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Hum Mutat. 2019 Sep;40(9):1346-1363. doi: 10.1002/humu.23822. Epub 2019 Aug 2.

Characterization of intellectual disability and autism comorbidity through gene panel sequencing.

Author information

1
Molecular Genetics of Neurodevelopment, Department of Woman and Child Health, University of Padova, C.so Stati Uniti, 4, Padova, Italy.
2
Fondazione Istituto di Ricerca Pediatrica, Città della Speranza, Padova, Italy.
3
Department of Biomedical Sciences, University of Padova, Padova, Italy.
4
Medical Genetics Unit, Ospedale Universitario S. Anna, Ferrara, Italy.
5
Medical Genetics Unit, San Martino Hospital, Belluno, Italy.
6
Epilepsy and Child Neurophysiology Unit, Scientific Institute IRCCS E. Medea, Treviso, Italy.
7
Medical Genetics Unit, Dolo General Hospital, Venezia, Italy.
8
Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, University of Milano, Milan, Italy.
9
Child Neuropsychiatry Unit, Epilepsy Center, Department of Health Sciences, Santi Paolo-Carlo Hospital, University of Milano, Milano, Italy.
10
Division of Medical Genetics, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah.
11
Paediatric Neurology Unit, Department of Woman and Child Health, University Hospital of Padova, Padova, Italy.
12
Medical Genetics Department, APSS Trento, Trento, Italy.
13
Medical Genetics Unit, Local Health Authority, Treviso, Italy.
14
Genetic Counseling Service, Department of Pediatrics, Regional Hospital of Bolzano, Bolzano, Italy.
15
Bioinformatics Unit, Fundación Instituto Leloir, Buenos Aires, Argentina.
16
Institute of Neuroscience, National Research Council, Padova, Italy.

Abstract

Intellectual disability (ID) and autism spectrum disorder (ASD) are clinically and genetically heterogeneous diseases. Recent whole exome sequencing studies indicated that genes associated with different neurological diseases are shared across disorders and converge on common functional pathways. Using the Ion Torrent platform, we developed a low-cost next-generation sequencing gene panel that has been transferred into clinical practice, replacing single disease-gene analyses for the early diagnosis of individuals with ID/ASD. The gene panel was designed using an innovative in silico approach based on disease networks and mining data from public resources to score disease-gene associations. We analyzed 150 unrelated individuals with ID and/or ASD and a confident diagnosis has been reached in 26 cases (17%). Likely pathogenic mutations have been identified in another 15 patients, reaching a total diagnostic yield of 27%. Our data also support the pathogenic role of genes recently proposed to be involved in ASD. Although many of the identified variants need further investigation to be considered disease-causing, our results indicate the efficiency of the targeted gene panel on the identification of novel and rare variants in patients with ID and ASD.

KEYWORDS:

ASD; ID; NGS; comorbidity; gene panel; variant interpretation

PMID:
31209962
DOI:
10.1002/humu.23822

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