ZMYND11 p.Arg600Trp variant associated with a distinctive neurodevelopmental phenotype

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Rare Diseases

Background:

• ZMYND11-related neurodevelopmental disorder is typically caused by loss-of-function (LoF) variants.
• Missense variants in ZMYND11 are rare, and their clinical and mechanistic aspects are not well understood.

Purpose of the Study:

• To characterize a patient with a novel ZMYND11 missense variant (c.1798C>T, p.(Arg600Trp)).
• To compare genotype-phenotype correlations between missense and LoF variants in ZMYND11-related disorders.
• To expand the understanding of the phenotypic spectrum of ZMYND11 missense variants.

Main Methods:

• Clinical evaluation and developmental assessment of a patient with a heterozygous ZMYND11 c.1798C>T variant.
• Whole-exome sequencing for variant identification.
• Systematic literature review of previously reported ZMYND11 cases.
• Comparative genotype-phenotype analysis.

Main Results:

• The patient presented with global developmental delay, hypotonia, distinctive craniofacial features, microcephaly, short stature, cryptorchidism, and inguinal hernia.
• Consistent features were observed in individuals with the same c.1798C>T variant, including microcephaly, broad nasal alae, short stature, cryptorchidism, and nipple anomalies.
• Aggregate analysis of 13 missense variants revealed higher frequencies of strabismus, hypotonia, and severe intellectual disability compared to LoF variants.

Conclusions:

• The ZMYND11 c.1798C>T missense variant defines a distinct clinical subgroup with specific features.
• Missense variants in ZMYND11 may lead to a partially distinct clinical phenotype compared to LoF variants, potentially through mechanisms beyond simple haploinsufficiency.
• These findings broaden the phenotypic spectrum of ZMYND11-related disorders and highlight variant-specific clinical patterns.