Exome Sequencing Reveals a Monogenic Cause for Syndromic Intellectual Disability in >50% of cases: Preliminary Results of 176 Consecutive Trios

בן פודה-שקד ^1,2,3,7 Ortal Barel ⁴ Bruria Ben-Zeev ^5,7 Annick Raas-Rothschild ^2,7 Moshe Friedman ^1,7 Miriam Regev ^1,7 Hani Poran ^1,7 Yael Finezilber ^1,7 Aviva Eliyahu ^1,7 Mordechai Shohat ^4,7 Gali Heimer ^3,5,7 Michal Tzadok ^5,7 Omer Bar-Yosef ^3,5,7 Andreea Nissenkorn ^5,7 Gideon Rechavi ^4,7 Elon Pras ^1,7 Amihood Singer ⁶ Lior Greenbaum ^1,7

¹The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel-Hashomer, ישראל
²The Institute for Rare Diseases, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, ישראל
³The Talpiot Medical Leadership Program, Sheba Medical Center, Tel-Hashomer, ישראל
⁴Sheba Cancer Research Center, Sheba Medical Center, Tel-Hashomer, ישראל
⁵Pediatric Neurology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, ישראל
⁶Community Genetics, Public Health Services, Ministry of Health, Jerusalem, ישראל
⁷Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, ישראל

Background: Neurodevelopmental disorders are a wide and heterozygous group of conditions, many of which caused by monogenic etiologies. The growing availability of Whole Exome Sequencing (WES) has revolutionized the field of medical genetics and significantly shortened the diagnostic odyssey for many affected families. We report the preliminary results of a governmentally-funded pilot at the Sheba Medical Center, aimed at elucidating the molecular basis of syndromic intellectual disability (ID) and/or multiple congenital anomalies.

Methods: Whole exome sequencing (WES) was pursued for probands and their parents (trio-WES) in a real-life setting of a large tertiary hospital. Inclusion criteria were severe ID (DQ<54); Mild-moderate ID (DQ<71) with dysmorphic features, epilepsy or major congenital anomaly; or multiple congenital anomalies. A chromosomal microarray analysis (CMA) which was found normal or did not explain the phenotype, and normal Fragile X testing were additional prerequisites for inclusion in the study.

Results: A total of 176 trios were included in the study. Of these, analysis was completed for 144 trios. Molecular diagnosis was reached in 53% (77/144) of cases, and 25 additional trios are pending. Most pathogenic variants were de-novo. Genes implicated in multiple probands included ARID1B (associated with Coffin-Siris syndrome), TCF4 (Pitt-Hopkins syndrome), AHDC1 (Xia-Gibbs syndrome), PPP2R5D, KCNQ2, KMT5B, STXBP1 and SMC1A (Cornelia de-Lange syndrome).

Conclusion: Our findings underscore the diagnostic role of WES in cases of intellectual disability with or without accompanying dysmorphic features, congenital anomalies and/or seizures. The diagnostic yield in our cohort is higher than previously reported, due in part to patient selection.