AUTHOR=Han Ji Yoon , Jang Ja Hyun , Park Joonhong , Lee In Goo 

TITLE=Targeted Next-Generation Sequencing of Korean Patients With Developmental Delay and/or Intellectual Disability

JOURNAL=Frontiers in Pediatrics

VOLUME=6

YEAR=2018

URL=https://www.frontiersin.org/journals/pediatrics/articles/10.3389/fped.2018.00391

DOI=10.3389/fped.2018.00391

ISSN=2296-2360

ABSTRACT=<p><bold>Background:</bold> Differential diagnosis of developmental delay (DD) and/or intellectual disability (ID) is challenging because of the diversity of phenotypic manifestations as DD/ID patients usually have combined congenital malformations, autism-spectrum disorders, and/or seizure disorder. Thus, unbiased genomic approaches are needed to discover genetic alterations leading to DD and/or ID.</p><p><bold>Objective:</bold> The aim of this study was to investigate the clinical usefulness of targeted next-generation sequencing (NGS) to investigate genetic causes in 35 Korean patients with unexplained DD/ID.</p><p><bold>Methods:</bold> Targeted next-generation sequencing (NGS) using the TruSight One Panel was analyzed in 35 patients with unexplained DD/ID. Sanger sequencing was used to confirm candidate variants, and to define genetic inheritance mode of candidate variant as familial segregation testing.</p><p><bold>Results:</bold> Of 35 patients with DD and/or ID, 10 were found to have underlying genetic etiology and carried X-linked recessive inheritance of <italic>ZDHHC9</italic> or autosomal dominant inheritance of <italic>SMARCB1, CHD8, LAMA5, NSD1, PAX6, CACNA1H, MBD5, FOXP1</italic>, or <italic>KCNK18</italic> mutations. No autosomal recessive inherited mutation was identified in this study. As a result, the diagnostic yield of DD/ID by targeted NGS was 29% (10/35), mostly involving may be <italic>de novo</italic> mutation present in the proband only. A total of seven may be <italic>de novo</italic> mutations, one paternally inherited, and one maternally inherited mutations that had been reported previously to concede the genetic pathogenesis as known DD and/or ID genes were found in nine patients with available inheritance pattern except <italic>LAMA5</italic>. Mutations in nine causative genes were detected in patients with similar DD/ID phenotypes in the OMIM database, providing support for genetic evidence as the cause of DD and/or ID.</p><p><bold>Conclusion:</bold> Targeted NGS through singleton analysis with phenotype-first approaches was able to explain 10 out of 35 DD/ID cases. However, the excavation of plausible genetic causes may be <italic>de novo</italic>, and X-linked disease-causative variants in DD/ID-associated genes requires further genetic analysis.</p>