16p

Relevance to autism:

Several genes, as well as deletions or duplications within several regions of chromosome 16 have been associated with autism and other neurodevelopmental disorders. Deletions or duplications, also called copy number variants (CNV), in 16p that are linked to autism include 16p11.2, 16p12.1 and 16p13.3.

The significance for autism varies for each of these regions. Some, such as 16p11.2, are highly associated with the disorder, whereas others — such as 16p12.1 — may increase the risk of developing autism only in combination with other mutations.

Two studies published in Neuron in June 2011 report associations between mutations in several regions of 16p and autism¹,². Researchers found two de novo and two inherited duplications at 16p13.2 and a duplication on 16p13.11. They also found seven deletions and four duplications in the 16p11.2 region and report that de novo mutations seem to recur at 16p13.2 and 16q13.3.

16p11.2:

Deletion of 16p11.2 is probably the most well known CNV linked to autism. Deletions in this region have been detected in as many as one percent of individuals with autism spectrum disorders³,⁴. A meta-analysis published in May 2011 finds that 0.76 percent of individuals with autism have a deletion of 16p11.2⁵.

However, a large clinical study of 3,450 people, published in October 2010, suggests that although 16p11.2 CNVs almost always result in some symptoms of autism, only about 30 percent of people with the deletion warrant an actual diagnosis ⁶.

CNVs of 16p11.2 have also been linked to other conditions such as schizophrenia ⁷, mental retardation ⁸, intellectual disability not diagnosed as fragile X, and other known syndromes ⁹.

Individuals who have a deletion of a specific region in 16p11.2 are also more likely than controls to be obese. A February 2010 study shows that nearly three percent of people who are both obese and have developmental delays carry the 16p deletion ¹⁰. In an independent study published in the same journal issue, researchers searched for rare variants in 300 people with severe early-onset obesity. They found four carrying deletions in 16p; all have developmental delay and two have autism ¹¹.

Deletions of 16p11.2 generally lead to macrocephaly — large head size — and autism, whereas duplications are linked with smaller head size, and are more likely to lead to symptoms that resemble schizophrenia¹².

The Simons Variation In Individuals Project, funded by SFARI.org’s parent organization, is recruiting 200 individuals with mutations in 16p11.2 to further characterize this region.

16p12.1:

A small deletion in this region is linked to developmental disability and autism when combined with other mutations. Researchers found a deletion on chromosomal region 16p12.1 in about 0.2 percent of 20,000 children with intellectual disability — about four times the frequency they saw in the healthy control population ¹³.

Ten of the children who carry this particular CNV also have a second large CNV on another chromosome. This ‘two-hit’ subgroup tends to have distinct or more severe symptoms than do children who carry the second CNV alone, suggesting that the 16p12.1 hit exacerbates the phenotypes from the second hit.

About 80 percent of the general population has a structural configuration in their DNA that puts them at risk of developing a 16p12.1 deletion ¹⁴.

Risk genes:

Genes on 16p that are associated with autism include, cadherin 8, or CDH8, GRIN2A and the tuberous sclerosis gene TSC2.