Klippel-Feil Syndrome 1
In affected members of a 3-generation family with autosomal dominant Klippel-Feil syndrome (KFS1; 118100), Tassabehji et al. (2008) identified a heterozygous 746C-A transversion in exon 2 of the GDF6 gene, resulting in an ala249-to-glu (A249E) substitution in the prodomain. The mutation was not found in 708 control chromosomes. The phenotype was characterized primarily by fusion of vertebral bodies C2 and C3. The authors suggested functional haploinsufficiency as the pathogenetic mechanism.
Isolated Microphthalmia 4
Asai-Coakwell et al. (2009) screened the GDF6 gene in patients with ocular and vertebral anomalies, and identified heterozygosity for the A249E mutation in 2 probands, 1 of whom was a patient with isolated microphthalmia (MCOP4; 613094). The other patient had coloboma and postaxial polydactyly without vertebral defects, and her unaffected mother also carried the mutation, demonstrating incomplete penetrance. Functional studies showed significantly reduced reporter activity and reduced levels of mature ligand with mutant GDF6 compared to wildtype, indicating that A249E represents a hypomorphic mutation. The mutation was not found in 366 controls.
Leber Congenital Amaurosis 17
In a female patient with Leber congenital amaurosis (LCA17; 615360), Asai-Coakwell et al. (2013) identified compound heterozygosity for the A249E mutation in the GDF6 gene and a c.169G-C transversion, resulting in an asp57-to-his (D57H; 601147.0008) substitution. The patient had vision limited to detection of hand motions with an extinguished electroretinogram (ERG) typical of the LCA phenotype; she did not have other ocular or systemic phenotypes, but the authors noted that she had not undergone radiologic imaging to detect milder GDF6-induced skeletal disease. Her clinically unaffected mother, who was heterozygous for the A249E mutation, exhibited a delayed rod b-wave implicit time on ERG; similarly, her father, who was heterozygous for D57H, showed reduced b-wave amplitude. The D57H mutation was absent from 1,500 control chromosomes, whereas the A249E mutation was found in 4. Expression analysis showed a 36% and 56% reduction in A249E mutant preproprotein and mature ligand levels compared to wildtype, and reporter assays showed that the A249E mutant has only 50% of wildtype activity. Levels of D57H preproprotein and mature ligand were markedly reduced, with an 80% and 97% reduction in the cytosolic fraction, respectively, and a 97% and 99% reduction in the media fraction; the D57H mutant had only 24% of wildtype activity in reporter assays. Asai-Coakwell et al. (2013) also identified heterozygosity for the A249E mutation in a female patient from an LCA/juvenile retinitis pigmentosa cohort, who had inherited the mutation from her unaffected father.
