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Copy Number Variants May Influence Clinical Presentation Among Individuals with PTEN Mutations

NEW YORK – Copy-number variants may influence whether someone with a PTEN mutation develops autism spectrum disorder or developmental delay, a new study has found.

Mutations in PTEN increase people's risk of developing certain cancers and cognitive or behavioral conditions, disorders collectively known as PTEN hamartoma tumor syndrome (PHTS). But people with the same germline PTEN mutations can manifest the condition in different ways, suggesting other factors may be at play.

Researchers from the Cleveland Clinic compared the number of CNVs within individuals with PHTS, but who exhibited different symptoms. Within a nearly 500-member cohort, individuals with autism or developmental delay were more likely than those without it or with cancer to harbor CNVs, as the researchers reported Friday in JAMA Network Open.

"These findings suggest that copy number variations are associated with the ASD/developmental delay clinical phenotype in PHTS, providing proof of principle for similarly heterogeneous disorders lacking outcome-specific associations," Cleveland Clinic's Charis Eng and her colleagues wrote in their paper.

The researchers assembled a cohort of 481 patients with PHTS, and confirmed their PTEN mutation status. They divvied this cohort into three phenotypic groups: 110 patients with ASD/developmental delay; 194 without ASD/developmental delay; and 121 with cancer. Most of the patients with cancer did not have ASD/developmental delay.

They tallied up the number of CNVs each participant had to find that, overall, patients in the ASD/developmental delay group had an increased CNV burden, compared to both the non-ASD/developmental delay group and the cancer group. Additionally, patients in the ASD/developmental delay group also had an increased burden of rare CNVs per person, as compared to the other groups. Patients in the ASD/developmental delay group also had an enrichment of duplications affecting genic regions.

There was no difference,however, in the overall CNV or rare CNV burden between the non-ASD/developmental delay and cancer groups.

Three patients with PHTS had pathogenic or likely pathogenic CNVs that affected genes associated with PTEN-linked cancers or other inherited cancer syndromes. Two had deletions affecting BMPR1A and one had a BRCA1 deletion.

About 10 percent of participants in the ASD/developmental delay group had pathogenic or likely pathogenic CNVs associated with ASD, developmental delay, or neurodevelopmental disorders. By contrast, 2.6 percent of participants from the no ASD/developmental delay group had such pathogenic or likely pathogenic CNVs and 1.7 percent of the cancer group did.

These findings suggest that CNVs may act as genomic modifiers of disease risk in conditions that present with a range of symptoms, like PHTS, the researchers said. For instance, they noted that CNVs such as the one they found in three unrelated individuals affecting CYFIP1, which is associated with ASD, could be a "second hit" for PHTS patients who already had deleterious PTEN mutations.

Additionally, CNV testing of individuals found to have germline PTEN mutations could potentially help identify individuals who may be at increased risk of developing ASD or developmental delay, and enable them to be referred early for evaluation and therapy, the researchers added.