RESUMO
The clinical diagnosis criteria for CHARGE syndrome have been revised several times in the last 25 years. Variable expressivity and reduced penetrance are known, particularly in mild and familial cases. Therefore, it has been proposed to include the detection of a pathogenic CHD7 variant as a major diagnostic criterion. However, intronic variants not located at the canonical splice site are still underrepresented in mutation databases, often because functional analysis is not performed in the diagnostic setting. Here, we report a two-generation family that did not meet the criteria for CHARGE syndrome, until the molecular findings were taken into account. By exome sequencing, we detected an intronic variant in a male individual, who presented with unilateral external ear malformation, bilateral semicircular canal aplasia, polydactyly, vertebral body fusion and a heart defect. The variant was inherited by his mother, who also had bilateral semicircular canal aplasia additionally to unilateral sensorineural hearing impairment, unilateral mandibular palpebral synkinesia, orofacial cleft, and dysphagia. Using RNA studies, we were able to demonstrate that aberrant splicing occurs at an upstream cryptic splice acceptor site, resulting in a frameshift and premature stop of translation. Our data show causality of the noncanonical intronic CHD7 variant and end the diagnostic odyssey of this unsolved phenotype of the family.