The deficiency of DIP2C leads to congenital heart defects in patients with 10p15.3 microdeletion syndrome.

BACKGROUND

Recurrent 10p15.3 microdeletion syndrome is a rare multisystem disorder characterized by abnormal facial features, global developmental delay (DD)/intellectual disability (ID), short stature, hand/foot malformation, and congenital heart defects (CHDs). However, the specific genetic defects that contribute to the cardiac phenotype remain unclear.

METHODS

We explored the genetic cause of CHDs in 10p15.3 microdeletion syndrome. Antisense morpholino oligonucleotide (MO)-mediated knockdown of dip2ca in zebrafish and rescue experiments in zebrafish were conducted to observe the role of dip2ca in regulating cardiac growth. Expression profile analysis was conducted between the dip2ca-MO group and the control group.

RESULTS

We report one male proband presenting a distinctive facial appearance, heterotropia, global DD/ID, congenital talipes equinovarus (CTEV), and atrial septal defect (ASD), who had a de novo 6.44 Mb microdeletion overlapping 10p15.3. We identified Disco Interacting Protein 2 Homolog C (DIP2C) as a putative candidate gene underlying CHDs by reviewing the 10p15.3 microdeletion cases with or without CHDs and performing candidate gene functional analysis. MO-mediated knockdown of dip2ca in zebrafish resulted in developmental defects consistent with the range of 10p15.3-associated human phenotypes include decreased body length, craniofacial malformations, and heart defects, including pericardial edema, a linear heart tube, looping defects, and arrhythmia. Coinjection of wild-type dip2ca mRNA with dip2ca-MO partially rescued these detects. Transcriptome analysis revealed the expression of zebrafish foxj1a increased in the dip2ca-MO zebrafish and was associated with cardiac looping.

CONCLUSIONS

This study expands the understanding of pathogenic genetic factors involved in 10p15.3 microdeletion syndrome and suggests that DIP2C plays an important role in heart development, especially with respect to cardiac looping.