Treatment and Management – Clinical management is complicated by multiple diagnoses. Reviewing each condition individually helped guide treatment decisions but required accommodation for the unique phenotype resulting from multilocus genetic contributions. RPE65-related LCA and Klinefelter Syndrome have established clinical guidelines; the patient had prior gene therapy for LCA and follows with ophthalmology and the Emory eXtraordinarY clinic. White Sutton Syndrome (POGZ) and DHX9-related NDD are more recently described and have significant clinical overlap and variable expressivity. The patient had seen relevant specialists in neurology, ophthalmology, developmental pediatrics, GI, and ENT. Based on several reported cases with cardiac concerns in individuals with DHX9 variants, he was referred for an echocardiogram.

Outcome and Follow-Up – Four individual genetic diagnoses were identified in one patient, resulting in a complex, syndromic phenotype. Together, these explain all observed symptoms. Follow-up with relevant specialists, as needed, was recommended.

Discussion – This case demonstrates how pathogenic variation at multiple loci can produce a blended phenotype and increased clinical complexity. Overlapping features associated with POGZ, DHX9, RPE65, and Klinefelter may synergistically influence phenotypic expression. Although Klinefelter syndrome typically causes tall stature, this patient’s short stature and broader phenotype are better explained by coexisting monogenic conditions.
DHX9 and POGZ variants in isolation are typically associated with milder phenotypes, though severe presentations with absent speech and profound NDD have been reported. The combined effect of variants across multiple genes may account for this patient’s more severe phenotype.

Conclusion – The diagnostic odyssey for this patient included five different genetic testing methods, but detection of all genetic findings can now be accomplished with exome and microarray alone. This case supports the 2025 American Academy of Pediatrics genetic testing guidelines, which recommend concurrent microarray and exome sequencing as first-line tests for children with NDD or ID.

Introduction – Multiple genetic diagnoses in a single individual are increasingly recognized with the use of broader testing technologies. We report a 10-year-old patient with complex neurodevelopmental symptoms found to have four distinct genetic conditions. In 18,766 patients tested at a large diagnostic laboratory, 4 concurrent genetic diagnoses have been identified in only 9 cases (∼0.05%). This case provides an opportunity to examine the blended phenotype and management challenges resulting from multiple co-occurring genetic conditions.

Case Presentation – The patient presented to Emory Genetics at 10 years old due to Klinefelter Syndrome (47,XXY). At that time, clinicians noted clinical features beyond what could be explained by this diagnosis. The patient was non-verbal with intractable seizures (Lennox-Gastaut syndrome), motor delay, intellectual disability (ID), and autism; microcephaly and abnormal brain MRI demonstrating non-progressive white matter lesions; short stature (2nd percentile) and poor growth requiring G-Tube feeds from 6-8 years old; Leber Congenital Amaurosis (LCA), nystagmus and myopia; hypotonia; GI concerns including GERD, constipation and eosinophilic esophagitis; and sleep apnea requiring tonsillectomy and adenoidectomy, recurrent acute otitis media.

Diagnostic Workup
• RPE65 targeted testing (2014): familial variants detected in proband and sister
• Epilepsy Panel (302 genes, 2023): Negative
• Karyotype Chromosome Analysis (2023): confirmed 47,XXY
• SNV Array (Ambry- 2024): full X chromosome duplication consistent with Klinefelter syndrome (47,XXY)
• Trio Exome Sequencing (Ambry- 2024)
○ A full X chromosome gain, consistent with Klinefelter syndrome, was also detected on exome analysis.
○ Pathogenic de novo heterozygous DHX9 NM_001357.5: c.1704C>A p.Tyr568*, associated with DHX9-related Neurodevelopmental Disorder (NDD)
○ Likely pathogenic de novo heterozygous POGZ NM_015100.4 c.3540_3543del p.M1180Ifs*12, associated with White-Sutton Syndrome
○ Compound heterozygous Pathogenic variants in RPE65 NM_000329.3 c.11+5G>A and c.1249G>C p.E417Q, associated with RPE65-related retinopathy

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