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Peer-reviewedCC BYBMC Pediatrics

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

  • Çağrı Doğan1
  • Mehmet Burak Mutlu2
  • Ali Cansu3
  • Esra Habiloğlu4
  • Murat Öztürk4
  • Uğur Gümüş5
  • Abdullah İhsan Gürler5
  • Bahtiyar Şahinoğlu5
  • Hamdi Kale5
  • Mustafa Tarık Alay6
  • Abdullah Sezer6
  • Aysel Kalaycı7
22 more authors
  • Elif Yılmaz Güleç8
  • Süheyla Emre8
  • Hamza Polat9
  • Zehra Manav Yiğit10
  • Hilmi Bolat11
  • Zeynep Esener11
  • Dilan Genç Akdağ11
  • Gül Ünsel Bolat12
  • Ayberk Türkyılmaz13
  • Akif Ayaz14
  • Abdulkerim Kolkıran15
  • Ahmet Cevdet Ceylan16
  • Taha Solmaz16
  • Yusuf Bahap17
  • Neslihan Cinkara18
  • Sümeyra Oğuz19
  • Elif Uzay19
  • Safiye Güneş Sager20
  • Alper Han Çebi21
  • Oğuzhan Demir21
  • Ezgi Susam22
  • İrem Kalay23
23 affiliations
  1. 1Department of Medical Genetics, Ordu University Training and Research Hospital
  2. 2Detagen Genetic Diagnosis Center
  3. 3Department of Pediatric Neurology, Faculty of Medicine, Karadeniz Technical University
  4. 4Department of Medical Genetics, Batman Training and Research Hospital
  5. 5Department of Medical Genetics, Dr. Ersin Arslan Training and Research Hospital
  6. 6Department of Medical Genetics, Ankara Etlik City Hospital
  7. 7Department of Medical Genetics, Cerrahpaşa University Hospital
  8. 8Department of Medical Genetics, Medeniyet University Hospital
  9. 9Department of Medical Genetics, Gazi Yaşargil Training and Research Hospital
  10. 10Department of Medical Genetics, Adnan Menderes University Hospital
  11. 11Department of Medical Genetics, Balıkesir University Hospital
  12. 12Department of Child and Adolescent Psychiatry, Balıkesir University Hospital
  13. 13Gelişim Medical Diagnostic Center
  14. 14Genetic Diseases Diagnosis and Evaluation Center, İstinye University
  15. 15Department of Pediatric Genetics, Ankara Etlik City Hospital
  16. 16Department of Medical Genetics, Ankara Bilkent City Hospital
  17. 17Department of Medical Genetics, Gazi University
  18. 18Department of Medical Genetics, Trabzon Kanuni Training and Research Hospital
  19. 19Department of Medical Genetics, Zeynep Kamil Women’s and Children’s Diseases Training and Research Hospital
  20. 20Hamidiye International School of Medicine, Kartal Dr. Lütfi Kırdar City Hospital, University of Health Sciences Türkiye
  21. 21Department of Medical Genetics, Faculty of Medicine, Karadeniz Technical University
  22. 22Ankara Bilkent City Hospital, Health Institutes of Türkiye (TÜSEB)
  23. 23Department of Medical Genetics, University of Health Sciences Sisli Hamidiye Etfal Training and Research Hospital
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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.

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Cite

BibTeXRIS
BibTeX
@article{dogan2026clinical,
  title = {{The clinical spectrum of MECP2 variants in males: a multicenter Turkish cohort of 22 probands, with implications for diagnosis and variant interpretation}},
  author = {Çağrı Doğan and Mehmet Burak Mutlu and Ali Cansu and Esra Habiloğlu and Murat Öztürk and Uğur Gümüş and Abdullah İhsan Gürler and Bahtiyar Şahinoğlu and Hamdi Kale and Mustafa Tarık Alay and Abdullah Sezer and Aysel Kalaycı and Elif Yılmaz Güleç and Süheyla Emre and Hamza Polat and Zehra Manav Yiğit and Hilmi Bolat and Zeynep Esener and Dilan Genç Akdağ and Gül Ünsel Bolat and Ayberk Türkyılmaz and Akif Ayaz and Abdulkerim Kolkıran and Ahmet Cevdet Ceylan and Taha Solmaz and Yusuf Bahap and Neslihan Cinkara and Sümeyra Oğuz and Elif Uzay and Safiye Güneş Sager and Alper Han Çebi and Oğuzhan Demir and Ezgi Susam and İrem Kalay},
  journal = {BMC Pediatrics},
  year = {2026},
  month = oct,
  doi = {10.1186/s12887-026-07905-0},
  url = {https://doi.org/10.1186/s12887-026-07905-0},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - The clinical spectrum of MECP2 variants in males: a multicenter Turkish cohort of 22 probands, with implications for diagnosis and variant interpretation
AU  - Çağrı Doğan
AU  - Mehmet Burak Mutlu
AU  - Ali Cansu
AU  - Esra Habiloğlu
AU  - Murat Öztürk
AU  - Uğur Gümüş
AU  - Abdullah İhsan Gürler
AU  - Bahtiyar Şahinoğlu
AU  - Hamdi Kale
AU  - Mustafa Tarık Alay
AU  - Abdullah Sezer
AU  - Aysel Kalaycı
AU  - Elif Yılmaz Güleç
AU  - Süheyla Emre
AU  - Hamza Polat
AU  - Zehra Manav Yiğit
AU  - Hilmi Bolat
AU  - Zeynep Esener
AU  - Dilan Genç Akdağ
AU  - Gül Ünsel Bolat
AU  - Ayberk Türkyılmaz
AU  - Akif Ayaz
AU  - Abdulkerim Kolkıran
AU  - Ahmet Cevdet Ceylan
AU  - Taha Solmaz
AU  - Yusuf Bahap
AU  - Neslihan Cinkara
AU  - Sümeyra Oğuz
AU  - Elif Uzay
AU  - Safiye Güneş Sager
AU  - Alper Han Çebi
AU  - Oğuzhan Demir
AU  - Ezgi Susam
AU  - İrem Kalay
PY  - 2026
DA  - 2026/10/25
JO  - BMC Pediatrics
DO  - 10.1186/s12887-026-07905-0
UR  - https://doi.org/10.1186/s12887-026-07905-0
AB  - 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.
SN  - 1471-2431
ER  -