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Despite advances in diagnostic methods, ~50% of individuals with ID remain without a molecular diagnosis. Genome sequencing (GS) can detect variant classes poorly captured by other methodologies, including deep intronic splice changes and structural variants. We performed short\u2010read GS on 38 Iranian autosomal recessive intellectual disability (ARID) families that remained unsolved after exome sequencing (ES) and two phases of reanalysis. Sequencing and variant calling were performed on DRAGEN Bio\u2010IT Platform with GRCh38 and variants were annotated in Golden helix Varseq software and the AnnotSV tool. GS yielded diagnoses in 2 of 38 families (5.3%), identifying a homozygous deep\u2010intronic\n                    <jats:italic>ATP8A2<\/jats:italic>\n                    variant (c.1473 + 519C &gt; T) that creates a cryptic donor site and a 57\u2010bp pseudoexon, and a homozygous ~103\u2010kb\n                    <jats:italic>CNTNAP2<\/jats:italic>\n                    deletion removing the in\u2010frame Exon 2. Additionally, GS uncovered a homozygous\n                    <jats:italic>NCOR1<\/jats:italic>\n                    missense variant that represents a novel candidate gene for ARID, but further studies are required to confirm the gene\u2013disease association. The\n                    <jats:italic>ATP8A2<\/jats:italic>\n                    and\n                    <jats:italic>CNTNAP2<\/jats:italic>\n                    variants were uniquely detectable by GS. In conclusion, in a challenging, ES\u2010negative ARID cohort, GS provided an additional ~5.3% diagnostic yield by uncovering a noncoding splice alteration and a large intragenic deletion. These results underscore GS as a valuable, though still modest, tool over ES and highlight significant interpretation challenges in noncoding regions. Continued advances in functional assays and complementary long\u2010read technologies will be essential to further reduce the diagnostic gap in unresolved ID.\n                  <\/jats:p>","DOI":"10.1155\/humu\/4623457","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T11:41:56Z","timestamp":1782906116000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Diagnostic Yield of Genome Sequencing in an Iranian Exome\u2010Negative Autosomal\u2010Recessive Intellectual Disability Cohort"],"prefix":"10.1155","volume":"2026","author":[{"given":"Ebrahim","family":"Shokouhian","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masoumeh","family":"Moslemi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8076-4279","authenticated-orcid":false,"given":"Masoumeh 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