The clinical spectrum of MECP2 variants in males: a multicenter Turkish cohort of 22 probands, with implications for diagnosis and variant interpretation
Year: 2026
Type: article
Study design: Observational Study
Abstract: BACKGROUND: In males, MECP2 loss of function was long thought to be lethal or uniformly severe, and affected boys remain under-recognised. Their clinical range is still poorly defined. METHODS: We assembled a multicentre Turkish series of 22 hemizygous male probands ascertained through routine diagnostic testing rather than severe-phenotype registries. Variants were classified under the ClinGen Expert Panel specification for MECP2 (GN036, version 6.0.0) and its combining rules, with the Panel's ClinVar classifications adopted where available. Phenotypic analysis was restricted to the 21 probands with pathogenic, likely pathogenic or uncertain variants. RESULTS: The 22 probands carried 17 distinct variants (11 missense, 5 frameshift and one 3' untranslated region deletion), of which 2 were classified as pathogenic, 1 likely pathogenic, 13 uncertain and 1 benign (3, 4, 14 and 1 probands, respectively). Where recorded, intellectual disability or developmental delay affected 7 of 7 probands with pathogenic or likely pathogenic variants and 8 of 10 with uncertain variants; seizures affected 2 of 3 and 8 of 10, respectively. Growth or head-circumference findings, recorded in 9 of 21 probands, included obesity or overgrowth (5), microcephaly (4, one borderline) and short stature (3). A maternal carrier was identified in 6 of 22 families (five laboratory-confirmed); the other 16 mothers were untested, so no de novo event was confirmed. Second-locus findings, reported by referring laboratories in 3 probands, could not be independently reclassified. CONCLUSIONS: In this diagnostically ascertained series, phenotypes observed among males carrying MECP2 variants were graded rather than uniformly severe. Fourteen of the 21 probands carry variants of uncertain significance, in whom causation is not established, so the range that may be attributed to MECP2 rests on seven individuals carrying variants classified as pathogenic or likely pathogenic under the stated criteria. In one of them, published functional data on the identical variant conflict with its pathogenic classification, so attribution of his phenotype to MECP2 remains uncertain. These provisional observations support a low threshold for MECP2 testing in males with unexplained neurodevelopmental presentations, attention to growth as well as head circumference, and consideration of additional loci.
Source: BMC Pediatrics
Authors: Çağrı Doğan, Mehmet Burak Mutlu, Ali Cansu, Esra Habiloğlu, Murat Öztürk, Uğur Gümüş, Abdullah İhsan Gürler, Bahtiyar Şahinoğlu, Hamdi Kale, Mustafa Tarık Alay, Abdullah Sezer, Aysel Kalaycı, Elif Yılmaz Güleç, Süheyla Emre, Hamza Polat, Zehra Manav Yiğit, Hilmi Bolat, Zeynep Esener, Dilan Genç Akdağ, Gül Ünsel Bolat, Ayberk Türkyılmaz, Akif Ayaz, Abdulkerim Kolkıran, Ahmet Cevdet Ceylan, Taha Solmaz, Yusuf Bahap, Neslihan Cinkara, Sümeyra Oğuz, Elif Uzay, Safiye Güneş Sager, Alper Han Çebi, Oğuzhan Demir, Ezgi Susam, İrem Kalay
Institutions: Ordu University, Karadeniz Technical University, Ankara Etlik City Hospital, Istanbul University-Cerrahpaşa, Istanbul Medeniyet University, Diyarbakır Gazi Yaşargil Eğitim ve Araştırma Hastanesi, Adnan Menderes University, Balıkesir University, Istinye University, Ankara Bilkent City Hospital, Gazi University, Zeynep Kamil Hospital, Dr Lütfi Kırdar Kartal Eğitim ve Araştırma Hastanesi, Sağlık Bilimleri Üniversitesi, Şişli Etfal Eğitim ve Araştırma Hastanesi
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,090
OpenAlex ID: W7223155137