A Complex Neurodevelopmental Phenotype Resembling a Chromatinopathy With Concurrent 7p Duplication and 10p Deletion...

The complex pathogenetic mechanisms of rare genetic diseases make the diagnostic process highly challenging. Advances in molecular genomic techniques, such as exome sequencing, have improved the identification of copy number variants (CNVs), increasing diagnostic yield.

We report the case of a female patient with global developmental delay, growth alterations, and dysmorphic features. Clinical exome sequencing did not reveal point mutations. CNV analysis from exome data identified a 6 Mb microdeletion in 10p15.3p14, involving the ZMYND11 gene, and a 7.6 Mb microduplication in 7p22.3p21.3; both rearrangements were subsequently confirmed by chromosomal microarray analysis. Conventional karyotyping revealed a derivative chromosome 10 [46,XX,der (10)], a finding consistent with the possibility of an unbalanced translocation involving chromosomes 7 and 10. The combined cytogenetic and molecular findings are consistent with the possibility that the duplicated 7p segment is inserted into the short arm of chromosome 10.

ZMYND11, a dosage-sensitive gene, has been associated with Cornelia de Lange Syndrome (CdLS)-like phenotypes, and its haploinsufficiency is linked to 10p15.3 microdeletion syndrome. Our patient presented a complex phenotype due to the concurrent 7p duplication and 10p deletion, highlighting the importance of ZMYND11 in chromatinopathies. A review of similar cases supports considering ZMYND11 in evaluating chromatinopathy-related features. Notably, she also exhibited unique characteristics that have not been previously described in association with either CNV.

Next-generation sequencing, capable of detecting both single nucleotide variants and CNVs, is a critical tool for diagnosing neurodevelopmental disorders and uncovering diverse causative variants. This case emphasizes how NGS facilitates the identification of co-occurring CNVs and expands the phenotypic spectrum associated with chromatinopathies. Detailed characterization of such complex phenotypes using NGS is essential for advancing our understanding of rare genetic conditions and improving diagnostic accuracy.