Publications by authors named "Katherine Agre"

11 Publications

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Impact of integrated translational research on clinical exome sequencing.

Genet Med 2020 Nov 4. Epub 2020 Nov 4.

Center for Individualized Medicine, College of Medicine, Mayo Clinic, Rochester, MN, USA.

Purpose: Exome sequencing often identifies pathogenic genetic variants in patients with undiagnosed diseases. Nevertheless, frequent findings of variants of uncertain significance necessitate additional efforts to establish causality before reaching a conclusive diagnosis. To provide comprehensive genomic testing to patients with undiagnosed disease, we established an Individualized Medicine Clinic, which offered clinical exome testing and included a Translational Omics Program (TOP) that provided variant curation, research activities, or research exome sequencing.

Methods: From 2012 to 2018, 1101 unselected patients with undiagnosed diseases received exome testing. Outcomes were reviewed to assess impact of the TOP and patient characteristics on diagnostic rates through descriptive and multivariate analyses.

Results: The overall diagnostic yield was 24.9% (274 of 1101 patients), with 174 (15.8% of 1101) diagnosed on the basis of clinical exome sequencing alone. Four hundred twenty-three patients with nondiagnostic or without access to clinical exome sequencing were evaluated by the TOP, with 100 (9% of 1101) patients receiving a diagnosis, accounting for 36.5% of the diagnostic yield. The identification of a genetic diagnosis was influenced by the age at time of testing and the disease phenotype of the patient.

Conclusion: Integration of translational research activities into clinical practice of a tertiary medical center can significantly increase the diagnostic yield of patients with undiagnosed disease.
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http://dx.doi.org/10.1038/s41436-020-01005-9DOI Listing
November 2020

Variants in SCAF4 Cause a Neurodevelopmental Disorder and Are Associated with Impaired mRNA Processing.

Am J Hum Genet 2020 09 29;107(3):544-554. Epub 2020 Jul 29.

Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany. Electronic address:

RNA polymerase II interacts with various other complexes and factors to ensure correct initiation, elongation, and termination of mRNA transcription. One of these proteins is SR-related CTD-associated factor 4 (SCAF4), which is important for correct usage of polyA sites for mRNA termination. Using exome sequencing and international matchmaking, we identified nine likely pathogenic germline variants in SCAF4 including two splice-site and seven truncating variants, all residing in the N-terminal two thirds of the protein. Eight of these variants occurred de novo, and one was inherited. Affected individuals demonstrated a variable neurodevelopmental disorder characterized by mild intellectual disability, seizures, behavioral abnormalities, and various skeletal and structural anomalies. Paired-end RNA sequencing on blood lymphocytes of SCAF4-deficient individuals revealed a broad deregulation of more than 9,000 genes and significant differential splicing of more than 2,900 genes, indicating an important role of SCAF4 in mRNA processing. Knockdown of the SCAF4 ortholog CG4266 in the model organism Drosophila melanogaster resulted in impaired locomotor function, learning, and short-term memory. Furthermore, we observed an increased number of active zones in larval neuromuscular junctions, representing large glutamatergic synapses. These observations indicate a role of CG4266 in nervous system development and function and support the implication of SCAF4 in neurodevelopmental phenotypes. In summary, our data show that heterozygous, likely gene-disrupting variants in SCAF4 are causative for a variable neurodevelopmental disorder associated with impaired mRNA processing.
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http://dx.doi.org/10.1016/j.ajhg.2020.06.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477272PMC
September 2020

Developmental brain abnormalities and acute encephalopathy in a patient with myopathy with extrapyramidal signs secondary to pathogenic variants in MICU1.

JIMD Rep 2020 May 20;53(1):22-28. Epub 2020 Mar 20.

Center for Individualized Medicine Mayo Clinic Rochester Minnesota USA.

Mitochondria play a variety of roles in the cell, far beyond their widely recognized role in ATP generation. One such role is the regulation and sequestration of calcium, which is done with the help of the mitochondrial calcium uniporter (MCU) and its regulators, MICU1 and MICU2. Genetic variations in MICU1 and MICU2 have been reported to cause myopathy, developmental disability and neurological symptoms typical of mitochondrial disorders. The symptoms of MICU1/2 deficiency have generally been attributed to calcium regulation in the metabolic and biochemical roles of mitochondria. Here, we report a female child with heterozygous MICU1 variants and multiple congenital brain malformations on MRI. Specifically, she shows anterior perisylvian polymicrogyria, dysmorphic basal ganglia, and cerebellar dysplasia in addition to white matter abnormalities. These novel findings suggest that MICU1 is necessary for proper neurodevelopment through a variety of potential mechanisms, including calcium-mediated regulation of the neuronal cytoskeleton, Miro1-MCU complex-mediated mitochondrial movement, or enhancing ATP production. This case provides new insight into the molecular pathogenesis of MCU dysfunction and may represent a novel diagnostic feature of calcium-based mitochondrial disease.
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http://dx.doi.org/10.1002/jmd2.12114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203647PMC
May 2020

Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.

