Homozygosity mapping: Autism in the family

Most genes identified in genome-wide analyses contribute only modestly to disease risk or protection, with already low relative risks changed only ~20%, and taken together probably contribute to a minority of disease cases. Morrow and colleagues took a different approach, believing that analyzing individual families might reveal higher-risk genes for autism spectrum disorders (ASDs). They noted that offspring of first-cousins have twice as many neurological birth defects, including ASDs.

They also noted that a significant involvement of autosomal recessive genes would be 'signaled' by change in the male-to-female ratio (because the M:F ratio is typically 1:1 for autosomal recessive traits vs. male-dominant ASD). Indeed, among the 104 families recruited for the study, the M:F ratio was 2.6 for the offspring of the 88 consanguineous families (cousins) vs. 7.4 for the non-consanguineous.

They genotyped using arrays of SNPs and BACs, the latter validated for comparative genomic hybridization (CGH) detection of copy number variation (CNV) due to deletions, etc. Few de novo (not inherited) CNVs were detected. Large deletions on both DNA strands of the affected child (homozygous), and one strand of each parent (hemizygous), were found in 5 of the 78 consanguineous families but not among any of the other ~400 ASD cases or ~2,400 controls. In the figure (from Figure 1C), the SNPs spanning a large deletion in the AU-3100 pedigree is shown: the parents 3103 & 3104 (top and second) are hemizygous as is one child (3102, third down) but the other child, 3101 (bottom), who is homozygous for the deleted chromosome, has autism and seizures.

The investigators were surprised to find 3 genes linked to the 2 largest deletions were previously identified as being regulated by neural activity, and thus candidates for involvement with learning. Mutations in one of these genes, NHE9, were detected in non-consanguineous families and associated with additional neurological disorders (epilepsy) and learning delays (language acquisition).

EM Morrow et al. Identifying autism loci and genes by tracing recent shared ancestry. Science. 2008 Jul 11;321(5886):218-23.