A-337 Study of the Relationship between the Variant Dup 4q26 and Autism Spectrum Disorder
Authors: Perez B B , dos Santos M V , Oliveira H R , Ramadan D R , Tufik S , Feres M C 
Published: September 2023

Background

Autistic Spectrum Disorder (ASD) refers to a neuronal condition, caused by a disorder in neurodevelopment. With hypersensitivity, repetitive behaviors and other symptoms, this condition has both genetic and environmental causes. The etiology is still not fully known, but it is known that there are chromosomal abnormalities (2%), monogenic syndromes (5%), microduplications and microdeletions (10%), environmental (3%), multifactorial and epigenetic (80%). In 2004, many authors studying the first genome wide screening for chromosomal regions involved in classical autism reported over 354 genetic markers for this disorder. In this context, techniques emerged for identifying these genes for the elucidation and diagnosis of ASD, among others - the Array. Revolutionary high-resolution technique capable of investigating thousands of chromosomal regions, detecting losses and add in a single exam. With this method it is possible to detect CNVs and SNPs (variations in the number of copies and polymorphism of a nucleotide), uniparental disomy and loss of heterozygosity.

Objective

With this technique, the authors of this study aimed to associate a dup 4q26 variant found with ASD and analyze its classification as a variant of uncertain meaning.

Method

Genetic data from CGH-ARRAY tests performed from June/2018 to December/2022 were analyzed in a large laboratory in São Paulo- Brazil. 149 patients with variants of uncertain and/or pathogenic significance were selected. Of these, 38 cases were under investigation for ASD, characterized by the diagnostic hypothesis. The authors found 49 variants. Of these, 6.12% were detected on chromosome 1, 4.08% on chromosome 2, 4.08% on chromosome 3, 14.28% on chromosome 4, 4.08% on chromosome 5, 6.12% on chromosome 7, 2.04% on chromosome 8, 6.12% on chromosome 9, 6.12% on chromosome 10, 4.08% on chromosome 11, 2.04% on chromosome 13, 4.08% on chromosome 15, 6.12% on chromosome 16, 6.12% on chromosome 18, 2.04% on chromosome 20, 12.24% on X chromosome and 10.02% on Y chromosome.

Results

The study showed that chromosome 4 had the highest number of detected variants. Therefore, we carefully analyzed all cases and 2 patients, who did not have consanguinity, had the 4q26 duplication, classified as VOUS (unclear meaning). This duplication is associated with genes:TRAM1L1, LINC01378, NDST3, SNHG8, SNORA24, PRSS12, CEP170P1, LOC729218, LOC101929741, METTL14, SEC24D, SYNPO2, MYOZ2, LOC101929762, USP53, C4orf3, FABP2, LINC01061, GTF2IP12, LOC645513, PDE5A, LINC01365, LOC100996694. Of these genes, only the PRSS12 gene correlated with autism. PRSS12 (Serine Protease 12) encodes a protein secreted by neuronal cells, located in the synaptic cleft and is associated with cognitive impairment.

Conclusion

The two cases studied had global delay in development with a suggestion, after medical evaluation, of ASD. The findings in the genetic exam did not show other alterations that justify the cognitive delay and the hypothesis of autism only the duplication of the PRSS12 gene. Thus, it is possible that this variant is associated with the observed phenotype and that it could be studied and reclassified as a probably pathogenic variant.