15q11.2 microdeletion (BP1-BP2) and developmental delay, behaviour issues, epilepsy and congenital heart disease: a series of 52 patients

Eur J Med Genet. 2015 Mar;58(3):140-7. doi: 10.1016/j.ejmg.2015.01.002. Epub 2015 Jan 14.

Abstract

Proximal region of chromosome 15 long arm is rich in duplicons that, define five breakpoints (BP) for 15q rearrangements. 15q11.2 microdeletion between BP1 and BP2 has been previously associated with developmental delay and atypical psychological patterns. This region contains four highly-conserved and non-imprinted genes: NIPA1, NIPA2, CYFIP1, TUBGCP5. Our goal was to investigate the phenotypes associated with this microdeletion in a cohort of 52 patients. This copy number variation (CNV) was prevalent in 0.8% patients presenting with developmental delay, psychological pattern issues and/or multiple congenital malformations. This was studied by array-CGH at six different French Genetic laboratories. We collected data from 52 unrelated patients (including 3 foetuses) after excluding patients with an associated genetic alteration (known CNV, aneuploidy or known monogenic disease). Out of 52 patients, mild or moderate developmental delay was observed in 68.3%, 85.4% had speech impairment and 63.4% had psychological issues such as Attention Deficit and Hyperactivity Disorder, Autistic Spectrum Disorder or Obsessive-Compulsive Disorder. Seizures were noted in 18.7% patients and associated congenital heart disease in 17.3%. Parents were analysed for abnormalities in the region in 65.4% families. Amongst these families, 'de novo' microdeletions were observed in 18.8% and 81.2% were inherited from one of the parents. Incomplete penetrance and variable expressivity were observed amongst the patients. Our results support the hypothesis that 15q11.2 (BP1-BP2) microdeletion is associated with developmental delay, abnormal behaviour, generalized epilepsy and congenital heart disease. The later feature has been rarely described. Incomplete penetrance and variability of expression demands further assessment and studies.

Keywords: 15q11.2 microdeletion; BP1–BP2; CYFIP1; Congenital heart disease; NIPA1; NIPA2; TUBGCP5.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Adolescent
  • Adult
  • Attention Deficit Disorder with Hyperactivity / genetics
  • Cation Transport Proteins
  • Child
  • Child Development Disorders, Pervasive / genetics
  • Child, Preschool
  • Chromosome Aberrations
  • Chromosome Deletion
  • Chromosomes, Human, Pair 15 / genetics
  • Cohort Studies
  • Comparative Genomic Hybridization
  • DNA Copy Number Variations
  • Developmental Disabilities / diagnosis
  • Developmental Disabilities / genetics*
  • Epilepsy / diagnosis
  • Epilepsy / genetics*
  • Female
  • Heart Diseases / congenital
  • Heart Diseases / diagnosis
  • Heart Diseases / genetics*
  • Humans
  • In Situ Hybridization, Fluorescence
  • Infant
  • Intellectual Disability / diagnosis
  • Intellectual Disability / genetics*
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mental Disorders / diagnosis
  • Mental Disorders / genetics*
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Middle Aged
  • Phenotype
  • Speech Disorders / genetics
  • Young Adult

Substances

  • 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