from Chris Walsh’s group is an elegant example linking human genetics, mouse genetics and molecular biology.
The disease of question is polymicrogyria, meaning too many small gyri on the surface of brain grey matter. Key to the design for their success: phenotypic classification. From over 1000 patients with gyri abnormality, they selected specifically those with polymicrogyria restricted to only one part of the cortex. They were able to reconstruct independent pedigrees from these selected patients. And the consanguineous nature of the pedigrees immediately suggest a recessive Mendelian disorder. 
The other point of this paper that strikes me is that people might have finally, for the first time, identified an inserted transposable element which creates novel cis-regulatory sites. From the linkage analysis, they found a 15 bp deletion as the culprit for causing the disease. The deletion lies in a conserved upstream non-coding area, which is derived from LINE, one of the most common transposable elements in the human genome. The deletion leads to mis-expression of one gene, GPR56, which the authors demonstrated with mouse lines expressing reporters driven by either the wild type or the deleted promoter. They were able to also identified transcription factors specifically bind to this part of the promoter, which is unique in the genome, and the deletion seen in patients abolishes the binding and subsequently alters transcription. It’ll be nicer if they can show similar phenotype in mice lacking these TFs to mice with the deleted promoter-reporter line.
People have speculated a lot about why transposons like LINEs are so prevalent in the human genome. One idea has been that by hoping and inserting into different places in the genome, often in a truncated form of the original transposon, they provide a basis for creating novel protein binding sites and therefore novel ways of expression regulation. Another intriguing observation is the fact that transposition is highly active in the brain compared to other organs. And one way to think about this is that this dynamics of tranposition generates a much complex gene regulatory program in human brain, and thus why we are more advanced.
Moral of the story? If you are careful enough (phenotypic classification, patient stratification, etc), you’ll probably get lucky finding easy-to-deal-with single gene cases out of a don’t-know-where-to-start complex disease.