Whole exome sequencing for handedness in a large and highly consanguineous family

- The genetics of handedness was investigated in a large and consanguineous family.
- Whole exome sequencing was used for the first time in a genetic study of handedness.
- Multipoint linkage was used to scan the genome under different models of inheritance.
- Single-point linkage was used to test DNA variants for co-segregation with handedness.
- The genetics of handedness in this unusual family are likely to be complex.

Pinpointing genes involved in non-right-handedness has the potential to clarify developmental contributions to human brain lateralization. Major-gene models have been considered for human handedness which allow for phenocopy and reduced penetrance, i.e. an imperfect correspondence between genotype and phenotype. However, a recent genome-wide association scan did not detect any common polymorphisms with substantial genetic effects. Previous linkage studies in families have also not yielded significant findings. Genetic heterogeneity and/or polygenicity are therefore indicated, but it remains possible that relatively rare, or even unique, major-genetic effects may be detectable in certain extended families with many non-right-handed members. Here we applied whole exome sequencing to 17 members from a single, large consanguineous family from Pakistan. Multipoint linkage analysis across all autosomes did not yield clear candidate genomic regions for involvement in the trait and single-point analysis of exomic variation did not yield clear candidate mutations/genes. Any genetic contribution to handedness in this unusual family is therefore likely to have a complex etiology, as at the population level.