Autism is a sex-biased, complex disorder in which the recurrence risk for siblings of girls with autism is 7 percent, compared with 3.2 percent for siblings of boys with autism. In multiplex families — those in which more than one individual has autism — the sex difference in sibling recurrence risk is far higher: 39 percent in families containing two or more females with autism, and 19 percent in families containing two or more males with autism.
Aravinda Chakravarti and his colleagues at Johns Hopkins University in Baltimore have done parallel studies of Hirschsprung disease, a dysfunction of the large intestine with an epidemiology similar to that of autism. These studies showed that affected individuals within the group with the highest risk of developing the disease have 94 percent detected variants at the RET gene (the gene that is mutated in Hirschsprung disease).
Of that 94 percent, 50 percent of variants are specifically within the protein-coding sequence of RET. Individuals within the lowest risk class have 71 percent detected variants, of which 3 percent are coding. The remainder of the variants in affected cases are in a noncoding enhancer of the RET gene.
In individuals with autism, the highest-risk groups for autism are girls, those with severe autism and individuals within a multiplex family, features that are likely to be associated with mutations in protein-coding genes. The researchers hope to use these criteria to define female-enriched multiplex autism families (FEMFs). They have identified 220 such families from the Autism Genetic Resource Exchange and the National Institute of Mental Health collections.
Chakravarti and his team aim to sequence the exomes, or protein-coding portions of the genome, of 220 FEMFs with severe autism in order to identify high-quality single nucleotide variants, insertions and deletions and copy number variants. The group plans to annotate sequence variants with respect to their predicted deleterious effect and functional conservation of the protein sequence in evolution. The researchers also plan to look at the frequency of these variants in FEMFs compared with a variety of publicly available controls.
In addition, the researchers aim to conduct novel statistical tests on variants and genes to assess whether they have an excess of deleterious alleles. They aim to compare the mutation profiles of identified genes from simplex and multiplex male autism probands — the first individual of a family to be diagnosed with autism.