title: Diagnostic Exome Sequencing Identifies a Novel Gene, EMILIN1, Associated with Autosomal-Dominant Hereditary Connective Tissue Disease.
abstract: Heritable connective tissue diseases are a highly heterogeneous family of over 200 disorders that affect the extracellular matrix. While the genetic basis of several disorders is established, the etiology has not been discovered for a large portion of patients, likely due to rare yet undiscovered disease genes. By performing trio-exome sequencing of a 55-year-old male proband presenting with multiple symptoms indicative of a connective disorder, we identified a heterozygous missense alteration in exon 1 of the Elastin Microfibril Interfacer 1 (EMILIN1) gene, c.64G>A (p.A22T). The proband presented with ascending and descending aortic aneurysms, bilateral lower leg and foot sensorimotor peripheral neuropathy, arthropathy, and increased skin elasticity. Sanger sequencing confirmed that the EMILIN1 alteration, which maps around the signal peptide cleavage site, segregated with disease in the affected proband, mother, and son. The impaired secretion of EMILIN-1 in cells transfected with the mutant p.A22T coincided with abnormal protein accumulation within the endoplasmic reticulum. In skin biopsy of the proband, we detected less EMILIN-1 with disorganized and abnormal coarse fibrils, aggregated deposits underneath the epidermis basal lamina, and dermal cells apoptosis. These findings collectively suggest that EMILIN1 may represent a new disease gene associated with an autosomal-dominant connective tissue disorder.
authors.affiliation: Department of Translational Research, CRO-IRCCS National Cancer Institute, Aviano, 33081, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Capuano
authors.affiliation: Department of Translational Research, CRO-IRCCS National Cancer Institute, Aviano, 33081, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bucciotti
authors.affiliation: Ambry Genetics, Aliso Viejo, California, 92656.
authors.forename: Kelly D
authors.initials: KD
authors.lastname: Farwell
authors.affiliation: Ambry Genetics, Aliso Viejo, California, 92656.
authors.forename: Brigette
authors.initials: B
authors.lastname: Tippin Davis
authors.affiliation: Ambry Genetics, Aliso Viejo, California, 92656.
authors.forename: Cameron
authors.initials: C
authors.lastname: Mroske
authors.affiliation: Center for Medical Genetics, NorthShore University HealthSystem, Evanston, Illinois, 60201.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Hulick
authors.affiliation: Center for Medical Genetics, NorthShore University HealthSystem, Evanston, Illinois, 60201.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Weissman
authors.affiliation: NorthShore Research Institute, NorthShore University HealthSystem, Evanston, Illinois, 60201.
authors.forename: Qingshen
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Department of Translational Research, CRO-IRCCS National Cancer Institute, Aviano, 33081, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Spessotto
authors.affiliation: Department of Translational Research, CRO-IRCCS National Cancer Institute, Aviano, 33081, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Colombatti
authors.affiliation: Department of Translational Research, CRO-IRCCS National Cancer Institute, Aviano, 33081, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Doliana
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001706:Biopsy; D002460:Cell Line; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D003240:Connective Tissue Diseases / Q000175:diagnosis* / Q000235:genetics*; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D015870:Gene Expression; D005799:Genes, Dominant; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D016415:Sequence Alignment; D012867:Skin / Q000473:pathology
chemical_list: D008562:Membrane Glycoproteins; C030340:elastin microfibril interface located protein
keywords: EMILIN-1; autosomal dominant; connective tissue; diagnostic exome sequencing; neuropathy