides a comprehensive description of POLR3-HLD caused by biallelic pathogenic variants based on the largest cohort of patients to date. These results suggest distinct characteristics of POLR1C-related disorder, with a spectrum of clinical involvement characterized by hypomyelinating leukodystrophy with or without abnormal craniofacial development reminiscent of TCS.
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http://dx.doi.org/10.1212/NXG.0000000000000369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927361PMC
December 2019

Psychometric properties of the Friedreich Ataxia Rating Scale.

Neurol Genet 2019 Dec 29;5(6):371. Epub 2019 Oct 29.

Clinical Data Science GmbH (C.R.), Basel, Switzerland; Bruce Lefroy Centre for Genetic Health Research (L.A.C., M.B.D.), Murdoch Children's Research Institute, Parkville, Victoria, Australia; Department of Paediatrics (L.A.C., M.B.D.), University of Melbourne, Parkville, Victoria, Australia; Department of Neurology (S.H.S.), McKnight Brain Institute, Room, Gainesville, FL; University of Minnesota (K.B.); University of Chicago (C.M.G.); Ohio State University (J.C.H.); Divisions of Neurology and Clinical and Metabolic Genetics (G.Y.), Department of Paediatrics, the Hospital for Sick Children, University of Toronto, Ontario, Canada Hospital; University of Rochester (B.R.); University of Iowa (K.D.M.); Emory University (G.W.); University of South Florida (T.Z.); Friedreich's Ataxia Research Alliance (S.P.), Downingtown, PA; and Division of Neurology (D.R.L.), Children's Hospital of Philadelphia.

Objective: To investigate the psychometric properties of the Friedreich Ataxia Rating Scale neurologic examination (FARSn) and its subscores, as well as the influence of the modifications resulting in the now widely used modified FARS (mFARS) examination.

Methods: Based on cross-sectional FARS data from the FA-Clinical Outcome Measures cohort, we conducted correlation-based psychometric analyses to investigate the interplay of items and subscores within the FARSn/mFARS constructs.

Results: The results provide support for both the FARSn and the mFARS constructs, as well as individually for their upper limb and lower limb coordination components. The omission of the peripheral nervous system subscore (D) and 2 items of the bulbar subscore (A) in the mFARS strengthens the overall construct compared with the complete FARS.

Conclusions: A correlation-based psychometric analysis of the neurologic FARSn score justifies the overall validity of the scale. In addition, omission of items of limited functional significance as created in the mFARS improves the features of the measures. Such information is crucial to the ongoing application of the mFARS in natural history studies and clinical trials. Additional analyses of longitudinal changes will be necessary to fully ascertain its utility, especially in nonambulant patients.
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http://dx.doi.org/10.1212/NXG.0000000000000371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927357PMC
December 2019

Parent Perspectives During Hospital Readmissions for Children With Medical Complexity: A Qualitative Study.

Hosp Pediatr 2020 03 6;10(3):222-229. Epub 2020 Feb 6.

Tufts Medical Center, and.

Objectives: Children with medical complexity (CMC) have high readmission rates, but relatively little is known from the parent perspective regarding care experiences surrounding and factors contributing to readmissions. We aimed to elicit parent perspectives on circumstances surrounding 30-day readmissions for CMC.

Methods: We conducted 20 semistructured interviews with parents of CMC experiencing an unplanned 30-day readmission at 1 academic medical center between December 2016 and January 2018, asking about topics such as previous discharge experiences, medical services and resources, and home environment and social support. Interviews were recorded, professionally transcribed, and analyzed thematically by using a modified grounded theory approach.

Results: Children ranged in age from 0 to 15 years, with neurologic complex chronic conditions being predominant (35%). Although the majority of parents did not identify any factors that they perceived to have contributed to readmission, themes emerged regarding challenges associated with chronicity of care and transitions of care that might influence readmissions, including frequency of hospital use, symptom confusion, lack of inpatient continuity, resources needed but not received, and difficulty filling prescriptions.

Conclusions: Parents identified multiple challenges associated with chronicity of medical management and transitions of care for CMC. Future interventions aiming to improve continuity and communication between admissions, ensure that home services are provided when applicable and prescriptions are filled, and provide comprehensive support for families in both the short- and long-term may help improve patient and family experiences while potentially decreasing readmissions.
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http://dx.doi.org/10.1542/hpeds.2019-0185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041550PMC
March 2020

Health related quality of life in Friedreich Ataxia in a large heterogeneous cohort.

