title: Phenotype variability of neural crest derived tumours in six Italian families segregating the same founder SDHD mutation Q109X.
abstract: BACKGROUND
  Mutations in genes coding for the mitochondrial complex II succinate dehydrogenase (SDH) subunits cause familial neural crest derived (NCD) tumours.
  
  
  METHODS
  Index cases from six apparently unrelated families affected by NCD tumours were analysed for mutations in the SDHB, SDHC, and SDHD genes.
  
  
  RESULTS
  The same nonsense germline heterozygous mutation (Q109X) in exon 4 of the SDHD gene was found in each of the six families. Overall, 43 heterozygotes were identified. These were evaluated for the presence of NCD tumours through radiological examination of the neck, thorax, and abdomen, and measurement of urinary metanephrines and plasma chromogranin A. A novel missense SDHD variant, T112I, which did not segregate with the Q109X mutation and was not associated with phenotypic manifestations, was observed in one of the families. Microsatellite analysis showed a common haplotype in all individuals heterozygous for the Q109X mutation, indicating a founder effect. Overall, 18 heterozygotes were clinically affected by at least one NCD tumour. Every affected patient inherited the germline mutation from the father, confirming SDHD maternal genomic imprinting. Penetrance of the paternally inherited mutation progressively increased from 33% to 83% at 30 and 60 years, respectively. Affected patients showed high clinical variability, ranging from monolateral to bilateral glomus tumours variably associated or not with paragangliomas or phaeochromocytomas. Loss of heterozygosity was observed in tumour cells isolated by laser capture microdissection.
  
  
  CONCLUSIONS
  This study shows that a single founder SDHD mutation is present in an area of central Italy and that this mutation is associated with widely variable interfamilial and intrafamilial expressivity.
authors.affiliation: Section of Endocrinology, Department of Clinical Physiopathology, University of Florence Medical School, Florence, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Simi
authors.forename: R
authors.initials: R
authors.lastname: Sestini
authors.forename: P
authors.initials: P
authors.lastname: Ferruzzi
authors.forename: M S
authors.initials: MS
authors.lastname: Gaglianò
authors.forename: F
authors.initials: F
authors.lastname: Gensini
authors.forename: M
authors.initials: M
authors.lastname: Mascalchi
authors.forename: L
authors.initials: L
authors.lastname: Guerrini
authors.forename: C
authors.initials: C
authors.lastname: Pratesi
authors.forename: P
authors.initials: P
authors.lastname: Pinzani
authors.forename: G
authors.initials: G
authors.lastname: Nesi
authors.forename: T
authors.initials: T
authors.lastname: Ercolino
authors.forename: M
authors.initials: M
authors.lastname: Genuardi
authors.forename: M
authors.initials: M
authors.lastname: Mannelli
mesh_terms: D000328:Adult; D000368:Aged; D020090:Chromosome Segregation; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D005260:Female; D018703:Founder Effect; D020022:Genetic Predisposition to Disease; D018392:Genomic Imprinting; D006239:Haplotypes; D006801:Humans; D007558:Italy; D019656:Loss of Heterozygosity; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D018895:Microsatellite Repeats; D008875:Middle Aged; D010235:Paraganglioma / Q000175:diagnosis / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D013385:Succinate Dehydrogenase
chemical_list: D018389:Codon, Nonsense; D008565:Membrane Proteins; C491545:SDHD protein, human; D013385:Succinate Dehydrogenase