P429: High-throughput sequencing technologies uncover a loss-of-function variant of the GATAB2B gene in a GAND patient

Case Presentation: A 16-month-old male presented in 1997 for evaluation of bilateral aniridia, microcephaly, external ear malformations, and developmental delays attributed to vision loss.By age 9, absent speech, intellectual disability, and autistic features were present.Oral aversion and limited jaw opening caused failure to thrive.Gastrostomy tube placement incidentally revealed intestinal malrotation.Skeletal abnormalities included shortened forearms and toes, and femoral anteversion.At age 21, he returned to clinic at which time he demonstrated profound vision loss and glaucoma after multiple retinal surgeries, severe pes cavus requiring multiple tendon releases, continued G-tube dependency, and confirmed autism.At age 29, he presented to clinic with onset of progressive spasticity.Diagnostic Workup: Initial workup included normal biochemical testing, EEG, and brain MRI.WAGR syndrome was suspected, which at that time was exclusively attributed to 11p13/PAX6 deletions.Microarray was normal.PAX6 sequencing revealed a novel missense variant (p.( Ile87Arg)), explaining his aniridia.His other anomalies and delays were tentatively attributed to PAX6, with limited gene-phenotype data at that time.By his return to clinic in 2022, PAX6 missense variant phenotypes were further delineated to include neurological abnormalities like cerebellar ataxia and cortical atrophy, in additional to ophthalmic abnormalities.Nevertheless, with multiple features remaining unexplained, further genetic testing was indicated.ES revealed a likely pathogenic variant in DYRK1A, establishing his second diagnosis: DYRK1A-related neurodevelopment disorder, characterized by gastrointestinal, skeletal, and neurological features.