GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE330nnn/GSE330364/primaryOK200GenomicsHomo sapiensGenome binding/occupancy profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE330364GEOGSEfalseA massively parallel reporter assay of MECP2 cis-regulatory elements reveals genetic candidates for male-biased autismAutism affects males four times more often than females, yet the basis of this sex bias remains unclear. One hypothesis is that hypomorphic variants in X-linked genes—genes where loss-of-function alleles cause syndromic neurodevelopmental disorders (NDDs) predominantly in females—produce milder, non-syndromic phenotypes in hemizygous males. We tested this by investigating cis-regulatory elements (CREs) of MECP2, a dosage-sensitive X-linked gene. Using a massively parallel reporter assay in human neurons, we mapped transcription factor binding sites within MECP2 CREs and tested autism-associated variants for functional impact. We identified two noncoding variants that change CRE activity, each with a male-biased phenotype. One of these, a promoter variant, disrupts NFY binding and reduces MECP2 expression by ~30%, a magnitude that produces autism-like phenotypes in mice. These findings suggest noncoding MECP2 variants can cause non-syndromic, male-biased autism, and provide a framework for uncovering regulatory variants in other X-linked NDD genes that may contribute to autism’s missing heritability.2026/05/08GSE330364GSM9724729GSM9724739GSM9724728GSM9724727GSM9724749GSM9724738GSM9724748GSM9724737GSM9724726GSM9724747GSM9724736GSM9724735GSM9724746GSM9724745GSM9724734GSM9724733GSM9724744GSM9724743GSM9724732GSM9724742GSM9724731GSM9724730GSM9724741GSM972474034284330364Homo sapiens