Sci Adv 2020 01 22;6(4):eaax0021. Epub 2020 Jan 22.

Rosalind and Morris Goodman Cancer Research Center, McGill University, Montreal, Quebec H3A 1A3, Canada.

Lysine acetyltransferase 6A (KAT6A) and its paralog KAT6B form stoichiometric complexes with bromodomain- and PHD finger-containing protein 1 (BRPF1) for acetylation of histone H3 at lysine 23 (H3K23). We report that these complexes also catalyze H3K23 propionylation in vitro and in vivo. Immunofluorescence microscopy and ATAC-See revealed the association of this modification with active chromatin. deletion obliterates the acylation in mouse embryos and fibroblasts. Moreover, we identify variants in 12 previously unidentified cases of syndromic intellectual disability and demonstrate that these cases and known variants impair H3K23 propionylation. Cardiac anomalies are present in a subset of the cases. H3K23 acylation is also impaired by cancer-derived somatic mutations. Valproate, vorinostat, propionate and butyrate promote H3K23 acylation. These results reveal the dual functionality of BRPF1-KAT6 complexes, shed light on mechanisms underlying related developmental disorders and various cancers, and suggest mutation-based therapy for medical conditions with deficient histone acylation.
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http://dx.doi.org/10.1126/sciadv.aax0021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976298PMC
January 2020

Genetic variants in DGAT1 cause diverse clinical presentations of malnutrition through a specific molecular mechanism.

Eur J Med Genet 2020 Apr 25;63(4):103817. Epub 2019 Nov 25.

Bioinformatics Research and Development Laboratory, Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA; Clinical and Translational Sciences Institute, Medical College of Wisconsin, Milwaukee, WI, 53226, USA. Electronic address:

Background: DGAT1, a gene encoding a protein involved in lipid metabolism, has been recently implicated in causing a rare nutritional and digestive disease presenting as Congenital Diarrheal Disorder (CDD). Genetic causes of malnutrition can be classified as metabolic disorders, caused by loss of a specific enzyme's function. However, disease driven by genetic variants in lipid metabolism genes is not well understood, and additional information is needed to better understand these effects.

Methods: We gathered a multi-institutional cohort of undiagnosed patients with a constellation of phenotypes presenting as malnutrition and metal ion dysregulation. Clinical Whole Exome Sequencing (WES) was performed on four patients and their unaffected parents. We prioritized genetic variants based on multiple criteria including population allele frequency and presumed inheritance pattern, and identified a candidate gene. Computational modeling was used to investigate if the altered amino acids are likely to result in a dysfunctional enzyme.

Results: We identified a multi-institutional cohort of patients presenting with malnutrition-like symptoms and likely pathogenic genomic variants within DGAT1. Multiple approaches were used to profile the effect these variants have on protein structure and function. Laboratory and nutritional intervention studies showed rapid and robust patient responses.

Conclusions: This report adds on to the database for existing mutations known within DGAT1, a gene recently implicated with CDD, and also expands its clinical spectrum. Identification of these DGAT1 mutations by WES has allowed for changes in the patients' nutritional rehabilitation, reversed growth failure and enabled them to be weaned off of total parenteral nutrition (TPN).
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http://dx.doi.org/10.1016/j.ejmg.2019.103817DOI Listing
April 2020

Familial implications of autoimmune disease: Recurrence risks of alopecia areata and associated conditions in first-degree relatives.

J Genet Couns 2020 02 11;29(1):35-43. Epub 2019 Oct 11.

Department of Dermatology, University of Minnesota Health, Minneapolis, MN, USA.

