A 2-month-old boy born to non-consanguineous parents presents with bilateral choanal atresia requiring emergency airway management. On examination, he has bilateral iris colobomas, cup-shaped ears with ossicular malformations, and a ventricular septal defect on echocardiography. Genetic testing reveals a heterozygous loss-of-function mutation in the gene located at the region marked **A** in the diagram. Which of the following best describes the pathogenic mechanism of this disorder?
A. Trinucleotide repeat expansion affecting DNA methylation in the neural crest
B. Haploinsufficiency of a chromatin-remodeling ATPase essential for neural-crest migration and otic/ocular development
C. Complete loss of function of a transcription factor required for pharyngeal pouch development
D. Microdeletion affecting the TBX1 gene and disrupting conotruncal cardiac development
Explanation
Why "Haploinsufficiency of a chromatin-remodeling ATPase essential for neural-crest migration and otic/ocular development" is right
The region marked A (8q12.2) harbors the CHD7 gene, which encodes chromodomain helicase DNA-binding protein 7, a chromatin-remodeling ATPase. CHARGE syndrome results from heterozygous loss-of-function mutations in CHD7 in ~65–70% of cases. The pathogenic mechanism is haploinsufficiency—a single functional copy is insufficient to support normal neural-crest migration and the development of structures derived from the neural crest, including the inner ear (semicircular canals, cochlea), eye (retina, optic disc), and cardiac neural crest (conotruncal septation). The clinical presentation in this case—colobomas, choanal atresia, ossicular malformations, and VSD—is pathognomonic for CHARGE syndrome caused by CHD7 mutation (Nelson Textbook of Pediatrics, 21st ed.).
Why each distractor is wrong
Complete loss of function of a transcription factor required for pharyngeal pouch development: While pharyngeal structures are affected in CHARGE (choanal atresia), the mechanism is not complete loss of function (heterozygous mutations are sufficient to cause disease) and CHD7 is a chromatin remodeler, not a transcription factor. This describes a different class of genetic defect.
Trinucleotide repeat expansion affecting DNA methylation in the neural crest: CHARGE syndrome is caused by point mutations or small indels leading to haploinsufficiency, not trinucleotide repeats. Trinucleotide repeat disorders (e.g., Fragile X) have a different inheritance pattern and pathogenic mechanism.
Microdeletion affecting the TBX1 gene and disrupting conotruncal cardiac development: TBX1 mutations/deletions occur in 22q11.2 deletion syndrome (DiGeorge syndrome), which is marked as region C in the diagram. While both CHARGE and DiGeorge present with conotruncal defects, DiGeorge lacks the characteristic colobomas and semicircular canal hypoplasia of CHARGE, and the genetic locus is different.
