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Background  Germline chromothripsis causes complex genomic rearrangements that are likely to affect multiple genes and their regulatory contexts. The contribution of individual rearrangements and affected genes to the phenotypes of patients with complex germline genomic rearrangements is generally unknown.    Methods  To dissect the impact of germline chromothripsis in a relevant developmental context, we performed trio-based RNA expression analysis on blood cells, induced pluripotent stem cells (iPSCs), and iPSC-derived neuronal cells from a patient with de novo germline chromothripsis and both healthy parents. In addition, Hi-C and 4C-seq experiments were performed to determine the effects of the genomic rearrangements on transcription regulation of genes in the proximity of the breakpoint junctions.    Results  Sixty-seven genes are located within 1 Mb of the complex chromothripsis rearrangements involving 17 breakpoints on four chromosomes. We find that three of these genes ( FOXP1 ,  DPYD , and  TWIST1 ) are both associated with developmental disorders and differentially expressed in the patient. Interestingly, the effect on  TWIST1  expression was exclusively detectable in the patient’s iPSC-derived neuronal cells, stressing the need for studying developmental disorders in the biologically relevant context. Chromosome conformation capture analyses show that  TWIST1  lost genomic interactions with several enhancers due to the chromothripsis event, which likely led to deregulation of  TWIST1  expression and contributed to the patient’s craniosynostosis phenotype.    Conclusions  We demonstrate that a combination of patient-derived iPSC differentiation and trio-based molecular profiling is a powerful approach to improve the interpretation of pathogenic complex genomic rearrangements. Here we have applied this approach to identify misexpression of  TWIST1 ,  FOXP1 , and  DPYD  as key contributors to the complex congenital phenotype resulting from germline chromothripsis rearrangements.    Electronic supplementary material  The online version of this article (doi:10.1186/s13073-017-0399-z) contains supplementary material, which is available to authorized users.

Molecular dissection of germline chromothripsis in a developmental context using patient-derived iPS cells