Disruption of the ProSAP2 gene in a t(12;22)(q24.1;q13.3) is associated with the 22q13.3 deletion syndrome

Am J Hum Genet. 2001 Aug;69(2):261-8. doi: 10.1086/321293. Epub 2001 Jun 18.


The terminal 22q13.3 deletion syndrome is characterized by severe expressive-language delay, mild mental retardation, hypotonia, joint laxity, dolichocephaly, and minor facial dysmorphisms. We identified a child with all the features of 22q13.3 deletion syndrome. The patient's karyotype showed a de novo balanced translocation between chromosomes 12 and 22, with the breakpoint in the 22q13.3 critical region of the 22q distal deletion syndrome [46, XY, t(12;22)(q24.1;q13.3)]. FISH investigations revealed that the translocation was reciprocal, with the chromosome 22 breakpoint within the 22q subtelomeric cosmid 106G1220 and the chromosome 12q breakpoint near STS D12S317. Using Southern blot analysis and inverse PCR, we located the chromosome 12 breakpoint in an intron of the FLJ10659 gene and located the chromosome 22 breakpoint within exon 21 of the human homologue of the ProSAP2 gene. Short homologous sequences (5-bp, CTG[C/A]C) were found at the breakpoint on both derivative chromosomes. The translocation does not lead to the loss of any portion of DNA. Northern blot analysis of human tissues, using the rat ProSAP2 cDNA, showed that full-length transcripts were found only in the cerebral cortex and the cerebellum. The FLJ10659 gene is expressed in various tissues and does not show tissue-specific isoforms. The finding that ProSAP2 is included in the critical region of the 22q deletion syndrome and that our proband displays all signs and symptoms of the syndrome suggests that ProSAP2 haploinsufficiency is the cause of the 22q13.3 deletion syndrome. ProSAP2 is a good candidate for this syndrome, because it is preferentially expressed in the cerebral cortex and the cerebellum and encodes a scaffold protein involved in the postsynaptic density of excitatory synapses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / genetics*
  • Child, Preschool
  • Chromosome Aberrations / genetics*
  • Chromosome Aberrations / physiopathology
  • Chromosome Breakage / genetics
  • Chromosome Deletion*
  • Chromosome Disorders
  • Chromosomes, Human, Pair 12 / genetics*
  • Chromosomes, Human, Pair 22 / genetics*
  • Exons / genetics
  • Gene Expression Profiling
  • Humans
  • In Situ Hybridization, Fluorescence
  • Infant
  • Infant, Newborn
  • Intellectual Disability / genetics
  • Intellectual Disability / physiopathology
  • Introns / genetics
  • Language Development Disorders / genetics
  • Language Development Disorders / physiopathology
  • Male
  • Molecular Sequence Data
  • Nerve Tissue Proteins / genetics*
  • RNA, Messenger / analysis
  • RNA, Messenger / genetics
  • Syndrome
  • Translocation, Genetic / genetics*


  • Carrier Proteins
  • Nerve Tissue Proteins
  • RNA, Messenger
  • SHANK3 protein, human

Associated data

  • OMIM/604299