The genetic basis of congenital heart malformations associated with disruption of left-right (L-R) asymmetry is broad and heterogenous, with variants in over twenty five genes implicated thus far. Of these, deleterious mutations in the growth/differentiation factor 1 (GDF1) gene have recently been shown to cause heterotaxy with varied complex heart malformations of left-right patterning, in thirteen individuals to date.
Following our experience with multiple affected individuals exhibiting heterotaxy with congenital heart defects originating from consanguineous kindreds of Arab-Muslim descent residing near Hebron, we pursued Whole Exome Sequencing in a proband of such a family. This had brought to the identification of a novel homozygous truncating c.608G>A (c.W203*) mutation in the GDF1 gene, as the molecular basis of his disease. The variant showed full segregation with over 15 individuals tested in the multiplex family. Subsequently, targeted Sanger sequencing of this variant among additional patients identified two additional probands to also harbor the mutation in homozygous form. These findings enable genetic counselling, prenatal diagnosis and planning of future pregnancies in the affected families.
Our findings further confirm the association of GDF1 variants with heterotaxy and congenital heart defects of left-right patterning, and expand the previously described phenotype and mutational profile.
