Selected Grantee Publications
Mendelian Gene Identification through Mouse Embryo Viability Screening
Cacheiro et al., Genome Medicine. 2022.
https://www.doi.org/10.1186/s13073-022-01118-7
The investigators dissected phenotypic similarities between patients and model organisms by assessing the embryonic stage at which homozygous loss of function results in lethality in mice of both sexes obtained from the International Mouse Phenotyping Consortium. Information on knockout mouse embryo lethality can be used to prioritize candidate genes associated with certain disorders. Access to unsolved cases from rare-disease genome sequencing programs allows for the screening of those genes for potentially pathogenic variants, which could lead to a diagnosis and new potential treatment options to inform the management of human disease. Supported by ORIP (UM1OD023221, UM1OD023222, U42OD011174) and NHGRI.
A Novel DPH5-Related Diphthamide-Deficiency Syndrome Causing Embryonic Lethality or Profound Neurodevelopmental Disorder
Shankar et al., Genetics in Medicine. 2022.
https://www.doi.org/10.1016/j.gim.2022.03.014
Neurodevelopmental disorders (NDDs) affect more than 3% of the pediatric population and often have associated neurologic or multisystem involvement. The underlying genetic etiology of NDDs remains unknown in many individuals. Investigators characterized the molecular basis of NDDs in children of both sexes with nonverbal NDDs from three unrelated families with distinct overlapping craniofacial features. The investigators also used a mouse model of both sexes to determine the pathogenicity of variants of uncertain significance, as well as genes of uncertain significance, to advance translational genomics and provide precision health care. They identified several variants in DPH5 as a potential cause of profound NDD. Their findings provide strong clinical, biochemical, and functional evidence for DPH5 variants as a novel cause of embryonic lethality or profound NDD with multisystem involvement. Based on these findings, the authors propose that “DPH5-related diphthamide deficiency syndrome” is a novel autosomal-recessive Mendelian disorder. Supported by ORIP (K01OD026608, U42OD012210) and NHGRI.
Sequence Diversity Analyses of an Improved Rhesus Macaque Genome Enhance its Biomedical Utility
Warren et al., Science. 2020.
https://science.sciencemag.org/content/370/6523/eabc6617
Investigators sequenced and assembled an Indian-origin female rhesus macaque (RM) genome using a multiplatform genomics approach that included long-read sequencing, extensive manual curation, and experimental validation to generate a new comprehensive annotated reference genome. As a result, 99.7% of the gaps in the earlier draft genome are now closed, and more than 99% of the genes are represented. Whole-genome sequencing of 853 RMs of both sexes identified 85.7 million single-nucleotide variants and 10.5 million indel variants, including potentially damaging variants in genes associated with human autism and developmental delay. The improved assembly of segmental duplications, new lineage-specific genes and expanded gene families provide a framework for developing noninvasive NHP models for human disease, as well as studies of genetic variation and phenotypic consequences. Supported by ORIP (P51OD011106, P51OD011107, P51OD011132, P51OD011104, U42OD024282, U42OD010568, R24OD011173, R24OD021324, R24OD010962), NHGRI, NIMH, NHLBI, and NIGMS.