The 15q11.2 BP1-BP2 Microdeletion ( Burnside-Butler) Syndrome: In Silico Analyses of the Four Coding Genes Reveal Functional Associations with Neurodevelopmental Phenotypes

Int J Mol Sci. 2020 May 6;21(9):3296. doi: 10.3390/ijms21093296.


The 15q11.2 BP1-BP2 microdeletion (Burnside-Butler) syndrome is emerging as the most frequent pathogenic copy number variation (CNV) in humans associated with neurodevelopmental disorders with changes in brain morphology, behavior, and cognition. In this study, we explored functions and interactions of the four protein-coding genes in this region, namely NIPA1, NIPA2, CYFIP1, and TUBGCP5, and elucidate their role, in solo and in concert, in the causation of neurodevelopmental disorders. First, we investigated the STRING protein-protein interactions encompassing all four genes and ascertained their predicted Gene Ontology (GO) functions, such as biological processes involved in their interactions, pathways and molecular functions. These include magnesium ion transport molecular function, regulation of axonogenesis and axon extension, regulation and production of bone morphogenetic protein and regulation of cellular growth and development. We gathered a list of significantly associated cardinal maladies for each gene from searchable genomic disease websites, namely HGMD, OMIM, ClinVar, GTR, Orphanet, DISEASES, Novoseek, and Through tabulations of such disease data, we ascertained the cardinal disease association of each gene, as well as their expanded putative disease associations. This enabled further tabulation of disease data to ascertain the role of each gene in the top ten overlapping significant neurodevelopmental disorders among the disease association data sets: (1) Prader-Willi Syndrome (PWS); (2) Angelman Syndrome (AS); (3) 15q11.2 Deletion Syndrome with Attention Deficit Hyperactive Disorder & Learning Disability; (4) Autism Spectrum Disorder (ASD); (5) Schizophrenia; (6) Epilepsy; (7) Down Syndrome; (8) Microcephaly; (9) Developmental Disorder, and (10) Peripheral Nervous System Disease. The cardinal disease associations for each of the four contiguous 15q11.2 BP1-BP2 genes are NIPA1- Spastic Paraplegia 6; NIPA2-Angelman Syndrome and Prader-Willi Syndrome; CYFIP1-Fragile X Syndrome and Autism; TUBGCP5-Prader-Willi Syndrome. The four genes are individually associated with PWS, ASD, schizophrenia, epilepsy, and Down syndrome. Except for TUBGCP5, the other three genes are associated with AS. Unlike the other genes, TUBGCP5 is also not associated with attention deficit hyperactivity disorder and learning disability, developmental disorder, or peripheral nervous system disease. CYFIP1 was the only gene not associated with microcephaly but was the only gene associated with developmental disorders. Collectively, all four genes were associated with up to three-fourths of the ten overlapping neurodevelopmental disorders and are deleted in this most prevalent known pathogenic copy number variation now recognized among humans with these clinical findings.

Keywords: 15q11.2 BP1-BP2 deletion (Burnside–Butler) syndrome; CYFIP1; Gene Ontology (GO); NIPA1; NIPA2; TUBGCP5; associated diseases; autism; biological processes; gene interactions and pathways; neurodevelopmental disorders.

Publication types

  • Review

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Cation Transport Proteins / genetics
  • Chromosome Aberrations
  • Chromosomes, Human, Pair 15 / genetics
  • Humans
  • Intellectual Disability / genetics*
  • Intellectual Disability / pathology
  • Membrane Proteins / genetics
  • Microtubule-Associated Proteins / genetics
  • Phenotype*


  • Adaptor Proteins, Signal Transducing
  • CYFIP1 protein, human
  • Cation Transport Proteins
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • NIPA1 protein, human
  • NIPA2 protein, human
  • TUBGCP5 protein, human

Supplementary concepts

  • Duplication 15q11-q13 Syndrome