THE CLINICAL AND GENETIC SPECTRUM OF THE HOLT-ORAM SYNDROME (HEART-HAND SYNDROME)
THE CLINICAL AND GENETIC SPECTRUM OF THE HOLT-ORAM SYNDROME (HEART-HAND SYNDROME)
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DOI：
10.1056/nejm199403313301302
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发表时间：
1994-03-31
影响因子：
158.5
通讯作者：
SEIDMAN, CE
中科院分区：
文献类型：
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作者：
BASSON, CT;COWLEY, GS;SEIDMAN, CE
背景Holt-Gram综合征是一种常染色体显性遗传疾病，其特征是骨骼异常，通常伴有先天性心脏缺陷。这些不同临床特征的原因尚不清楚。为了确定Holt-Gram综合征基因的染色体定位，我们进行了临床和遗传学研究。通过手部X线摄影、心电图和经胸超声心动图对两个患有Holt-Gram综合征的大家族进行了评价。遗传连锁分析与多态性DNA位点分散在整个基因组中，以确定一个位点，这是遗传与Holt-Gram综合征的家庭成员。A家族共有19名成员患有Holt-Oram综合征，伴有轻度至中度骨骼畸形，包括三指拇指和腕骨畸形。家族A的所有受累成员均患有中度至重度先天性心脏畸形，如室间隔缺损或房间隔缺损或房室管缺损。第二个家族（家族B）的18名成员患有霍尔特-格拉姆综合征，伴有中度至重度骨骼畸形，包括短肢畸形。12名受影响的成员没有心脏缺陷; 6名只有房间隔缺损。遗传分析表明，每个家庭的疾病连锁的12号染色体长臂上的多态性位点（联合多点lod评分，16.8）。这些数据表明Holt-Gram综合征的遗传缺陷存在于12号染色体长臂（12 q2）上的几率大于10（16）：1。染色体12 q2上的基因突变可产生广泛的Holt-Gram综合征特征性疾病表型。该基因在骨骼和心脏发育中具有重要作用。
Background. The Holt-Gram syndrome is an autosomal dominant condition characterized by skeletal abnormalities that are frequently accompanied by congenital cardiac defects. The cause of these disparate clinical features is unknown. To identify the chromosomal location of the Holt-Gram syndrome gene, we performed clinical and genetic studies.Methods. Two large families with the Holt-Gram syndrome were evaluated by radiography of the hands, electrocardiography, and transthoracic echocardiography. Genetic-linkage analyses were performed with polymorphic DNA loci dispersed throughout the genome to identify a locus that was inherited with the Holt-Gram syndrome in family members.Results. A total of 19 members of Family A had Holt-Oram syndrome with mild-to-moderate skeletal deformities, including triphalangeal thumbs and carpal-bone dysmorphism. All affected members of Family A had moderate-to-severe congenital cardiac abnormalities, such as ventricular or atrial septal defects or atrioventricular-canal defects. Eighteen members of a second kindred (Family B) had Holt-Gram syndrome with moderate-to-severe skeletal deformities, including phocomelia. Twelve of the affected members had no cardiac defects; six had only atrial septal defects. Genetic analyses demonstrated linkage of the disease in each family to polymorphic loci on the long arm of chromosome 12 (combined multipoint lod score, 16.8). These data suggest odds greater than 10(16):1 that the genetic defect for Holt-Gram syndrome is present on the long arm of chromosome 12 (12q2).Conclusions. Mutations in a gene on chromosome 12q2 can produce a wide range of disease phenotypes characteristic of the Holt-Gram syndrome. This gene has an important role in both skeletal and cardiac development.