Clinical manifestations of chromosome 19p13.11 duplication

Chromosome 19 is the most gene-dense chromosome in the human genome, with a high frequency of segmental duplications that predispose it to genomic rearrangements. While deletions of chromosome 19 have been associated with various clinical conditions, duplications remain poorly characterised. Here, we report three cases involving 19p13.11 duplication and describe the associated clinical phenotype.

We describe three unrelated individuals with microduplications at 19p13.11 identified either via clinical whole-exome sequencing or chromosomal microarray. The probands underwent detailed clinical genetic evaluations, and CNVs were confirmed with parental testing when available. Sequencing reads were aligned to the GRCh37/hg19 human genome build.

All three probands exhibited neurodevelopmental delays, attention-deficit/hyperactivity disorder and speech delay. Additional overlapping features included joint hypermobility, short stature and craniofacial anomalies. Patient-specific manifestations included haematological abnormalities, musculoskeletal asymmetries and cardiac findings. Duplicated regions spanned 1.2-1.6 Mb and encompassed 41-49 protein-coding genes. Patients 2 and 3 have CNVs that overlap 76% with those of Patient 1. Several genes have predicted high triplosensitivity scores and are associated with autosomal dominant neurodevelopmental and skeletal disorders. Patient 1, with the largest duplication, had more extensive systemic involvement, likely reflecting the broader gene dosage effect.

This is the first comprehensive clinical and molecular characterisation of 19p13.11 duplications, suggesting a recurring multisystem phenotype driven by gene dosage sensitivity. These findings support the inclusion of 19p13.11 duplications in diagnostic evaluations for neurodevelopmental and multisystem disorders.