Jongmans Marjolijn C J, Hoefsloot Lies H, van der Donk Kim P, Admiraal Ronald J, Magee Alex, van de Laar Ingrid, Hendriks Yvonne, Verheij Joke B G M, Walpole Ian, Brunner Han G, van Ravenswaaij Conny M A
Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Am J Med Genet A. 2008 Jan 1;146A(1):43-50. doi: 10.1002/ajmg.a.31921.
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.
CHARGE综合征是一种常染色体显性疾病，由CHD7基因突变引起。该综合征的家族病例报道较少，且临床变异性较大。我们在此报告5个CHD7突变阳性家族，并对其临床特征进行评论。我们观察到体细胞和生殖系嵌合体以及非嵌合CHD7突变的亲子传递是家族性CHARGE综合征的病因。在一个有两个患病同胞的家族中，在一名临床未受影响的父母的淋巴细胞中鉴定出体细胞突变（外显子8中的2520G > A）。这是未受影响的父母中体细胞CHD7嵌合体的第二篇报道。在另外两个有患病同胞的家族中，我们在父母的淋巴细胞中未检测到突变，提示生殖系嵌合体。先前报道的临床变异性在所有5个家族中均显著存在。我们发现CHD7的改变可导致非常轻微的表型，其特征仅为CHARGE综合征临床谱中的一些轻微症状。这种轻微表型存在于两个共享相同6322G > A错义突变的家族中。这两个家族显示了亲子传递。表型较轻的CHARGE综合征形式向多个家庭成员传递的风险更高。
