Nelson K, Holmes L B
Department of Newborn Medicine, Brigham and Women's Hospital, Boston, MA.
N Engl J Med. 1989 Jan 5;320(1):19-23. doi: 10.1056/NEJM198901053200104.
We conducted hospital-based surveillance of congenital malformations to determine the rate of apparently spontaneous single mutations leading to recognized phenotypes. Through surveillance of 69,277 infants with gestational ages of at least 20 weeks, we identified 48 infants (0.07 percent) with major malformations, with phenotypes that suggested that the malformations were due to single mutant genes. Family studies suggested that 11 of these infants (10 with autosomal dominant disorders and 1 with an X-linked condition) were affected as the result of a new (spontaneous) genetic mutation. The spontaneous mutation rates per gene were 0.7 x 10(-5) and 1.44 x 10(-5) for the disorders in which one and two infants were affected, respectively. In addition, 5 of the 10 infants with autosomal recessive malformations had negative family histories, but we were unable to infer the presence of spontaneous mutations in these cases. Because the family history was negative in 44.4 percent of the infants with disorders considered due to autosomal or X-linked genes, counseling should include the understanding that genetic disorders often occur unexpectedly among children of healthy parents.
我们开展了基于医院的先天性畸形监测，以确定导致公认表型的明显自发单基因突变率。通过对69277名孕周至少20周的婴儿进行监测，我们识别出48名（0.07%）患有主要畸形的婴儿，其表型提示这些畸形是由单突变基因所致。家系研究表明，这些婴儿中有11名（10名患有常染色体显性疾病，1名患有X连锁疾病）是新的（自发）基因突变的结果。对于分别有1名和2名婴儿受影响的疾病，每个基因的自发突变率分别为0.7×10⁻⁵和1.44×10⁻⁵。此外，10名患有常染色体隐性畸形的婴儿中有5名家族史为阴性，但我们无法推断这些病例中存在自发突变。由于在被认为由常染色体或X连锁基因导致疾病的婴儿中，44.4%的婴儿家族史为阴性，因此咨询应包括这样的认识，即遗传疾病常在健康父母的子女中意外发生。
