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

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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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