SCS occurs when there is a mutation on chromosome 7 in the region 7p21 SCS is typically inherited as an autosomal dominant trait. However, on occasion, children with a microdeletion of 7p21 (chromosome containing the locus responsible for SCS) develop new abnormalities and typically show significant neurological abnormalities. An increased parental age may play a role in the development of new mutations and abnormalities. Linkage analysis and chromosomal rearrangement revealed the cause of SCS to be mutations in the TWIST gene (twist transcription factor gene) located on chromosome 7p21. The TWIST gene encodes a basic helix-loop-helix (b-HLH) transcription factor that controls head mesenchyme development as the cranial tube forms. More than 35 varying TWIST mutations involving the b-HLH domain of the protein have been identified in people with SCS. The mutations include missense, nonsense, and frameshift deletion/insertion mutations that either shorten or disrupt the b-HLH domain. Most individuals with SCS have a single large deletion in the region 7p21, which contains the region that codes for the TWIST gene. In searching for the gene responsible for SCS, scientists at Johns Hopkins Children’s Center began studying the TWIST gene because its effects on mice. The TWIST gene in mice, functions in the development of the muscle and skeleton of the face, head, hands, and feet. Mice that were lacking both copies of the TWIST gene were spontaneously aborted prior to birth, and had serious deformities including abnormal limb and head defects and failure of the neural tube to properly close. However, mice with a single copy of the non-working TWIST gene survived. Further examination revealed that these mice had only minor skull, hand, and foot defects similar to those seen in SCS. The mouse TWIST gene is located on chromosome 12 in mice, which corresponds to the short arm of chromosome 7 in humans. With this information, scientists began to isolate and map the human TWIST gene on the short arm of human chromosome 7. They revealed that the human TWIST gene was in the same region that was absent in people with SCS. While looking for different mutations in the human TWIST gene, five different types of mutations were discovered in individuals with SCS. Since none of these mutations were seen in normal individuals who didn't have SCS, this provided enough evidence to conclude that the TWIST gene was the causative agent of SCS1. Researchers also studied the TWIST gene in Drosophila (fruit fly) in order to determine its function. They discovered that in the presence of two TWIST protein molecules combined together, the TWIST gene functions as a DNA transcription factor, meaning it binds to the DNA double-helix at specific locations in order to control which genes are "turned on" or activated. The majority of the identified mutations in the TWIST gene interfere with how the protein attaches to DNA, preventing the activation of other genes that would normally be turned on during fetal development.
Saethre–Chotzen syndrome
Pelger–Huët anomaly
Goldberg–Shprintzen syndrome
Marshall–Smith syndrome
Langer–Giedion syndrome
Bardet–Biedl syndrome
Smith–Magenis syndrome
Schinzel–Giedion syndrome