Guidelines from the AAP, AAN, and ACMG recommend whole-genome or whole-exome sequencing with mitochondrial analysis for patients with GDD, ID, or congenital anomalies.  This genetic workup coupled with metabolic testing as outlined by Treatable-ID and TIDE protocol, is essential to identify an underlying etiology and enable early detection of treatable conditions. Complementary studies such as neuroimaging, EEG and lumbar puncture should be considered with follow- up until the evaluation is complete. 

In practice, shortages of specialists and long wait times cause behavioral diagnoses to be assigned without full diagnostic workup. Follow-up is often delayed by over a year or missed entirely, resulting in lost opportunities to detect underlying—and in some cases treatable—etiologies. This study aimed to apply guideline-based evaluations in an outpatient practice to assess feasibility in a resource-limited setting and potential benefits to patients.

• 1) Laboratory Testing: 95 patients completed baseline/metabolic labs; 50 (53%) had significant abnormalities, including low vitamin D, low omega-3, elevated lead, abnormal TFTs, elevated CK, and alanine/lysine ratios.
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• 2) Chromosomal Microarray: 51 tested; 1 (2%) pathogenic finding, 17 (33%) with VUS or long runs of homozygosity.
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• 3) Next-Generation Sequencing: 44 tested; 8 (18%) pathogenic and 16 (36%) VUS. Combined yield 54%, with variants in ID-associated genes such as SHANK2, MT-TL2, LRPPRC, PDHA1, STXBP1, GRIN2A, SPAST, FOXP4, and KCNC2.