 Hello, my name is Raluca Nicoli and I'm a visiting fellow at NHGRI. I would like to talk to you today about Shedia Kigashi disease. Just like in a house, cells have to recycle cellular waste. For this task, they rely on this spherical organelle called the lysosome, which works like the rubbish can of the cell. To visualize lysosomes in human fibroblasts, we stain with an antibody against the lysosomal membrane. This is shown here in green. Containing acids and several types of digestive enzymes, the lysosomes recycle and digest the unwanted cellular waste. An inability to make one of these enzymes, or a problem in lysosomal formation, can lead to rare disorders called lysosomal diseases. Shedia Kigashi disease, or CHD, is one example of a rare lysosomal disease caused by mutations in lysosomal regulated gene, LIST. CHD is characterized by partial albinism, prolonged bleeding times, recurrent life-threatening infections, and lay neurological involvement. Our question is, what would be the correlation between the clinical phenotypes and the molecular genotypes, while broadly speaking, two severe LIST mutations would characterize a classical CHD phenotype, whereas at least one milder mutation would describe a atypical CHD patient. The genotype-phenotype correlation is important because the compromised immune system in classical CHD patients can be treated with bone marrow transplant. Normal human fibroblasts show a normal-sized lysosomes throughout the whole cell, whereas a typical and classical CHD will show enlarged lysosomes restricted to the area around the nucleus. And this is more evident in the classical versus the atypical one, which is more of an intermediate phenotype. More than 80 mutations have been reported so far scattered throughout the LIST gene. Sphere nonsense mutations, where variants can result into a non-functional protein product and it can be frame shifts, splice sites, insertion or deletion mutations, where are mostly found in classical CHD patients. Mean-sense milder mutations found in atypical CHD patients can be due to the substitution of a single amino acid and can result into a partially functional protein product. Through our NIH clinical protocol, we have discovered 19 novel LIST mutations from 13 patients in our cohort so far. And to summarize, the clinical severity of the classical and atypical CHD patients correlates with the molecular genotyping and lysosomal distribution and size in human fibroblasts. Our results are valuable for understanding the spectrum of disease, establishing a genotype phenotype correlation, improving diagnosis and clinical care for CHD patients. And nonetheless, it might serve as another example for other lysosomal diseases. Thank you for listening to me and think about CHD.