Alopecia areata (AA), a complex autoimmune hair loss condition, affects approximately 2.1% of the population. Individuals with AA have increased susceptibility to diseases such as atopy and autoimmune disorders, but little is known about first-degree relatives' risk to develop AA and associated conditions. Genetic counseling for multifactorial conditions, including autoimmune disease is complex, but potentially valuable. Anecdotally we know patients with AA ask medical providers about recurrence risk for family members as well as question whether they and their relatives are at risk for other conditions. Data on AA recurrence risks and comorbid conditions among relatives of affected individuals comprise valuable information that may guide clinical management by genetic counselors. This study investigated the recurrence risk of AA and compared the prevalence of associated conditions among first-degree relatives to the general population. The study also assessed the validity of self-reported conditions for a subset of participants. Relatives of individuals with AA (N = 155), recruited from the National Alopecia Areata Foundation Registry, completed telephone surveys about their personal medical history for 70 medical conditions associated with AA. Medical records for 60 participants were compared to self-reported responses. One-sided proportional tests, in which it is assumed the disease prevalence in first-degree relatives is higher than for those in the general population, yielded a 7.8% estimated risk of AA versus the general population prevalence of 2.1%. Furthermore, there are increased risks of 33 associated conditions, including atopy and other autoimmune conditions. Comparison of medical reports to self-reported conditions indicated only 12% was incongruent. The findings may help genetic counselors better serve patients and their families by informing them of lifetime risk estimates of developing AA and comorbid conditions, resulting in early diagnosis of autoimmune diseases in AA families. Findings also provide evidence supporting the validity of self-report data in AA families.
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http://dx.doi.org/10.1002/jgc4.1178DOI Listing
February 2020

Genetics of dilated cardiomyopathy: practical implications for heart failure management.

Nat Rev Cardiol 2020 05 11;17(5):286-297. Epub 2019 Oct 11.

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.

Given the global burden of heart failure, strategies to understand the underlying cause or to provide prognostic information are critical to reducing the morbidity and mortality associated with this highly prevalent disease. Cardiomyopathies often have a genetic cause, and the field of heart failure genetics is progressing rapidly. Through a deliberate investigation, evaluation for a familial component of cardiomyopathy can lead to increased identification of pathogenic genetic variants. Much research has also been focused on identifying markers of risk in patients with cardiomyopathy with the use of genetic testing. Advances in our understanding of genetic variants have been slightly offset by an increased recognition of the heterogeneity of disease expression. Greater breadth of genetic testing can increase the likelihood of identifying a variant of uncertain significance, which is resolved only rarely by cellular functional validation and segregation analysis. To increase the use of genetics in heart failure clinics, increased availability of genetic counsellors and other providers with experience in genetics is necessary. Ultimately, through ongoing research and increased clinical experience in cardiomyopathy genetics, an improved understanding of the disease processes will facilitate better clinical decision-making about the therapies offered, exemplifying the implementation of precision medicine.
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http://dx.doi.org/10.1038/s41569-019-0284-0DOI Listing
May 2020

Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability.

Authors:
Benjamin Cogné Sophie Ehresmann Eliane Beauregard-Lacroix Justine Rousseau Thomas Besnard Thomas Garcia Slavé Petrovski Shiri Avni Kirsty McWalter Patrick R Blackburn Stephan J Sanders Kévin Uguen Jacqueline Harris Julie S Cohen Moira Blyth Anna Lehman Jonathan Berg Mindy H Li Usha Kini Shelagh Joss Charlotte von der Lippe Christopher T Gordon Jennifer B Humberson Laurie Robak Daryl A Scott Vernon R Sutton Cara M Skraban Jennifer J Johnston Annapurna Poduri Magnus Nordenskjöld Vandana Shashi Erica H Gerkes Ernie M H F Bongers Christian Gilissen Yuri A Zarate Malin Kvarnung Kevin P Lally Peggy A Kulch Brina Daniels Andres Hernandez-Garcia Nicholas Stong Julie McGaughran Kyle Retterer Kristian Tveten Jennifer Sullivan Madeleine R Geisheker Asbjorg Stray-Pedersen Jennifer M Tarpinian Eric W Klee Julie C Sapp Jacob Zyskind Øystein L Holla Emma Bedoukian Francesca Filippini Anne Guimier Arnaud Picard Øyvind L Busk Jaya Punetha Rolph Pfundt Anna Lindstrand Ann Nordgren Fayth Kalb Megha Desai Ashley Harmon Ebanks Shalini N Jhangiani Tammie Dewan Zeynep H Coban Akdemir Aida Telegrafi Elaine H Zackai Amber Begtrup Xiaofei Song Annick Toutain Ingrid M Wentzensen Sylvie Odent Dominique Bonneau Xénia Latypova Wallid Deb Sylvia Redon Frédéric Bilan Marine Legendre Caitlin Troyer Kerri Whitlock Oana Caluseriu Marine I Murphree Pavel N Pichurin Katherine Agre Ralitza Gavrilova Tuula Rinne Meredith Park Catherine Shain Erin L Heinzen Rui Xiao Jeanne Amiel Stanislas Lyonnet Bertrand Isidor Leslie G Biesecker Dan Lowenstein Jennifer E Posey Anne-Sophie Denommé-Pichon Claude Férec Xiang-Jiao Yang Jill A Rosenfeld Brigitte Gilbert-Dussardier Séverine Audebert-Bellanger Richard Redon Holly A F Stessman Christoffer Nellaker Yaping Yang James R Lupski David B Goldstein Evan E Eichler Francois Bolduc Stéphane Bézieau Sébastien Küry Philippe M Campeau

