Rapid whole-genome sequencing identifies a novel AIRE variant associated with autoimmune polyendocrine syndrome type 1

Autoimmune polyendocrine syndrome type 1 (APS-1; OMIM #240300), also referred to as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is a rare monogenic autoimmune disorder caused by mutations in the autoimmune regulator (AIRE) gene. APS-1 is classically characterized by a triad of chronic mucocutaneous candidiasis, autoimmune hypoparathyroidism, and autoimmune adrenocortical insufficiency. We report a 5-yr-old female who presented with symptoms of tetany due to hypocalcemia and was subsequently found to be secondary to hypoparathyroidism. Rapid trio whole-genome sequencing revealed compound heterozygous variants in AIRE in the proband, with a paternally inherited, pathogenic, frameshift variant (c.1265delC; p.Pro422LeufsTer58) and a novel, likely pathogenic, maternally inherited missense variant (c.268T>C; p.Tyr90His).

[1]  R. Bilous,et al.  A common and recurrent 13-bp deletion in the autoimmune regulator gene in British kindreds with autoimmune polyendocrinopathy type 1. , 1998, American journal of human genetics.

[2]  Hui Yang,et al.  Phenolyzer: phenotype-based prioritization of candidate genes for human diseases , 2015, Nature Methods.

[3]  W. Newman,et al.  Dominant Mutations in the Autoimmune Regulator AIRE Are Associated with Common Organ-Specific Autoimmune Diseases. , 2015, Immunity.

[4]  Martin G Reese,et al.  Clinical analysis of genome next-generation sequencing data using the Omicia platform , 2013, Expert review of molecular diagnostics.

[5]  R. Aggarwal,et al.  Autoimmune polyendocrine syndrome type 1 in an Indian cohort: a longitudinal study , 2017, Endocrine connections.

[6]  Laurie D. Smith,et al.  A 26-hour system of highly sensitive whole genome sequencing for emergency management of genetic diseases , 2015, Genome Medicine.

[7]  P. Knappskog,et al.  Expanding the Phenotypic and Genotypic Landscape of Autoimmune Polyendocrine Syndrome Type 1 , 2017, The Journal of clinical endocrinology and metabolism.

[8]  Qiaoyi Chen,et al.  Mutation analyses of North American APS‐1 patients , 1999, Human mutation.

[9]  Tudor Groza,et al.  The Human Phenotype Ontology in 2017 , 2016, Nucleic Acids Res..

[10]  Bale,et al.  Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology , 2015, Genetics in Medicine.

[11]  N. Maclaren,et al.  Two Types of Autoimmune Addison's Disease Associated with Different Polyglandular Autoimmune (PGA) Syndromes , 1981, Medicine.

[12]  H. Grabsch,et al.  A multidisciplinary approach to management of autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) , 2013, BMJ Case Reports.

[13]  M. Manns,et al.  Prevalence and clinical associations of 10 defined autoantibodies in autoimmune polyendocrine syndrome type I. , 2004, The Journal of clinical endocrinology and metabolism.

[14]  J. Abramson,et al.  AIRE: From promiscuous molecular partnerships to promiscuous gene expression , 2016, European journal of immunology.

[15]  P. Peterson,et al.  Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED): a model disease to study molecular aspects of endocrine autoimmunity , 2004, Clinical and experimental immunology.

[16]  J. Perheentupa,et al.  Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients. , 1990, The New England journal of medicine.

[17]  A. Miettinen,et al.  Adrenal and steroidal cell antibodies in patients with autoimmune polyglandular disease type I and risk of adrenocortical and ovarian failure. , 1987, The Journal of clinical endocrinology and metabolism.

[18]  C. Marcocci,et al.  A novel mutation of the autoimmune regulator gene in an Italian kindred with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, acting in a dominant fashion and strongly cosegregating with hypothyroid autoimmune thyroiditis. , 2001, The Journal of clinical endocrinology and metabolism.

[19]  S. Antonarakis,et al.  APECED mutations in the autoimmune regulator (AIRE) gene , 2001, Human mutation.

[20]  H. Kong,et al.  Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. , 2016, JCI insight.

[21]  C. Pignata,et al.  APECED: A Paradigm of Complex Interactions between Genetic Background and Susceptibility Factors , 2013, Front. Immunol..

[22]  R. Deterding,et al.  Autoimmune polyendocrine syndrome type 1: Utility of KCNRG autoantibodies as a marker of active pulmonary disease and successful treatment with rituximab , 2012, Pediatric pulmonology.

[23]  J. Svartberg,et al.  A Longitudinal Follow-up of Autoimmune Polyendocrine Syndrome Type 1 , 2016, The Journal of clinical endocrinology and metabolism.

[24]  Daniel G. MacArthur,et al.  The ExAC browser: displaying reference data information from over 60 000 exomes , 2016, bioRxiv.

[25]  C. A. Speck-Hernandez,et al.  Update on Aire and thymic negative selection , 2018, Immunology.

[26]  Marcel H. Schulz,et al.  Clinical diagnostics in human genetics with semantic similarity searches in ontologies. , 2009, American journal of human genetics.