Each sibling (i.e., A and B) in kindred 1 was found to have at least a single NS/SS/I variant in ~4,600 genes and two or more NS/SS/I variants in ~2,800 genes. For a dominant model, in which each sib was required to have at least one novel NS/SS/I variant in the same gene, filtering these variants against dbSNP129 and 8 HapMap exomes reduced the candidate gene pool ~40-fold. For a recessive model in which each sib was required to have at least two novel NS/SS/I variants in the same gene, the candidate pool was reduced >500-fold compared to all known human genes. Both siblings were predicted to share the causal variant for Miller syndrome so we next considered novel NS/SS/I variants shared between them. Under our dominant model, this reduced the pool of candidate genes to 228, and under our recessive model, the number of candidate genes was reduced to 9.