J Neurol Sci 2020 Mar 24;410:116642. Epub 2019 Dec 24.

Division of Neurology, Children's Hospital of Philadelphia, 502 Abramson Research Center, 3615 Civic Center Blvd, Philadelphia, PA 19104-4318, United States of America. Electronic address:

Introduction: This study assessed the Health Related Quality of Life (HRQOL) of individuals with Friedreich Ataxia (FRDA) through responses to HRQOL questionnaires.

Methods: The SF-36, a generic HRQOL instrument, and symptom specific scales examining vision, fatigue, pain and bladder function were administered to individuals with FRDA and analyzed by comparison with disease features. Multiple linear regression models were used to study independent effects of genetic severity and age. Assessments were performed at baseline then intermittently after that.

Results: Subjects were on average young adults. For the SF36, the subscale with the lowest HRQOL score was the physical function scale, while the emotional well-being score was the highest. The physical function scale correlated with age of onset, duration, and subject age. In assessment of symptom specific scales, bladder control scores (BLCS) correlated with duration and age, while impact of visual impairment scores (IVIS) correlated with duration. In linear regression models, the BLCS, Pain Effect Score, and IVIS scores were predicted by age and GAA length; modified fatigue impact scale scores were predicted only by GAA length. Physical function and role limitation scores declined over time. No change was seen over time in other SF-36 subscores. Symptom specific scales also worsened over time, most notably the IVIS and BLCS.

Conclusion: The SF-36 and symptom specific scales capture dysfunction in FRDA in a manner that reflects disease status. HRQOL dysfunction was greatest on physically related scales; such scales correlated with disease duration, indicating that they worsen with progressing disease.
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http://dx.doi.org/10.1016/j.jns.2019.116642DOI Listing
March 2020

Homozygous pathogenic variant in associated with nonprogressive cerebellar ataxia.

Neurol Genet 2019 Oct 4;5(5):e359. Epub 2019 Sep 4.

Division of Neurology (A.M., G.Y.), Department of Paediatrics, University of Toronto, The Hospital for Sick Children, Canada; Department of Genome Dynamics (Z.C., K.W.C., H.H.), Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic; Faculty of Science (Z.C.), Charles University in Prague, Czech Republic; Department of Neuroscience (M.T.), Université de Montréal, CHUM, Montréal, Québec, Canada; Department of Paediatric Laboratory Medicine (L.M.), Hospital for Sick Children; Department of Lab Medicine and Pathobiology (L.M.), University of Toronto, Ontario, Canada; Program in Genetics and Genome Biology (N.S.), SickKids Research Institute, Toronto, Ontario, Canada; Division of Clinical and Metabolic Genetics (N.S., G.Y.), Department of Paediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Canada; and Genome Damage and Stability Centre (K.W.C., H.H.), School of Life Sciences, University of Sussex, Falmer, Brighton, UK.

Objective: To investigate the pathogenicity of a novel homozygous variant in 2 siblings with nonprogressive cerebellar ataxia (NPCA) through functional studies on primary and immortalized patient cell lines.

Methods: BRAT1 protein levels and ataxia-telangiectasia mutated (ATM) kinase activity in patient-derived and control cell lines were assessed by Western blotting. The impact of the novel variants on mitochondrial function was also assessed, by comparing patient and control cell lines for rates of oxygen consumption and for phosphorylation (S293) of the E1⍺ subunit of pyruvate dehydrogenase (PDH).

Results: Two male siblings with NPCA, mild intellectual disability, and isolated cerebellar atrophy were found to be homozygous for a c.185T>A (p.Val62Glu) variant in by whole exome sequencing. Western blotting revealed markedly decreased BRAT1 protein levels in lymphocytes and/or fibroblast cells from both affected siblings compared to control cell lines. There were no differences between the patient and control cells in ATM kinase activation, following ionizing radiation. Mitochondrial studies were initially suggestive of a defect in regulation of PDH activity, but there was no evidence of increased phosphorylation of the E1⍺ subunit of the PDH complex. Measurement of oxygen consumption rates similarly failed to identify differences between patient and control cells.

