ZMYND11 p.Arg600Trp variant associated with a distinctive neurodevelopmental phenotype

TL;DR

A specific ZMYND11 gene variant is linked to a unique neurodevelopmental disorder with distinct symptoms compared to other variants.

Contribution

The study identifies a missense variant in ZMYND11 associated with a distinct clinical subgroup of neurodevelopmental features.

Findings

The c.1798C>T variant in ZMYND11 is associated with microcephaly, short stature, and distinctive facial features.

Missense variants in ZMYND11 are linked to higher rates of strabismus, hypotonia, and severe intellectual disability compared to loss-of-function variants.

The findings suggest that missense variants may reflect a different mechanism than simple haploinsufficiency.

Abstract

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.

Zinc finger MYND-type containing 11 (ZMYND11) is a gene linked to a rare neurodevelopmental disorder. This disorder often causes developmental delays, intellectual disabilities and unique facial features. Most cases are due to loss-of-function variants, but missense variants are less understood. This study focuses on a specific missense variant in ZMYND11. The researchers studied a young boy carrying this variant, who exhibited symptoms such as developmental delay and distinctive facial features. They used genetic testing to identify the variant and compared his symptoms with other known cases. The study involved detailed clinical evaluations and genetic analysis using exome sequencing. The findings suggest that missense variants might lead to different symptoms than loss-of-function variants, such as more severe intellectual disabilities. The study highlights the need for more research to understand these differences better.

This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Figures