Using human sequencing to guide craniofacial research.
Ryan P LiegelErin FinnertyLauren BlizzardAndrew DiStasioRobert B HufnagelHoward M SaalKristen L SundCynthia A ProwsRolf W StottmannPublished in: Genesis (New York, N.Y. : 2000) (2018)
A recent convergence of technological innovations has re-energized the ability to apply genetics to research in human craniofacial development. Next-generation exome and whole genome sequencing have significantly dropped in price, making it relatively trivial to sequence and analyze patients and families with congenital craniofacial anomalies. A concurrent revolution in genome editing with the use of the CRISPR-Cas9 system enables the rapid generation of animal models, including mouse, which can precisely recapitulate human variants. Here, we summarize the choices currently available to the research community. We illustrate this approach with the study of a family with a novel craniofacial syndrome with dominant inheritance pattern. The genomic analysis suggested a causal variant in AMOTL1 which we modeled in mice. We also made a novel deletion allele of Amotl1. Our results indicate that Amotl1 is not required in the mouse for survival to weaning. Mice carrying the variant identified in the human sequencing studies, however, do not survive to weaning in normal ratios. The cause of death is not understood for these mice complicating our conclusions about the pathogenicity in the index patient. Thus, we highlight some of the powerful opportunities and confounding factors confronting current craniofacial genetic research.
Keyphrases
- crispr cas
- endothelial cells
- genome editing
- induced pluripotent stem cells
- pluripotent stem cells
- end stage renal disease
- chronic kidney disease
- mechanical ventilation
- escherichia coli
- healthcare
- mental health
- single cell
- type diabetes
- high fat diet induced
- adipose tissue
- metabolic syndrome
- intensive care unit
- case report
- ejection fraction
- squamous cell carcinoma
- newly diagnosed
- radiation therapy
- insulin resistance
- quantum dots
- sensitive detection
- peritoneal dialysis
- staphylococcus aureus
- loop mediated isothermal amplification
- biofilm formation