Conclusions: Biallelic pathogenic variants in can be associated with NPCA, a phenotype considerably milder than previously reported. Surprisingly, despite the molecular role currently proposed for BRAT1 in ATM regulation, this disorder is unlikely to result from defective ATM kinase or mitochondrial dysfunction.
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http://dx.doi.org/10.1212/NXG.0000000000000359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773431PMC
October 2019

Adult Human Dermal Progenitor Cell Transplantation Modulates the Functional Outcome of Split-Thickness Skin Xenografts.

Stem Cell Reports 2019 12 14;13(6):1068-1082. Epub 2019 Nov 14.

Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada; Section of Plastic Surgery, Department of Surgery, University of Calgary, Calgary, AB, Canada; Alberta Children's Hospital Research Institute, Calgary, AB, Canada; Hotchkiss Brain Institute, Calgary, AB, Canada. Electronic address:

Following full-thickness skin injuries, epithelialization of the wound is essential. The standard of care to achieve this wound "closure" in patients is autologous split-thickness skin grafting (STSG). However, patients living with STSGs report significant chronic impairments leading to functional deficiencies such as itch, altered sensation, fragility, hypertrophic scarring, and contractures. These features are attributable to the absence of functional dermis combined with the formation of disorganized fibrotic extracellular matrix. Recent work has demonstrated the existence of dermal progenitor cells (DPCs) residing within hair follicles that function to continuously regenerate mesenchymal tissue. The present work examines whether cultured DPCs could regenerate dermis within an STSG and improve overall graft function. Adult human DPCs were transplanted into a full-thickness skin wound in immune-compromised mice and closed with a human STSG. At 3 months, human DPCs (hDPCs) had successfully integrated into the xenograft and differentiated into various regionally specified phenotypes, improving both viscoelastic properties of the graft and mitigating pruritus.
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http://dx.doi.org/10.1016/j.stemcr.2019.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915850PMC
December 2019

Epigenetic age acceleration and metabolic syndrome in the coronary artery risk development in young adults study.

Clin Epigenetics 2019 11 15;11(1):160. Epub 2019 Nov 15.

Department of Preventive Medicine and Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 680 N. Lake Shore Dr., Suite 1400, Chicago, IL, 60611, USA.

Background: The metabolic syndrome (MetS) is a collection of metabolic disturbances that can lead to various cardiovascular diseases. Previous studies have shown a more adverse metabolic risk profile is associated with more advanced biological aging. The associations between epigenetic biomarkers of age with MetS, however, are not well understood. We therefore investigated the associations between epigenetic age acceleration and MetS severity score and incident MetS.

Results: A subset of study participants with available whole blood at examination years 15 and 20 from the Coronary Artery Risk Development in Young Adults Study underwent epigenomic profiling using the Illumina MethylationEPIC Beadchip (~ 850,000 sites). Intrinsic and extrinsic epigenetic age acceleration (IEAA and EEAA) were calculated from DNA methylation levels. The MetS severity score was positively associated with IEAA at years 15 (P = 0.016) and 20 (P = 0.016) and EEAA at year 20 (P = 0.040) in cross-sectional analysis. IEAA at year 20 was significantly associated with incident MetS at year 30 (OR = 1.05 [95% CI 1.01, 1.10], P = 0.028).

Conclusions: To our knowledge, this is the first report of the longitudinal association between epigenetic age acceleration and MetS. These findings suggest that a higher MetS severity score is associated with accelerated epigenetic aging and such aging may play a role in the development of metabolic disorders, potentially serving as a useful biomarker of and early detection tool for future MetS.
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http://dx.doi.org/10.1186/s13148-019-0767-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858654PMC
November 2019

Hypolipidaemia among patients with PMM2-CDG is associated with low circulating PCSK9 levels: a case report followed by observational and experimental studies.

J Med Genet 2020 01 7;57(1):11-17. Epub 2019 Aug 7.

Department of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec, Canada

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are novel therapeutics for reducing low-density lipoprotein cholesterol (LDLc). While serious side-effects have not been observed in short-term clinical trials, there remain concerns that long-term PCSK9 inhibition may cause neurocognitive side-effects.

