TY - JOUR
T1 - Familial CHARGE syndrome and the CHD7 gene
T2 - A recurrent missense mutation, intrafamilial recurrence and variability
AU - Jongmans, Marjolijn C.J.
AU - Hoefsloot, Lies H.
AU - Van Der Donk, Kim P.
AU - Admiraal, Ronald J.
AU - Magee, Alex
AU - Van De Laar, Ingrid
AU - Hendriks, Yvonne
AU - Verheij, Joke B.G.M.
AU - Walpole, Ian
AU - Brunner, Han G.
AU - Van Ravenswaaij, Conny M.A.
PY - 2008/1/1
Y1 - 2008/1/1
N2 - 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.
AB - 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.
KW - CHARGE syndrome
KW - CHD7
KW - Familial
KW - Mild phenotype
UR - http://www.scopus.com/inward/record.url?scp=37549039003&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.31921
DO - 10.1002/ajmg.a.31921
M3 - Article
C2 - 18074359
AN - SCOPUS:37549039003
SN - 1552-4825
VL - 146
SP - 43
EP - 50
JO - American Journal of Medical Genetics
JF - American Journal of Medical Genetics
IS - 1
ER -