Phenotypic spectrum of 1q21.1 copy number variants in 42 children: genotype-phenotype correlations and clinical implications.

UNLABELLED: Chromosome 1q21.1 copy number variants (CNVs) are associated with a broad and variable clinical spectrum encompassing neurodevelopmental, anthropometric, and systemic anomalies. The incomplete penetrance and variable expressivity of these rearrangements pose significant challenges for clinical interpretation and genotype-phenotype correlation. We retrospectively analyzed 42 pediatric patients with 1q21.1 CNVs, identified by chromosomal microarray analysis (CMA), evaluated at a single tertiary center between 2019 and 2025. Patients were classified according to CNV type and localization: distal deletions (n = 30), distal duplications (n = 7), proximal deletions (n = 3), and proximal duplications (n = 2). Clinical findings were compared according to CNV type, sex, inheritance pattern, parental origin, and deletion size. The median age at presentation was 27 months. Among distal deletion carriers, microcephaly (60.0%), short stature (40.0%), and developmental delay (39.3%) were the most frequently observed findings. Cardiac anomalies were present in 34.5% of deletion patients, with two patients dying due to severe cardiac complications during follow-up. Macrocephaly was identified exclusively in duplication carriers (28.6%), corroborating the mirror phenotype of reciprocal 1q21.1 rearrangements. Developmental delay was significantly more frequent in duplication compared with deletion carriers (85.7% vs. 39.3%; p = 0.041). Cardiac anomalies were significantly more common in female patients (p < 0.05). No significant differences were identified according to inheritance status, parental origin, or deletion size, reflecting the variable expressivity of this locus. One proximal deletion patient was diagnosed with TAR syndrome through combined microarray and exome sequencing, confirming the two-hit molecular mechanism involving a 1q21.1 deletion and a pathogenic RBM8A variant.

CONCLUSION: This study delineates the broad phenotypic spectrum of 1q21.1 CNVs in a pediatric cohort, highlighting microcephaly and cardiac anomalies as clinically significant findings and reinforcing the mirror phenotype of reciprocal rearrangements. The absence of consistent genotype-phenotype correlations underscores the contribution of modifier factors beyond the CNV itself. Routine cardiac evaluation and multidisciplinary follow-up are recommended for all carriers.

WHAT IS KNOWN: • Distal 1q21.1 CNVs cause microcephaly, developmental delay, and cardiac anomalies with incomplete penetrance and variable expressivity. • Reciprocal rearrangements show a mirror phenotype: microcephaly in deletion and macrocephaly in duplication carriers.

WHAT IS NEW: • This is among the few single-center cohorts characterizing all four 1q21.1 CNV subtypes in a pediatric series. • Cardiac anomalies were more frequent in female carriers, a sex-specific observation warranting further investigation. • Inheritance status, parental origin, and deletion size did not appear to significantly influence clinical phenotype.