Methods And Results: An adult male with childhood-onset global developmental delay, cerebellar atrophy and severe hypolipidaemia underwent extensive biochemical and genetic investigations. Initial testing revealed low circulating PCSK9 levels and a common loss-of-function PCSK9 polymorphism, but these findings did not fully account for severe hypolipidaemia. Whole-exome sequencing was subsequently performed and identified two pathogenic phosphomannose mutase 2 (PMM2) variants (p.Arg141His and p.Pro69Ser) known to cause PMM2-associated congenital disorder of glycosylation (PMM2-CDG). A diagnosis of PMM2-CDG was consistent with the proband's neurological symptoms and severe hypolipidaemia. Given that PMM2-CDG is characterised by defective protein N-glycosylation and that PCSK9 is a negative regulator of LDLc, we postulated that loss of PCSK9 N-glycosylation mediates hypolipidaemia among patients with PMM2-CDG. First, in an independent cohort of patients with PMM2-CDG (N=8), we verified that circulating PCSK9 levels were significantly lower in patients than controls (p=0.0006). Second, we conducted in vitro experiments in hepatocyte-derived cells to evaluate the effects of PCSK9 N-glycosylation loss on LDL receptor (LDLR) activity. Experimental results suggest that defective PCSK9 N-glycosylation reduces the ability of circulating PCSK9 to degrade LDLR.

Conclusion: Life-long exposure to genetically lower PCSK9 per se is unlikely to cause neurocognitive impairment. Both observational and experimental findings suggest that hypolipidaemia in PMM2-CDG may be partially mediated by loss of PCSK9 N-glycosylation and/or its regulators.
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http://dx.doi.org/10.1136/jmedgenet-2019-106102DOI Listing
January 2020

Insurance Stability and Cancer Screening Behaviors.

Health Equity 2019 3;3(1):177-182. Epub 2019 Apr 3.

Department of Internal Medicine, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio.

Disparities in rates of cancer screening are observed in underserved populations. Lack of stable health insurance may contribute to these disparities. The goal of this study was to examine the association between insurance stability and up-to-date cancer screening in underserved populations. We enrolled 333 community participants aged 40-74 years across four different sites in three states: Chinese Americans in Boston, Massachusetts; Hispanics in Columbus, Ohio; Appalachian populations from Ohio's Appalachian counties; and Blacks and African Americans in Philadelphia, Pennsylvania. Self-reported screening rates were 77.9% for breast cancer, 71.1% for cervical cancer, and 67.7% for colorectal cancer (CRC). Screening rates fell short of Health People 2020 targets for breast, colorectal, and cervical cancer screenings. Being currently insured was associated with current CRC screenings (69.7% among insured vs. 30.7% among uninsured, =0.0055), but not with breast or cervical cancer screenings. Stable 12-month insurance coverage was not statistically associated with up-to-date screenings. Having current insurance was associated with CRC screening; stability of insurance was not associated with cancer screening. Insurance coverage alone is not the main driver of cancer screening.
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http://dx.doi.org/10.1089/heq.2018.0093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6608696PMC
April 2019

Microbial Networks in SPRING - Semi-parametric Rank-Based Correlation and Partial Correlation Estimation for Quantitative Microbiome Data.

Front Genet 2019 6;10:516. Epub 2019 Jun 6.

Center for Computational Mathematics, Flatiron Institute, New York, NY, United States.

High-throughput microbial sequencing techniques, such as targeted amplicon-based and metagenomic profiling, provide low-cost genomic survey data of microbial communities in their natural environment, ranging from marine ecosystems to host-associated habitats. While standard microbiome profiling data can provide sparse relative abundances of operational taxonomic units or genes, recent advances in experimental protocols give a more quantitative picture of microbial communities by pairing sequencing-based techniques with orthogonal measurements of microbial cell counts from the same sample. These tandem measurements provide absolute microbial count data albeit with a large excess of zeros due to limited sequencing depth. In this contribution we consider the fundamental statistical problem of estimating correlations and partial correlations from such quantitative microbiome data. To this end, we propose a semi-parametric rank-based approach to correlation estimation that can naturally deal with the excess zeros in the data. Combining this estimator with sparse graphical modeling techniques leads to the Semi-Parametric Rank-based approach for INference in Graphical model (SPRING). SPRING enables inference of statistical microbial association networks from quantitative microbiome data which can serve as high-level statistical summary of the underlying microbial ecosystem and can provide testable hypotheses for functional species-species interactions. Due to the absence of verified microbial associations we also introduce a novel quantitative microbiome data generation mechanism which mimics empirical marginal distributions of measured count data while simultaneously allowing user-specified dependencies among the variables. SPRING shows superior network recovery performance on a wide range of realistic benchmark problems with varying network topologies and is robust to misspecifications of the total cell count estimate. To highlight SPRING's broad applicability we infer taxon-taxon associations from the American Gut Project data and genus-genus associations from a recent quantitative gut microbiome dataset. We believe that, as quantitative microbiome profiling data will become increasingly available, the semi-parametric estimators for correlation and partial correlation estimation introduced here provide an important tool for reliable statistical analysis of quantitative microbiome data.
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http://dx.doi.org/10.3389/fgene.2019.00516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563871PMC
June 2019

Reply: IREB2-associated neurodegeneration.

