title: Exome sequencing in children of women with skewed X-inactivation identifies atypical cases and complex phenotypes.
abstract: BACKGROUND
  More than 100 X-linked intellectual disability (X-LID) genes have been identified to be involved in 10-15% of intellectual disability (ID).
  
  
  METHODS
  To identify novel possible candidates, we selected 18 families with a male proband affected by isolated or syndromic ID. Pedigree and/or clinical presentation suggested an X-LID disorder. After exclusion of known genetic diseases, we identified seven cases whose mother showed a skewed X-inactivation (>80%) that underwent whole exome sequencing (WES, 50X average depth).
  
  
  RESULTS
  WES allowed to solve the genetic basis in four cases, two of which (Coffin-Lowry syndrome, RPS6K3 gene; ATRX syndrome, ATRX gene) had been missed by previous clinical/genetics tests. One further ATRX case showed a complex phenotype including pontocerebellar atrophy (PCA), possibly associated to an unidentified PCA gene mutation. In a case with suspected Lujan-Fryns syndrome, a c.649C>T (p.Pro217Ser) MECP2 missense change was identified, likely explaining the neurological impairment, but not the marfanoid features, which were possibly associated to the p.Thr1020Ala variant in fibrillin 1. Finally, a c.707T>G variant (p.Phe236Cys) in the DMD gene was identified in a patient retrospectively recognized to be affected by Becker muscular dystrophy (BMD, OMIM 300376).
  
  
  CONCLUSIONS
  Overall, our data show that WES may give hints to solve complex ID phenotypes with a likely X-linked transmission, and that a significant proportion of these orphan conditions might result from concomitant mutations affecting different clinically associated genes.
authors.affiliation: University of Torino, Department of Medical Sciences, 10126, Turin, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Giorgio
authors.affiliation: University of Torino, Department of Medical Sciences, 10126, Turin, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Brussino
authors.affiliation: University of Torino, Department of Public Health and Pediatrics, 10126, Turin, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Biamino
authors.affiliation: University of Torino, Department of Public Health and Pediatrics, 10126, Turin, Italy.
authors.forename: Elga Fabia
authors.initials: EF
authors.lastname: Belligni
authors.affiliation: Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù IRCSS, Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bruselles
authors.affiliation: Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù IRCSS, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ciolfi
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Caputo
authors.affiliation: Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù IRCSS, Rome, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Pizzi
authors.affiliation: University of Torino, Department of Medical Sciences, 10126, Turin, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Calcia
authors.affiliation: University of Torino, Department of Medical Sciences, 10126, Turin, Italy; Città della Salute e della Scienza University Hospital, Medical Genetics Unit, Turin, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Di Gregorio
authors.affiliation: University of Torino, Department of Medical Sciences, 10126, Turin, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Cavalieri
authors.affiliation: University of Torino, Department of Medical Sciences, 10126, Turin, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Mancini
authors.affiliation: University of Torino, Department of Medical Sciences, 10126, Turin, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Pozzi
authors.affiliation: University of Torino, Department of Medical Sciences, 10126, Turin, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Ferrero
authors.affiliation: University of Torino, Department of Public Health and Pediatrics, 10126, Turin, Italy.
authors.forename: Evelise
authors.initials: E
authors.lastname: Riberi
authors.affiliation: University of Torino, Department of Medical Sciences, 10126, Turin, Italy.
authors.forename: Iolanda
authors.initials: I
authors.lastname: Borelli
authors.affiliation: University of Torino, Department of Medical Sciences, 10126, Turin, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Amoroso
authors.affiliation: University of Torino, Department of Public Health and Pediatrics, 10126, Turin, Italy.
authors.forename: Giovanni Battista
authors.initials: GB
authors.lastname: Ferrero
authors.affiliation: Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù IRCSS, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
authors.affiliation: University of Torino, Department of Medical Sciences, 10126, Turin, Italy; Città della Salute e della Scienza University Hospital, Medical Genetics Unit, Turin, Italy. Electronic address: alfredo.brusco@unito.it.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Brusco
mesh_terms: D000293:Adolescent; D002648:Child; D038921:Coffin-Lowry Syndrome / Q000235:genetics; D019465:Craniofacial Abnormalities / Q000235:genetics; D059472:Exome / Q000235:genetics*; D050172:Genes, X-Linked / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D008382:Marfan Syndrome / Q000235:genetics; D038901:X-Linked Intellectual Disability / Q000235:genetics; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D049951:X Chromosome Inactivation / Q000235:genetics*; D017085:alpha-Thalassemia / Q000235:genetics
keywords: ATRX; DMD; MECP2; RPS6KA3; Skewed X-inactivation; WES; Whole exome sequencing