Clinical and neurodevelopmental features of chromosome 1 copy number variations in children

Copy number variations (CNVs) constitute a significant component of genomic variation and are implicated in the etiopathogenesis of neurodevelopmental and congenital disorders. Chromosome 1, the largest chromosome in the human genome, contains numerous dosage-sensitive regions, and CNVs affecting this chromosome are associated with a broad clinical spectrum. This study aimed to contribute to the delineation of the chromosome 1 disease map through a comprehensive analysis of individuals with chromosome 1 CNVs.

Among 1480 individuals who underwent chromosomal microarray analysis, twenty individuals with pathogenic or likely pathogenic CNVs involving chromosome 1 were retrospectively evaluated, including 19 postnatal patients and one prenatally diagnosed fetus.

CNVs were located on the short arm (1p) in ten patients and on the long arm (1q) in ten. Deletions predominated (18/20), whereas duplications were detected in two patients. The most frequently affected regions were 1q21, 1p36, and 1p31. Neurodevelopmental delay, language impairment, and intellectual disability were the most common clinical features, accompanied by behavioral problems, microcephaly, or epilepsy. Segregation analysis revealed that 13 CNVs were de novo, while 4 were inherited from clinically asymptomatic parents, indicating variable expressivity and reduced penetrance. One patient exhibited a mosaic 1p21.1-p11.2 duplication. Additionally, a homozygous deletion involving HMGCS2, consistent with mitochondrial HMG-CoA synthase deficiency, was detected in a consanguineous family.

This study highlights the clinical and molecular heterogeneity of chromosome 1 CNVs and underscores the diagnostic value of chromosomal microarray analysis in children with unexplained neurodevelopmental disorders. Our findings further expand the genotype-phenotype spectrum and emphasize the importance of considering inheritance patterns and mosaicism in the interpretation of CNVs.