J Mol Endocrinol. 2026 May 18:JME-25-0134. doi: 10.1530/JME-25-0134. Online ahead of print.
ABSTRACT
The late 20th century saw major advances in mapping genes and mutations in endocrine disorders, driven by biochemical studies that identified defects endocrinologically and by family-based studies that mapped them genetically. In the 21st century, however, the world of genetics has been transformed by mapping of the human genome and by development of next generation sequencing technologies that allow genomes to be sequenced at population scale. This has led us to be swamped by a surfeit of information about genetic variation, with so called genetic "variants of unknown significance" (VUS) greatly outnumbering pathogenic mutations in genes of clinical relevance. A revolution in functional genomics has since gathered pace, driven by the need to evaluate the function of rare genetic variants at scale. Recent advances in saturation mutagenesis enable the synthesis of libraries of thousands of gene variants. When coupled to increasingly creative use of a growing repertoire of downstream assays, this permits assessment of disease-relevant function of thousands of variants simultaneously. Such assays, widely known as Multiplexed Assays of Variant Effect (MAVEs), have major potential in endocrinology when applied to hormone receptors and their downstream signalling pathways. They help determine functional significance or otherwise of VUS, enable patient stratification for rare disease treatments, and yield new insights into structure-function relationships for target genes. We review the current state of development of MAVEs and their application to date to endocrine genetic disease, with particular reference to hormone receptors.
PMID:42149708 | DOI:10.1530/JME-25-0134