The relationship between MRPS16 and mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of June 16, 2022. The MRPS16 gene encodes the mitochondrial ribosomal protein S16, a component of the small subunit of the mitochondrial ribosome.
The MRPS16 gene was first reported in relation to autosomal recessive mitochondrial disease in 2004 (PMID: 15505824). While various names have been given to the constellation of features seen in those with MRPS16-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MRPS16 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included one homozygous nonsense variant identified in one case from one publication (PMID: 15505824). This individual was of Bedouin descent and was born to consanguineous parents. Medical concerns included severe lactic acidosis, agenesis of the corpus callosum, ventriculomegaly, lethargy, and neonatal hypotonia. This individual died in the first few days of life. While this report pre-dated the comprehensive genomic sequencing, this GCEP agreed the biochemical and genetic evaluation performed was sufficient for this case to be included in this curation, and functional validation of the variant identified in this case was performed in a subsequent publication (PMID:18539099). Loss-of-function is implicated as a mechanism of disease. This gene-disease relationship is also supported by its known biochemical function that is shared with other genes associated with primary mitochondrial disease and functional alteration in patient cells (PMID: 15505824).
In summary, there is limited evidence to support this gene-disease relationship. Although the total score (7) falls in the moderate range, only one case with primary mitochondrial disease has been reported, therefore this gene-disease association can only reach a limited classification at this time. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on June 16, 2022 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.