Abstract
BackgroundIntellectual disability/developmental delay is a complex condition with extraordinary heterogeneity. A large proportion of patients lacks a specific diagnosis. Next generation sequencing, enabling identification of genetic variations in multiple genes, has become an efficient strategy for genetic analysis in intellectual disability/developmental delay.MethodsClinical data of 112 Chinese families with unexplained intellectual disability/developmental delay was collected. Targeted next generation sequencing of 454 genes related to intellectual disability/developmental delay was performed for all 112 index patients. Patients with promising variants and their other family members underwent Sanger sequencing to validate the authenticity and segregation of the variants.ResultsFourteen promising variants in genes EFNB1, MECP2, ATRX, NAA10, ANKRD11, DHCR7, LAMA1, NFIX, UBE3A, ARID1B and PTPRD were identified in 11 of 112 patients (11/112, 9.82%). Of 14 variants, eight arose de novo, and 13 are novel. Nine patients (9/112, 8.03%) got definite molecular diagnoses. It is the first time to report variants in EFNB1, NAA10, DHCR7, LAMA1 and NFIX in Chinese intellectual disability/developmental delay patients and first report about variants in NAA10 and LAMA1 in affected individuals of Asian ancestry.ConclusionsTargeted next generation sequencing of 454 genes is an effective test strategy for patients with unexplained intellectual disability/developmental delay. Genetic heterogenicity is significant in this Chinese cohort and de novo variants play an important role in the diagnosis. Findings of this study further delineate the corresponding phenotypes, expand the mutation spectrum and support the involvement of PTPRD in the disease.
Highlights
Intellectual disability/developmental delay is a complex condition with extraordinary heterogeneity
Intellectual disability/developmental delay (ID/DD) is a common group of neurodevelopmental disorders with a prevalence of 1% ~ 3%, which starts before the age of 18 years and is characterized by substantial limitations in intellectual functioning and adaptive behavior [1]
Variants were annotated by Variant Effect Predictor [10] and filtered according to the following criteria: 1) nonsynonymous SNV or indel located in exonic or splicing regions; 2) absent from controls or allele frequency < 0.01 and no homozygotes or hemizygotes if recessive in Exome Sequencing Project (ESP) [11], 1000 Genomes Project (1000G) [12], Exome Aggregation Consortium (ExAC) or Genome Aggregation Database [13]; 3) predicted to be damaging by at least four of the following six software: SIFT [14], Polyphen2 [15], Mutationtaster [16], CADD [17], M-CAP [18], Condel [19] and PROVEAN [20]
Summary
Intellectual disability/developmental delay is a complex condition with extraordinary heterogeneity. A large proportion of patients lacks a specific diagnosis. Generation sequencing, enabling identification of genetic variations in multiple genes, has become an efficient strategy for genetic analysis in intellectual disability/ developmental delay. Intellectual disability/developmental delay (ID/DD) is a common group of neurodevelopmental disorders with a prevalence of 1% ~ 3%, which starts before the age of 18 years and is characterized by substantial limitations in intellectual functioning and adaptive behavior [1]. Discerning the precise genetic causes of ID/DD patients will inform prognosis, management and therapy, enable access to disorder-specific support groups, and facilitate family planning [3]. Due to extreme genetic heterogeneity, genetic causes are remaining to be clarified in most ID/DD patients [4]
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