ESPE Yearbook of Paediatric Endocrinology

Nature Reviews Genetics 2025 Apr 7. Online ahead of print. PubMed: 40189669 https://doi.org/10.1038/s41576-025-00834-1

In Brief: This review article summarises and beautifully illustrates recent progress in the common and rare genetic determinants of human height, and the resulting mechanistic insights. It shows how findings from different study designs (rare monogenic cases through to large population-based studies) converge on the same genes and pathways, and how these inform new treatment targets for rare skeletal disorders.

Comment: Human height (in particular adult height) has long been considered the exemplar phenotype for genetics studies due to its very high heritability: estimated >80% with only <20% due to environment. Therefore, while this topic is of particular relevance to Paediatric Endocrinologists, height is also a useful trait to illustrate the value of recent advances in the studies of both common and rare genetic variants.

There are now a remarkable 12,111 independent common genetic ‘signals’ identified through genome-wide association studies (GWAS) that have pooled data on millions of participants. Indeed, these studies have now reached ‘saturation’, at least in European ancestry populations. But this explains only ~50% of heritability. The remaining heritability is likely due to ‘low frequency’ variants that are being increasingly revealed by genome sequence data in large population studies and these findings will shed light on yet unidentified ‘very rare’ monogenic disorders.

While studies of syndromic short stature have identified mutations in several components of the growth hormone-IGF-1 pathway (GH1, IGF1, IGF2, IGF1R, GHR, STAT3, STAT5, IGFALS), most of the mechanisms targeted by genetic findings are skeletal. The authors highlight various core cellular processes that regulate bone plate function, including: DNA Replication Cell cycle progression, DNA damage response & DNA repair, and several epigenetic regulators. Finally, they describe how genetic evidence for CNP and NPR2 affecting the regulation of FGFR3 support new and emerging treatments for achondroplasia.