title: Brief Report: First Identification of Intrafamilial Recurrence of Blau Syndrome due to Gonosomal NOD2 Mosaicism.
abstract: OBJECTIVE
  Blau syndrome is characterized by noncaseating granulomatous arthritis, dermatitis, and uveitis, and results from gain-of-function NOD2 mutations. This study was undertaken to identify the genetic cause of the disease in a family with 3 members with Blau syndrome.
  
  
  METHODS
  We studied a family with 3 affected members across 2 consecutive generations. The children's symptoms started early (at 6 and 7 months of age) and included polyarthritis, dermatitis, uveitis, and fever. In contrast, the father's symptoms started later (at 22 years of age) and included noncaseating granulomatous dermatitis and uveitis. We analyzed the NOD2 gene in all patients by both the Sanger method of DNA sequencing and amplicon-based deep sequencing using an Ion Torrent PGM platform.
  
  
  RESULTS
  Sanger chromatograms revealed the heterozygous c.1001G>A transition in both children, which resulted in the p.Arg334Gln mutation that causes Blau syndrome. In contrast, the father's chromatograms revealed a small peak of adenine at the c.1001 position, suggesting the presence of a somatic NOD2 mutation. To evaluate this hypothesis, we performed amplicon-based deep sequencing using DNA from different tissues, which confirmed a variable degree (0.9-12.9%) of somatic NOD2 mosaicism. The previous detection of the NOD2 mutation in his daughters strongly suggests the presence of gonosomal (somatic plus gonadal) NOD2 mosaicism in the father. Comparative analyses with Blau syndrome patients carrying the germline p.Arg334Gln NOD2 mutation revealed late onset of the disease, a mild inflammatory phenotype, and an absence of complications in patients with NOD2 mosaicism.
  
  
  CONCLUSIONS
  This is the first description of gonosomal NOD2 mosaicism as the cause of intrafamilial recurrence of Blau syndrome. Our findings also indicate that Blau syndrome includes more diverse and milder phenotypes than previously described.
authors.affiliation: Hospital Clinic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Mensa-Vilaro
authors.affiliation: Selayang Hospital, Kuala Lumpur, Malaysia.
authors.forename: Weng Tarng
authors.initials: WT
authors.lastname: Cham
authors.affiliation: Selayang Hospital, Kuala Lumpur, Malaysia.
authors.forename: Swee Ping
authors.initials: SP
authors.lastname: Tang
authors.affiliation: Selayang Hospital, Kuala Lumpur, Malaysia.
authors.forename: Sern Chin
authors.initials: SC
authors.lastname: Lim
authors.affiliation: Hospital Clinic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: González-Roca
authors.affiliation: Hospital Clinic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
authors.forename: Estibaliz
authors.initials: E
authors.lastname: Ruiz-Ortiz
authors.affiliation: Kuala Lumpur Hospital, Kuala Lumpur, Malaysia.
authors.forename: Roziana
authors.initials: R
authors.lastname: Ariffin
authors.affiliation: Hospital Clinic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Yagüe
authors.affiliation: Hospital Clinic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
authors.forename: Juan I
authors.initials: JI
authors.lastname: Aróstegui
mesh_terms: D001168:Arthritis / Q000235:genetics* / Q000473:pathology; D005260:Female; D018095:Germ-Line Mutation; D006099:Granuloma / Q000473:pathology; D006801:Humans; D007223:Infant; D008297:Male; D009030:Mosaicism; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D010375:Pedigree; D012507:Sarcoidosis; D017422:Sequence Analysis, DNA; D012867:Skin / Q000473:pathology; D013585:Synovitis / Q000235:genetics* / Q000473:pathology; D014605:Uveitis / Q000235:genetics* / Q000473:pathology; D055815:Young Adult; D056660:Hereditary Autoinflammatory Diseases
chemical_list: C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein