Beyond CHD7 gene: unveiling genetic diversity in clinically suspected CHARGE syndrome

The Verloes or Hale diagnostic criteria have been applied for diagnosing CHARGE syndrome in suspected patients. This study was conducted to evaluate the diagnostic rate of CHD7 according to these diagnostic criteria in suspected patients and also to investigate other genetic defects in CHD7-negative patients. The clinical findings and the results of genetic testing of CHD7, chromosome microarray, exome sequencing, or genome sequencing of 59 subjects were reviewed. CHD7 pathogenic variants were identified in 78% of 46 subjects who met either the Verloes or Hale diagnostic criteria and in 87% of 38 subjects who met both criteria, whereas no CHD7 variant was detected in 13 subjects who met neither criterion. Among 23 patients without the CHD7 variant, six genetic diseases were identified in 7 patients, including Wolf-Hirschhorn syndrome, 1q21 deletion syndrome, 19q13 microdeletion, and pathogenic variants in PLCB4, TRRAP, and OTX2. Based on these comprehensive analyses, the overall diagnostic rate was 73% for seven different genetic diseases. This study emphasizes the importance of comprehensive clinical and genetic evaluation in patients with clinically suspected CHARGE syndrome, recognizing the overlapping phenotypes in other rare genetic disorders.