Am J Hum Genet 2019 03 28;104(3):530-541. Epub 2019 Feb 28.

Centre Hospitalier Universitaire Sainte-Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada; Department of Pediatrics, University of Montreal, Montreal, QC H3T1J4, Canada. Electronic address:

Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.
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http://dx.doi.org/10.1016/j.ajhg.2019.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407527PMC
March 2019

Perspectives on facilitating whole exome sequencing for international patients at Mayo Clinic.

J Genet Couns 2019 04 14;28(2):398-406. Epub 2019 Feb 14.

Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota.

Whole exome sequencing (WES) has become a fundamental component of genetic evaluation and diagnosing rare genetic diseases. This test is now offered to patients from a wide variety of cultural backgrounds and in various clinical and research settings. This commentary is a reflection of one group of clinical genetic counselors' experiences in facilitating WES for patients who come from outside the United States for genetic evaluation and pursue WES. This patient population in our clinic primarily consists of individuals from the Middle East and presents recurrent logistical and counseling challenges. We aim to describe our international patient population, illuminate the challenges we have faced and illustrate how we have addressed these challenges.
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http://dx.doi.org/10.1002/jgc4.1100DOI Listing
April 2019

Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies.

Am J Hum Genet 2018 05 12;102(5):985-994. Epub 2018 Apr 12.

Stanley Institute for Cognitive Genomics, 1Bungtown Road, Cold Spring Harbor Laboratory, NY 11724, USA. Electronic address:

N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.
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http://dx.doi.org/10.1016/j.ajhg.2018.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986698PMC
May 2018

Mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA Synthase Deficiency: Unique Presenting Laboratory Values and a Review of Biochemical and Clinical Features.

JIMD Rep 2018 14;40:63-69. Epub 2017 Oct 14.

Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.

We report an 8-month-old infant with decreased consciousness after a febrile episode and reduced oral intake. He was profoundly acidotic but his lactate was normal. Serum triglycerides were markedly elevated and HDL cholesterol was very low. The urine organic acid analysis during the acute episode revealed a complex pattern of relative hypoketotic dicarboxylic aciduria, suggestive of a potential fatty acid oxidation disorder. MRI showed extensive brain abnormalities concerning for a primary energy deficiency. Whole exome sequencing revealed heterozygotic HMGCS2 variants. HMGCS2 encodes mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase-2 (HMGCS2), which catalyzes the irreversible and rate-limiting reaction of ketogenesis in the mitochondrial matrix. Autosomal recessive HMG-CoA synthase deficiency (HMGCS2D) is characterized by hypoketotic hypoglycemia, vomiting, lethargy, and hepatomegaly after periods of prolonged fasting or illness. A retrospective analysis of the urine organic acid analysis identified 4-hydrox-6-methyl-2-pyrone, a recently reported putative biomarker of HMGCS2D. There was also a relative elevation of plasma acetylcarnitine as previously reported in one case. Our patient highlights a unique presentation of HMGCS2D caused by novel variants in HMGCS2. This is the first report of HMGCS2D with a significantly elevated triglyceride level and decreased HDL cholesterol level at presentation. Given this, we suggest that HMGCS2D should be considered in the differential diagnosis when hypertriglyceridemia, or low HDL cholesterol levels are seen in a child who presents with acidosis, mild ketosis, and mental status changes after illness or prolonged fasting. Although HMGCS2D is a rare disorder with nonspecific symptoms, with the advent of next-generation sequencing, and the recognition of novel biochemical biomarkers, the incidence of this condition may become better understood.
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http://dx.doi.org/10.1007/8904_2017_59DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122033PMC
October 2017