Resumo

Autism Spectrum Disorders (ASD) are genetically heterogeneous diseases defined by repetitive behaviour and impairment in social interaction and communication. Approximately 10% of the cases are related to monogenic syndromes or chromosomal abnormalities, but for most of the cases, the genetic causes are unknown. Recently, it was verified that small duplications or deletions in the chromosomes not detectable by karyotype, called copy number variations, can also be involved in ASD etiology. Multiplex Ligation-Dependent Probe Amplification (MLPA) is a high resolution molecular technique used to detect copy number variations (CNV) in selected chromosomal areas, as the subtelomeric regions. Subtelomeric alterations are found in ~5-7% of the individuals who have idiopathic cognitive impairment or congenital malformations. OBJECTIVES Our aim is to verify the frequency of subtelomeric microdeletions and microduplications (CNV) in patients in whom the major clinical alteration is autism. MATERIALS AND METHODS The subtelomeric MLPA kit P036 and P070 (MHC Holland) was used to analyze the DNA samples of 57 patients (30 girls and 27 boys) diagnosed with ASD. The parents of the patients who presented any alteration were also tested in order to identify if the alterations were inherited or de novo. In one case, GeneChip Human Mapping 100k Array Set (Affymetrix) was also used to confirm the alteration. RESULTS Two out of the 57 cases (3.5%) showed an alteration in copy number of subtelomeric regions. In one female patient, a duplication in 9p was detected, which was shown to be inherited from her mother. Considering that this region has previously been reported as polymorphic and that patient’s mother does not present any cognitive impairment or malformation, we did not consider this CNV as related to ASD. On the other hand, a deletion of the subtelomeric region on chromosome 22q was found in another female patient. This deletion was not present in the parents and SNP array based technique besides confirming the deletion, also showed that the deletion is interstitial and has ~1Mb. Among the genes deleted by this alteration is SHANK3. SHANK3 has gained attention in ASD field since an increasing number of studies have found alterations in this gene in autistic patients. CONCLUSION Although our sample is relatively small, we found a pathogenic subtelomeric alteration in one ASD patient that does not have congenital malformations. The main clinical findings of this patient is ASD, but the patient also had delayed motor development. These results, although still preliminary, suggest that it is important to investigate subtelomeric CNVs in ASD patients to better establish the genetic cause of the disease. Also, our study reinforces the role of SHANK3 gene in ASD etiology. FAPESP, CNPq