From Array-CGH to Whole-Genome Sequencing: A 29-Year Diagnostic Journey Culminating in the Identification of a De Novo ABCC9 Variant Consistent with Cantú Syndrome

Background and Clinical Significance: Cantú syndrome (OMIM #239850) is a rare autosomal dominant disorder caused by gain-of-function variants in ABCC9 or KCNJ8, which encode subunits of the ATP-sensitive potassium (KATP) channel. Its characteristic features—generalized hypertrichosis, coarse facial appearance, skeletal abnormalities, and cardiovascular involvement—may be overlooked when other major comorbidities dominate the clinical picture. Case Presentation: A 29-year-old Taiwanese woman, born prematurely and complicated by neonatal hydrocephalus with subdural hemorrhage requiring ventriculoperitoneal shunt placement, had been followed since infancy under a working diagnosis of cerebral palsy with left hemiparesis and borderline-to-mild intellectual disability. Over the ensuing years, additional features gradually emerged, including generalized hypertrichosis with thick scalp and body hair, coarse facial features, bilateral hallux valgus, mild thoracic scoliosis, polycystic ovaries, mild aortic regurgitation, recurrent hemoptysis associated with abnormal pulmonary vasculature, and iron-deficiency anemia. Earlier genetic investigations—including chromosome analysis (46,XX), array comparative genomic hybridization (array-CGH; 2013), and a trio-based next-generation sequencing study performed under a national rare disease research initiative (2019)—were unrevealing. Whole-genome sequencing performed in December 2025 identified a heterozygous ABCC9 variant (NM_020297.4:c.4174A>G, p.(Ile1392Val)), initially classified as a variant of uncertain significance. Parental Sanger sequencing confirmed the variant to be de novo, and reclassification according to ACMG/AMP criteria supported a likely pathogenic interpretation. Re-evaluation of the patient’s phenotype demonstrated findings consistent with Cantú syndrome. Conclusions: This case illustrates how Cantú syndrome may remain unrecognized for years when a prominent neurological comorbidity—perinatally acquired hydrocephalus and presumed cerebral palsy—dominates the clinical narrative. We report a previously undescribed de novo ABCC9 missense variant (c.4174A>G, p.(Ile1392Val)), thereby expanding the mutational spectrum associated with Cantú syndrome. This case also highlights the practical value of resequencing and periodic reanalysis using updated next-generation sequencing platforms in patients with long-standing undiagnosed disease, even after prior negative genetic testing.