title: Germline and mosaic mutations of FLN1 in men with periventricular heterotopia.
abstract: OBJECTIVE
  To describe the phenotypic spectrum and genetics of periventricular nodular heterotopia (PNH) caused by FLN1 mutations in four men.
  
  
  BACKGROUND
  X-linked PNH caused by FLN1 mutations (MIM #300049) implies prenatal or early postnatal lethality in boys and 50% recurrence risk in daughters of affected women.
  
  
  METHODS
  Clinical examination, cognitive testing, MRI, and mutation analysis (denaturing high-performance liquid chromatography and direct sequencing) on blood lymphocytes and single hair roots were performed for nine affected individuals, including three men. Neuropathologic study of the brain was performed for an affected boy.
  
  
  RESULTS
  In two families, missense mutations were transmitted from mother to son (Met102Val) and from father to daughter (Ser149Phe), causing mild phenotypes in both genders, including unilateral PNH. In a third family, a man was mosaic for an A>G substitution (intron 11 acceptor splice site) on leukocyte DNA and hair roots (mutant = 42% and 69%). Single hair root analysis confirmed that the mutation was not present in all ectodermal derivative cells. A healthy daughter had inherited the X chromosome from her father's wild-type germinal cell population. In the fourth family, an eight-base deletion (AGGAGGTG, intron 25 donor splice site) led to early deaths of boys. Postmortem study in a newborn boy revealed PNH and cardiovascular, genitourinary, and gut malformations.
  
  
  CONCLUSIONS
  Periventricular nodular heterotopia caused by FLN1 mutations in men has a wide clinical spectrum and is caused by different genetic mechanisms, including somatic mosaicism. Mutation analysis of FLN1 should support genetic counseling in men with periventricular nodular heterotopia.
authors.affiliation: Division of Child Neurology and Psychiatry, University of Pisa and IRCCS Fondazione Stella Maris, via dei Giacinti 2, 56018 Calambrone Pisa, Italy. renzo.guerrini@inpe.unipi.it
authors.forename: R
authors.initials: R
authors.lastname: Guerrini
authors.forename: D
authors.initials: D
authors.lastname: Mei
authors.forename: S
authors.initials: S
authors.lastname: Sisodiya
authors.forename: F
authors.initials: F
authors.lastname: Sicca
authors.forename: B
authors.initials: B
authors.lastname: Harding
authors.forename: Y
authors.initials: Y
authors.lastname: Takahashi
authors.forename: T
authors.initials: T
authors.lastname: Dorn
authors.forename: A
authors.initials: A
authors.lastname: Yoshida
authors.forename: J
authors.initials: J
authors.lastname: Campistol
authors.forename: G
authors.initials: G
authors.lastname: Krämer
authors.forename: F
authors.initials: F
authors.lastname: Moro
authors.forename: W B
authors.initials: WB
authors.lastname: Dobyns
authors.forename: E
authors.initials: E
authors.lastname: Parrini
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D001927:Brain Diseases / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics; D002552:Cerebral Ventricles / Q000002:abnormalities*; D002675:Child, Preschool; D002828:Choristoma / Q000235:genetics*; D041321:Chromosomes, Human, X / Q000235:genetics*; D002946:Cisterna Magna / Q000002:abnormalities*; D003285:Contractile Proteins / Q000172:deficiency / Q000235:genetics*; D004252:DNA Mutational Analysis; D004303:Dosage Compensation, Genetic; D005260:Female; D064448:Filamins; D005804:Genes, Lethal; D040181:Genetic Diseases, X-Linked / Q000175:diagnosis / Q000235:genetics*; D018095:Germ-Line Mutation; D018859:Hair Follicle / Q000737:chemistry; D006801:Humans; D007231:Infant, Newborn; D007438:Introns / Q000235:genetics; D008297:Male; D008840:Microfilament Proteins / Q000172:deficiency / Q000235:genetics*; D008875:Middle Aged; D009030:Mosaicism; D020125:Mutation, Missense; D009474:Neurons / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D022821:RNA Splice Sites / Q000235:genetics; D017384:Sequence Deletion
chemical_list: D003285:Contractile Proteins; C578663:FLNA protein, human; D064448:Filamins; D008840:Microfilament Proteins; D022821:RNA Splice Sites