Brain 2019 08;142(8):e41

Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA.

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http://dx.doi.org/10.1093/brain/awz185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658843PMC
August 2019

Simple Quasi-Bayes Approach for Modeling Mean Medical Costs.

Int J Biostat 2019 06 5;16(1). Epub 2019 Jun 5.

Department of Health Services Research, MD Anderson Cancer Center, Houston, TX, USA.

AbstractSeveral statistical issues associated with health care costs, such as heteroscedasticity and severe skewness, make it challenging to estimate or predict medical costs. When the interest is modeling the mean cost, it is desirable to make no assumption on the density function or higher order moments. Another challenge in developing cost prediction models is the presence of many covariates, making it necessary to apply variable selection methods to achieve a balance of prediction accuracy and model simplicity. We propose Spike-or-Slab priors for Bayesian variable selection based on asymptotic normal estimates of the full model parameters that are consistent as long as the assumption on the mean cost is satisfied. In addition, the scope of model searching can be reduced by ranking the Z-statistics. This method possesses four advantages simultaneously: robust (due to avoiding assumptions on the density function or higher order moments), parsimonious (feature of variable selection), informative (due to its Bayesian flavor, which can compare posterior probabilities of candidate models) and efficient (by reducing model searching scope with the use of Z-ranking). We apply this method to the Medical Expenditure Panel Survey dataset.
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http://dx.doi.org/10.1515/ijb-2018-0122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020650PMC
June 2019

Provider and Staff Feedback on Screening for Social and Behavioral Determinants of Health for Pediatric Patients.

J Am Board Fam Med 2019 May-Jun;32(3):297-306

From the Department of Medicine, Tufts Medical Center; Institute for Clinical Research and Health Policy Studies, Tufts CTSI, Boston, MA (EB); Department of Medicine, Tufts University School of Medicine, Boston (EB); Department of Pediatrics, Boston University School of Medicine, Boston Medical Center, Boston (AG, MP); Department of Health Law Policy & Management, Boston University School of Public Health, Boston (YD, GHY, MPC, M-LD); VA Center for Healthcare Organization and Implementation Research, Department of Veterans Affairs, Boston, MA (MPC); Section of Infectious Diseases, Evans Center for Implementation and Improvement Sciences, Department of Medicine, Boston University School of Medicine, Boston (M-LD).

Introduction: Screening and referral for Social and Behavioral Determinants of Health (SDOH) are increasingly recommended in clinical guidelines and consensus statements. It is important to understand barriers and facilitators to implementation of standardized SDOH screening and referral practices, as well as the scope of current existing SDOH screening.

Methods: We conducted a mixed-methods study to understand the current state of SDOH screening and to assess the barriers and facilitators to implementing a standardized SDOH screening and referral practice in Boston community health centers (CHCs) for pediatric patients. We requested all SDOH screening documents from 15 Boston CHCs and conducted provider and staff focus groups at intervention sites of an SDOH implementation pilot in Boston.

Results: All CHCs screened in some form for SDOH, but there was no agreement on which domains to screen. Participating CHCs screened for a mean of 8 SDOH domains (range, 5 to 16). Overall, 16 SDOH domains emerged. From the focus groups, 5 themes emerged: 1) provider perspectives, 2) work flow, 3) prior experience, 4) site resources and staffing, and 5) sustainability. There was little agreement among participants within each theme, as all were seen as barriers and facilitators depending on the respondent.

Discussion: This study highlights the various SDOH screening methods currently used in Boston CHCs, and the need for workflow and process individualization of SDOH screening and referral. Providers and clinical staff should be part of the discussion when implementing SDOH screening and referral procedures to ensure appropriate work flow, staff buy-in, and to maximize resources available.
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http://dx.doi.org/10.3122/jabfm.2019.03.180276DOI Listing
June 2020