title: The new neuromuscular disease related with defects in the ASC-1 complex: report of a second case confirms ASCC1 involvement.
abstract: Next-generation sequencing technology aided the identification of the underlying genetic cause in a female newborn with a severe neuromuscular disorder. The patient presented generalized hypotonia, congenital bone fractures, lack of spontaneous movements and poor respiratory effort. She died within the first days of life. Karyotyping and screening for several genes related with neuromuscular diseases all tested negative. A male sibling was subsequently born with the same clinical presentation. Whole-exome sequencing was performed with variant filtering assuming a recessive disease model. Analysis focused on genes known to be related firstly with congenital myopathies, extended to muscle diseases and finally to other neuromuscular disorders. No disease-causing variants were identified. A similar disorder was described in patients with recessive variants in two genes: TRIP4 (three families) and ASCC1 (one family), both encoding subunits of the nuclear activating signal cointegrator 1 (ASC-1) complex. Our patient was also found to have a homozygous frameshift variant (c.157dupG, p.Glu53Glyfs*19) in ASCC1 , thereby representing the second known case. This confirms ASCC1 involvement in a severe neuromuscular disease lying within the spinal muscular atrophy or primary muscle disease spectra.
authors.affiliation: Unidade de Genética Molecular, Centro de Genética Médica Dr. Jacinto Magalhães, Centro Hospitalar do Porto, Porto, Portugal.|Unidade Multidisciplinar de Investigação Biomédica (UMIB), Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.
authors.forename: J
authors.identifier: http://orcid.org/0000-0003-3924-6385
authors.initials: J
authors.lastname: Oliveira
authors.affiliation: Centro Hospitalar de Trás-os-Montes e Alto Douro, Unidade de Genética, Vila Real, Portugal.
authors.forename: M
authors.initials: M
authors.lastname: Martins
authors.affiliation: Centro Hospitalar de Trás-os-Montes e Alto Douro, Unidade de Genética, Vila Real, Portugal.
authors.forename: R
authors.initials: R
authors.lastname: Pinto Leite
authors.affiliation: Unidade Multidisciplinar de Investigação Biomédica (UMIB), Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.|Laboratório de Biologia Celular, Departamento de Microscopia, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.|Centro de Genética da Reprodução Prof. Alberto Barros, Porto, Portugal.
authors.forename: M
authors.initials: M
authors.lastname: Sousa
authors.affiliation: Unidade de Genética Molecular, Centro de Genética Médica Dr. Jacinto Magalhães, Centro Hospitalar do Porto, Porto, Portugal.|Unidade Multidisciplinar de Investigação Biomédica (UMIB), Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.|UCIBIO\REQUIMTE, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
authors.forename: R
authors.initials: R
authors.lastname: Santos
mesh_terms: D002352:Carrier Proteins / Q000235:genetics*; D059472:Exome; D005260:Female; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000503:physiopathology; D009468:Neuromuscular Diseases / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology; D010375:Pedigree; D000073359:Exome Sequencing
chemical_list: C000605778:ASCC1 protein, human; D002352:Carrier Proteins
keywords: 
  ASCC1
  ; ASC-1 complex; bone fractures; congenital; neuromuscular; whole-exome sequencing