The Prevalence And Phenotypic Heterogeneity Of Recurrent 16p11.2 Microdeletion In Children With Intellectual Disability/Developmental Retardation

Objective:The prevalence of recurrent 16p11.2 microdeletion syndrome in children with unknown intellectual disability/developmental delay（ID/DD）and the extensive phenotypic variability and diverse clinical phenotypes in the subjects with 16p11.2microdeletionwereinvestigated.The underlying genetic mechanismof neuropsychiatric-developmental disorders in the patients with 16p11.2 microdeletion was identified.Method:1.The peripheral blood of 318 patients with unknown ID/DD were determined from department of pediatric neurology,Affiliated Children’s Hospital of Capital Institute of of Pediatrics to find 16p11.2 microdeletion by array-CGH.2.The clinical data of the 11 family members of cases with recurrent 16p11.2microdeletion syndrome were collected.The 16p11.2 deletion in all family members was screening by array-CGH or multiplex ligation-dependent probe amplification.3.The genome-wide RNA expression profiling analysis in two families was performed,and then whether there was different gene expression between the subjects with and without 16p11.2 microdeletion was identified by bioinformational softwares（IPA and i Report）.4.We performed the target sequencing of the 25 genes residing within the16p11.2 microdeletion by Ion Torrent PGM^TM in the three pedigrees.Results:1.We identified three unrelated cases carrying recurrent 16p11.2 microdeletion in 318 children with unknown ID/DD,of which prevalence of carrying 16p11.2microdeletion in subjects with unknown ID/DD was 0.94%.2.In the three families of 11 members,we found seven subjects with 16p11.2microdeletion,of which there were normal phenoltype in 3 cases and neuropsychiatric-developmental disorders in 4.3.Based on the whole genome expression profiling,we revealed that expression of seven genes,which were SPN,ALDOA,PPP4C,MVP,TAOK2,KIF22 and PAGR1,’were decreased due to the 16p11.2 microdeletion.4.By next gene sequencing,we didn’t detect any pathogenic,rare mutation in the patients.However,we found the obvious difference of some haplotype genes between the patients and carriers,which includes SEZ6L2,TAOK2,DOC2A,KCTD13and TMEM219.The C-A-C risk haplotype in single nucleotide polymorphism rs3814883 and rs4077410 in the TAOK2 gene and rs3935873 in the DOC2A were consistent with the three patients,and the T-G-T protective haplotype were identical to the two normal carriers.Conclusions:1.The prevalence of 16p11.2 microdeletion among the 318 children with unknown ID/DD is 0.94%.2.The subjects with 16p11.2 microdeletion manifested diverse clinical phenotypes.3.The pathogenic mechanism in recurrent 16p11.2 microdeletion syndrome is complex.The copy number variation of some genes（SPN,ALDOA,PPP4C,MVP,TAOK2,KIF22 and PAGR1）would be resulted from 16p11.2 microdeletion.The halopytypes of some genes within the residual 16p11.2 region may co-contribute to different neuropsychiatric-developmental phenotypes in the subjects with 16p11.2microdeletion.4.We inferred from our pedigree study that the C-A-C haplotype may be a risk factor for neuropsychiatric-developmental disorders,and the T-G-T haplotype a protective factor for normal.5.When the children manifest ID/DD combined with ASD or congenital Scoliosis,recurrent 16p11.2 microdeletion syndrome is possibly indicated and array-CGH/MLPA could be recommended as a confirmatory test.