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Kallmann syndrome (KS) is a congenital disorder characterized by idiopathic hypogonadotropic hypogonadism and olfactory dysfunction. KS is linked to variants in &gt;34 genes, which are scattered across the human genome and show disparate biological functions. Although the genetic basis of KS is well studied, the mechanisms by which disruptions of these diverse genes cause the same outcome of KS are not fully understood. Here we show that disruptions of KS-linked genes affect the same biological processes, indicating convergent molecular mechanisms underlying KS. We carried out machine learning-based predictions and found that KS-linked mutations in heparan sulfate 6- O -sulfotransferase 1 ( HS6ST1 ) are likely loss-of-function mutations. We next disrupted  Hs6st1  and another KS-linked gene, fibroblast growth factor receptor 1 ( Fgfr1 ), in mouse neuronal cells and measured transcriptome changes using RNA sequencing. We found that disruptions of  Hs6st1  and  Fgfr1  altered genes in the same biological processes, including the upregulation of genes in extracellular pathways and the downregulation of genes in chromatin pathways. Moreover, we performed genomics and bioinformatics analyses and found that Hs6st1 and Fgfr1 regulate gene transcription likely via the transcription factor Sox9/Sox10 and the chromatin regulator Chd7, which are also associated with KS. Together, our results demonstrate how different KS-linked genes work coordinately in a convergent signaling pathway to regulate the same biological processes, thus providing new insights into KS.

Convergent biological pathways underlying the Kallmann syndrome-linked genes Hs6st1 and Fgfr1