The cohort was assembled through routine diagnostic testing rather than through a registry that preferentially recruited boys with severe presentations. All 22 probands were hemizygous males and collectively carried 17 distinct MECP2 variants: 11 missense variants, five frameshift variants and one deletion affecting the 3′ untranslated region. Investigators classified the variants using the ClinGen Expert Panel specification for MECP2, its combining rules and existing ClinVar classifications where available. Two variants were classified as pathogenic, one as likely pathogenic, 13 as uncertain and one as benign, representing three, four, 14 and one probands, respectively.

Phenotypic analysis excluded the boy with the benign variant and was therefore restricted to 21 probands. Where clinical information was available, intellectual disability or developmental delay affected all seven probands with pathogenic or likely pathogenic variants and eight of 10 with uncertain variants. Seizures affected two of three boys in the pathogenic or likely pathogenic group and eight of 10 in the uncertain group. These figures describe the participants with available records rather than risks for all males carrying MECP2 variants. The small and uneven groups also prevent firm generalization about how clinical features differ among variant classes.

Growth or head-circumference findings were recorded in nine of the 21 clinically assessed probands. Five had obesity or overgrowth, four had microcephaly—including one borderline case—and three had short stature. These observations prompted the researchers to emphasize evaluation of growth as well as head circumference in males with unexplained neurodevelopmental presentations. Family testing also found a maternal carrier in six of 22 families, with five confirmed by laboratories; the other 16 mothers were not tested, so the study did not confirm a de novo occurrence for any variant.

Additional findings reported by referring laboratories introduced uncertainty in three probands because the investigators could not independently reclassify the second-locus findings. The authors also identified a participant whose variant was classified as pathogenic or likely pathogenic even though published functional data on the identical variant conflicted with that classification; attribution of his phenotype to MECP2 therefore remained uncertain. Overall, the diagnostically ascertained series provides provisional evidence that MECP2-associated presentations in males may not always be severe, while the predominance of uncertain variants makes the boundaries of the clinical spectrum provisional. The researchers concluded that the observations support a low threshold for considering MECP2 testing in males with unexplained neurodevelopmental presentations, alongside cautious variant interpretation and consideration of additional genetic loci.

Subject of Research: Clinical findings and variant interpretation for MECP2 variants in 22 Turkish male probands

Article Title: The clinical spectrum of MECP2 variants in males: a multicenter Turkish cohort of 22 probands, with implications for diagnosis and variant interpretation

Article References: Doğan, Ç., Mutlu, M. B., Cansu, A., Habiloğlu, E., Öztürk, M., Gümüş, U., Gürler, A. İ., Şahinoğlu, B., Kale, H., Alay, M. T., Sezer, A., Kalaycı, A., Güleç, E. Y., Emre, S., Polat, H., Yiğit, Z. M., Bolat, H., Esener, Z., Akdağ, D. G., … Kalay, İ. (2026). The clinical spectrum of MECP2 variants in males: a multicenter Turkish cohort of 22 probands, with implications for diagnosis and variant interpretation. BMC Pediatrics. https://doi.org/10.1186/s12887-026-07905-0

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07905-0

Keywords: MECP2 variants, male probands, neurodevelopmental disability, developmental delay, seizures, microcephaly, growth abnormalities, variant classification, clinical genetics, rare disease, multicenter cohort, diagnostic testing