Novel promoters and coding first exons in DLG2 linked to developmental disorders and intellectual disability

Abstract

BackgroundTissue-specific integrative omics has the potential to reveal new genic elements important for developmental disorders.MethodsTwo pediatric patients with global developmental delay and intellectual disability phenotype underwent array-CGH genetic testing, both showing a partial deletion of the DLG2 gene. From independent human and murine omics datasets, we combined copy number variations, histone modifications, developmental tissue-specific regulation, and protein data to explore the molecular mechanism at play.ResultsIntegrating genomics, transcriptomics, and epigenomics data, we describe two novel DLG2 promoters and coding first exons expressed in human fetal brain. Their murine conservation and protein-level evidence allowed us to produce new DLG2 gene models for human and mouse. These new genic elements are deleted in 90% of 29 patients (public and in-house) showing partial deletion of the DLG2 gene. The patients’ clinical characteristics expand the neurodevelopmental phenotypic spectrum linked to DLG2 gene disruption to cognitive and behavioral categories.ConclusionsWhile protein-coding genes are regarded as well known, our work shows that integration of multiple omics datasets can unveil novel coding elements. From a clinical perspective, our work demonstrates that two new DLG2 promoters and exons are crucial for the neurodevelopmental phenotypes associated with this gene. In addition, our work brings evidence for the lack of cross-annotation in human versus mouse reference genomes and nucleotide versus protein databases.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0452-y) contains supplementary material, which is available to authorized users.

Rare copy number variation in extremely impulsively violent males

“…The other 26 identified clinically relevant CNVs were private. The 19q11‐19q12 duplication, 16p12.1 microdeletion, microdeletions of DLG2 and ARID1B and microduplications of MTOR, ACMSD, MDGA2 and ZFYVE27 were present in individuals who also reported history of criminal conviction in their relatives, further supporting their either firmly established or highly suspected clinical relevance. For the remaining 18 clinically relevant CNVs, the criminal history of siblings was either not mentioned or denied.…”

“…There were 18 CNVs that affected genes definitively associated with AD neurologic phenotypes. These include: (a) a duplication impacting the open reading frame of KIF26B , which is associated with AD cerebellar ataxia (OMIM 614026); (b) a contiguous deletion of XPR1 associated with AD basal ganglia calcification (OMIM 605237) and LHX4 associated with AD combined pituitary hormone deficiency type 4 (MIM 262700); (c) a duplication impacting RAB39B and CLIC2 that was found in individuals with X‐linked intellectual and developmental disability; (d) a duplication impacting the open reading frame of KMT2C that has been associated with AD Kleefstra syndrome 2 (606833) and neurodevelopmental phenotypes; (e) a duplication impacting the open reading frame of CACNG2 associated with AD mental retardation 10 (OMIM 602911) and nonsyndromic intellectual disability; (f) a duplication impacting the open reading frame of MTOR associated with Smith‐Kingsmore syndrome (OMIM 616638); (g) a duplication impacting the open reading frame of CDK13 associated with AD intellectual developmental disorder (OMIM 617360) and behavioral problems; (h) a duplication of ZFYVE27 associated with AD spastic paraplegia 33 (MIM 610244), (i) a deletion of the regulatory region of ARID1B associated with Coffin‐Siris syndrome 1 (MIM 135900) presenting with a broad range of neurodevelopmental and behavioral abnormalities including hyperactivity and aggressive behavior; (j) a heterozygous multiexonic deletion of the NRXN1 that has been detected in multiple patients referred for intellectual disability, autism spectrum disorder, or seizures (MIM 614332); (k) a microduplication in LRRC7 , de novo variants of which were found in patients with neurodevelopmental disorders; (l) a heterozygous deletion encompassing exon 3 of DPP associated with AD mental retardation 33 (MIM 616311); (m) a microduplication in the ACMSD that encodes aminocarboxymuconate semialdehyde decarboxylase (ACMSD), which prevents the accumulation of the neuronal excitotoxin quinolinate that is associated with suicidal behavior, and mutations of which leads to AD parkinsonism; (n) a multiexonic deletion of CDH7 leading to AD CHARGE syndrome (MIM 214800), which is often associated with behavioral abnormalities; (o) an exonic deletion of DLG2 , encoding a synaptic protein that is linked to developmental disorders and intellectual disability, bipolar disorder and autism; (p) a multiexonic deletion of PTPRD that is highly constrained against loss‐of‐functions in the ExAC database, reported in numerous individuals with behavioral abnormalities in the DECIPHER database, and variants of which have been associated with a range of neurobehavioral phenotypes affecting conformity, and associated with mood instability, obsessive‐compulsive disorder and attention‐deficit hyperactivity disorder . Deletion and haploinsufficiency of PTPRD alter locomotion, sleep behaviors and cocaine‐conditioned place preference in mice .…”

A DLG2 deficiency in mice leads to reduced sociability and increased repetitive behavior accompanied by aberrant synaptic transmission in the dorsal striatum

“…It has been established that genetic variations in DLG2 are associated with neurodevelopmental disorders, including schizophrenia [9][10][11][12][13] and intellectual disability [14]. For example, de novo loss-of-function mutations in DLG2 have been repeatedly found in schizophrenia patients [11,13].…”

Systematic re-annotation of 191 genes associated with early-onset epilepsy unmasks de novo variants linked to Dravet syndrome in novel SCN1A exons

“…Additional sequences can be added to existing exome 'panels' used for diagnostics in the clinic and used to select novel regions for resequencing in patients without a molecular genetic diagnosis. Indeed, this has already been demonstrated for DLG2, where newly-identified exons were observed to be deleted in patients with neurodevelopmental disorders 12 . Furthermore, the resequencing of novel annotated regions identified previously-missed pathogenic variants linked to epilepsy in SCN8A 13 .…”