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Peer-reviewedCC BY 4.0BMC Psychiatry

Whole-exome sequencing in a Turkish autism spectrum disorder cohort: a retrospective study of molecular diagnostic yield in isolated and complex presentations

  • Mehmet Burak Mutlu1
  • Aslıhan Sanrı2
  • Oğuzhan Yaralı3
  • Özlem Sezer4
  • Fethiye Kılıçaslan5
  • Hakan Gümüş6
  • Sefer Kumandaş6
  • Özlem Öz7
7 affiliations
  1. 1Detagen Genetic Diseases Evaluation Center, Tacettin Veli, Deliklitaş Cd. No: 12/A, Melikgazi, Kayseri 38000 Türkiye
  2. 2Department of Pediatric Genetics, Samsun Education and Research Hospital, Samsun, Türkiye
  3. 3Department of Medical Genetics, Erzurum Regional Training and Research Hospital, Erzurum, Türkiye
  4. 4Department of Medical Genetics, Samsun University Faculty of Medicine, Samsun, Türkiye
  5. 5Department of Child and Adolescent Psychiatry, Faculty of Medicine, Harran University, Şanlıurfa, Türkiye
  6. 6Department of Pediatrics, Division of Pediatric Neurology, Faculty of Medicine, Erciyes University, Kayseri, Türkiye
  7. 7Department of Medical Genetics, Harran University Faculty of Medicine, Şanlıurfa, Türkiye
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Abstract

Background: Whole-exome sequencing (WES) can identify molecular etiologies in autism spectrum disorder (ASD), particularly when ASD occurs with developmental delay/intellectual disability (DD/ID), epilepsy, dysmorphism, congenital anomalies, or neuroimaging abnormalities. Data on WES yield and candidate-gene findings in Turkish ASD cohorts remain limited. We assessed molecular diagnostic yield and variant spectrum in a Turkish clinical ASD cohort, with comparison of isolated and complex ASD presentations.

Methods: This retrospective cohort study included 320 individuals with ASD evaluated by WES between 2020 and 2025. Patients were classified as having isolated or complex ASD based on co-occurring neurodevelopmental, neurological, dysmorphic, congenital, or systemic findings. Variants were interpreted using ACMG/AMP criteria. Established molecular diagnoses required pathogenic or likely pathogenic (P/LP) variants associated with OMIM-defined disorders or occurring in genes with definitive, strong, or moderate ClinGen evidence for a neurodevelopmental disorder (NDD). Categorical comparisons used two-sided Fisher’s exact test.

Results: Established molecular diagnoses were identified in 104/320 patients (32.5%; 95% confidence interval [CI], 27.4–37.9%), including 2/22 patients with isolated ASD (9.1%; 95% CI, 1.1–29.2%) and 102/298 patients with complex ASD (34.2%; 95% CI, 28.9–39.9%; p = 0.017). An additional 12 patients had P/LP variants in candidate or emerging genes, resulting in an overall P/LP finding rate of 116/320 (36.3%; 95% CI, 31.0–41.8%). Variants of uncertain significance were identified in 147 patients, while no ASD/NDD-related variant was identified in 57 patients.

Conclusions: WES supports etiological clarification in clinically complex ASD. Established molecular diagnoses were substantially more frequent in complex than isolated ASD. Candidate and emerging gene findings should be reported separately and interpreted as hypothesis-generating.

Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12888-026-08739-x.

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Cite

BibTeXRIS
BibTeX
@article{mutlu2026wholeexome,
  title = {{Whole-exome sequencing in a Turkish autism spectrum disorder cohort: a retrospective study of molecular diagnostic yield in isolated and complex presentations}},
  author = {Mehmet Burak Mutlu and Aslıhan Sanrı and Oğuzhan Yaralı and Özlem Sezer and Fethiye Kılıçaslan and Hakan Gümüş and Sefer Kumandaş and Özlem Öz},
  journal = {BMC Psychiatry},
  year = {2026},
  month = oct,
  doi = {10.1186/s12888-026-08739-x},
  url = {https://doi.org/10.1186/s12888-026-08739-x},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Whole-exome sequencing in a Turkish autism spectrum disorder cohort: a retrospective study of molecular diagnostic yield in isolated and complex presentations
AU  - Mehmet Burak Mutlu
AU  - Aslıhan Sanrı
AU  - Oğuzhan Yaralı
AU  - Özlem Sezer
AU  - Fethiye Kılıçaslan
AU  - Hakan Gümüş
AU  - Sefer Kumandaş
AU  - Özlem Öz
PY  - 2026
DA  - 2026/10/13
JO  - BMC Psychiatry
DO  - 10.1186/s12888-026-08739-x
UR  - https://doi.org/10.1186/s12888-026-08739-x
AB  - Background: Whole-exome sequencing (WES) can identify molecular etiologies in autism spectrum disorder (ASD), particularly when ASD occurs with developmental delay/intellectual disability (DD/ID), epilepsy, dysmorphism, congenital anomalies, or neuroimaging abnormalities. Data on WES yield and candidate-gene findings in Turkish ASD cohorts remain limited. We assessed molecular diagnostic yield and variant spectrum in a Turkish clinical ASD cohort, with comparison of isolated and complex ASD presentations.  Methods: This retrospective cohort study included 320 individuals with ASD evaluated by WES between 2020 and 2025. Patients were classified as having isolated or complex ASD based on co-occurring neurodevelopmental, neurological, dysmorphic, congenital, or systemic findings. Variants were interpreted using ACMG/AMP criteria. Established molecular diagnoses required pathogenic or likely pathogenic (P/LP) variants associated with OMIM-defined disorders or occurring in genes with definitive, strong, or moderate ClinGen evidence for a neurodevelopmental disorder (NDD). Categorical comparisons used two-sided Fisher’s exact test.  Results: Established molecular diagnoses were identified in 104/320 patients (32.5%; 95% confidence interval [CI], 27.4–37.9%), including 2/22 patients with isolated ASD (9.1%; 95% CI, 1.1–29.2%) and 102/298 patients with complex ASD (34.2%; 95% CI, 28.9–39.9%; p = 0.017). An additional 12 patients had P/LP variants in candidate or emerging genes, resulting in an overall P/LP finding rate of 116/320 (36.3%; 95% CI, 31.0–41.8%). Variants of uncertain significance were identified in 147 patients, while no ASD/NDD-related variant was identified in 57 patients.  Conclusions: WES supports etiological clarification in clinically complex ASD. Established molecular diagnoses were substantially more frequent in complex than isolated ASD. Candidate and emerging gene findings should be reported separately and interpreted as hypothesis-generating.  Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12888-026-08739-x.
SN  - 1471-244X
ER  -