ZMYND11 p.Arg600Trp variant associated with a distinctive neurodevelopmental phenotype

Zinc finger MYND-type containing 11 (ZMYND11)-related neurodevelopmental disorder is an autosomal dominant condition caused by pathogenic variants in ZMYND11. Most previously reported patients harbor loss-of-function (LoF) variants, whereas missense variants are rare and their clinical and mechanistic characteristics remain insufficiently defined. Here we report a patient with a heterozygous ZMYND11 c.1798C>T, p.(Arg600Trp) variant identified through the Initiative on Rare and Undiagnosed Diseases program. Detailed clinical evaluation, developmental assessment and whole-exome sequencing were performed. In addition, a systematic review of previously published ZMYND11 cases was conducted to compare genotype-phenotype correlations between missense and LoF variants. The present patient showed global developmental delay, hypotonia, distinctive craniofacial features, microcephaly, short stature, cryptorchidism and right-sided inguinal hernia. Comparison with two previously reported individuals carrying the same c.1798C>T variant demonstrated consistent shared features, including microcephaly, broad nasal alae, short stature, cryptorchidism and nipple anomalies, findings that are not typically emphasized in LoF-associated cases. Aggregate analysis of reported 13 missense variants suggested higher frequencies of strabismus, hypotonia and severe intellectual disability compared with LoF variants, supporting the hypothesis that missense variants including c.1798C>T may define a partially distinct clinical subgroup. These findings expand the phenotypic spectrum associated with ZMYND11 missense variants and suggest variant-specific clinical patterns, particularly for c.1798C>T, which may reflect a mechanism different from simple haploinsufficiency.