Lethal Congenital Contracture Syndrome 4

A number sign (#) is used with this entry because of evidence that lethal congenital contracture syndrome-4 (LCCS4) can be caused by homozygous mutation in the MYBPC1 gene (160794) on chromosome 12q23.

For a general phenotypic description and discussion of genetic heterogeneity of LCCS, see LCCS1 (253310).

Molecular Genetics

Markus et al. (2012) studied 2 consanguineous families from apparently unrelated Bedouin tribes in southern Israel in which affected individuals had a clinical phenotype 'identical to that of LCCS3' (611369) but were negative for mutation in the PIP5K1C gene (606102) as well as in the 2 other genes known to cause LCCS. After homozygosity mapping of 1 affected individual from each family proved unsuccessful, whole-exome sequencing was performed, which revealed homozygosity for a nonsense mutation in the MYBPC1 gene (R318X; 160794.0003) in both probands as well as the affected sister of 1 of the probands. The mutation, confirmed by Sanger sequencing, was present in heterozygosity in both sets of parents as well as unaffected sibs, and was not found in 150 unrelated Bedouin controls. Markus et al. (2012) noted that heterozygous mutation in the MYBPC1 gene had previously been shown to cause the much less severe phenotype of distal arthrogryposis type 1B (DA1B; 614335).