Disruption of the ProSAP2 Gene in a t(12;22)(q24.1;q13.3) Is Associated with the 22q13.3 Deletion Syndrome

Abstract

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.

Interstitial 22q13 deletions: genes other than SHANK3 have major effects on cognitive and language development

“…23 In most 22q13 deletions, there is relatively little correlation between the severity of cognitive defects and deletion size, as might be expected if the loss of SHANK3 accounts for most neurological features. However, two out of three patients with the smallest deletions 8,10 and the patient with SHANK3 disrupted by a translocation 11 have milder cognitive deficits, although speech was severely affected in all. This implies that genes proximal to SHANK3 may make major contributions to the neurological symptoms.…”

“…This hypothesis is supported by the presence of deletion breakpoints within SHANK3 in the three patients 8 -10 and the disruption of SHANK3 in a child with a balanced translocation and all the features of the 22q13 deletion syndrome. 11 Recently, dosage imbalance of the SHANK3 gene has been implicated in several patients with autism spectrum disorder. 12,13 Two brothers with a frameshift mutation within SHANK3 showed a severe autistic/mental retardation phenotype that is similar to patients with the 22q13 deletion syndrome, but without any other typical features such as hypotonia.…”

Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders

“…The PSD has been identified in several glutamate synapses. SHANK3 haploinsufficiency seems to be responsible for the major neurological symptoms in 22q13 deletion syndrome (MIM #606232), 25,26 a condition characterized by speech delay, neonatal hypotonia, and behavioral problems along with other features.…”

Fluorescence in situ hybridization characterization of apparently balanced translocation reveals cryptic complex chromosomal rearrangements with unexpected level of complexity

“…1,2 Although most carriers of balanced translocations are phenotypically normal, an association of cytogenetically balanced translocations with phenotypic abnormalities has been reported. 3 The risk of phenotypic abnormality associated with de novo balanced translocations is likely to be due to the chance of chromosome breakage disrupting a gene 4 or they may not be truly balanced at the DNA level. 5 Families in which a cytogenetically balanced translocation is present in both a normal and a child with a phenotypic anomaly have been a long-standing puzzle for human geneticists.…”