title: Familial CHARGE syndrome and the CHD7 gene: a recurrent missense mutation, intrafamilial recurrence and variability.
abstract: CHARGE syndrome is an autosomal dominant condition that is caused by mutations in the CHD7 gene. Few familial cases of this syndrome have been reported and these were characterized by a wide clinical variability. We here report on five CHD7 mutation positive families and comment on their clinical features. We observed somatic and germline mosaicism as well as parent-to-child transmission of non-mosaic CHD7 mutations as causes of familial CHARGE syndrome. In one family with two affected sibs a somatic mutation was identified in lymphocytes of a clinically unaffected parent (2520G > A in exon 8). This is the second report of somatic CHD7 mosaicism in an unaffected parent. In two further families with affected siblings, we could not detect the mutation in parental lymphocytes suggesting germline mosaicism. The previously reported clinical variability was strikingly present in all five families. We find that alterations in CHD7 can result in a very mild phenotype, characterized by only a few minor symptoms of the CHARGE syndrome clinical spectrum. Such a mild phenotype was present in two families that shared the same 6322G > A missense mutation. These two families showed parent-to-child transmission. Phenotypically milder forms of CHARGE syndrome have a higher risk of transmission to multiple family members.
authors: Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors: Marjolijn C J
authors: MC
authors: Jongmans
authors: Lies H
authors: LH
authors: Hoefsloot
authors: Kim P
authors: KP
authors: van der Donk
authors: Ronald J
authors: RJ
authors: Admiraal
authors: Alex
authors: A
authors: Magee
authors: Ingrid
authors: I
authors: van de Laar
authors: Yvonne
authors: Y
authors: Hendriks
authors: Joke B G M
authors: JB
authors: Verheij
authors: Ian
authors: I
authors: Walpole
authors: Han G
authors: HG
authors: Brunner
authors: Conny M A
authors: CM
authors: van Ravenswaaij
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001120:Arginine / Q000378:metabolism; D016022:Case-Control Studies; D017124:Conserved Sequence; D004265:DNA Helicases / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004200:Diseases in Twins; D005260:Female; D005799:Genes, Dominant; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009030:Mosaicism; D020125:Mutation, Missense; D010375:Pedigree; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D035781:Siblings; D013577:Syndrome; D014430:Twins, Monozygotic
chemical_list: D004268:DNA-Binding Proteins; D001120:Arginine; D004265:DNA Helicases; C491434:CHD7 protein, human