Genetic study of a case of complex neurodevelopmental disorder using whole-exome sequencing combined with optical genome mapping

The clinical phenotypes of complex neurodevelopmental disorders are highly heterogeneous. Besides single-gene mutations, complex chromosomal structural variations are also an important cause of this type of disease. However, some complex structural variants may remain undetected by conventional genetic testing methods, and the underlying molecular etiology remains unresolved in some patients. This study aimed to integrate multi-platform genetic testing techniques, analyze complex chromosomal structural rearrangements and possible pathogenicity, and provide information support for clinical diagnosis and treatment as well as genetic counseling. Chromosome karyotype analysis and Whole-Exome Sequencing (WES) were conducted respectively for a child with multiple abnormal manifestations such as delayed language and motor development, microcephaly, and single palmar crease in a family, as well as her parents. WES and Optical Genome Mapping (OGM) were performed, and functional annotation and gene interaction mapping analysis were performed on the copy number variation regions obtained from OGM. Based on family validation and database search, the source of the mutation and the genotype-phenotype association were analyzed. Karyotype analysis suggested a possible paracentric inversion involving the 1q24-q43 region of chromosome 1 in the child, while both parents had normal karyotypes. WES did not identify definite pathogenic or likely pathogenic point mutations strongly associated with the patient’s phenotype. However, heterozygous variants in * SYNE1* , * PEX2 *, * COLQ * and * RBBP8 * genes were detected, which were all inherited from phenotypically unaffected parents. In addition, WES copy number analysis suggested a single copy deletion in 1q24.2-q25.1 region. OGM further revealed a deletion of approximately 4.6 Mb on the long arm of chromosome 1 (1q), accompanied by a complex rearrangement involving breakpoint rejoining. This de novo event encompasses multiple genes associated with nervous system development, cellular metabolism, and cellular function. Functional enrichment and interaction network analysis of the deleted genes showed that most of the deleted genes were concentrated in the functional classification of basic life activities such as metabolic regulation, immune-related processes, mRNA metabolism and protein synthesis, with multi-pathway and non-specific functional disorders. This study suggests that in children with complex neurodevelopmental disorders, a single-gene point mutation may not fully explain the clinical manifestations, and complex chromosomal structural abnormalities and CNVs may be the main causes. Integrating WES and OGM enables more accurate identification and interpretation of complex structural abnormalities. This approach improves genetic diagnosis and supports mechanistic studies of rare neurodevelopmental disorders.