Genetics of Autism: The Maternal Genotype at the Dopamine Beta Hydroxylase Locus may be a Factor in the Etiology of Autism and Related Pervasive Developmental Disorders

Abstract

Autism is a severe developmental disorder characterized by impairments in reciprocal social interaction and communication, coupled with repetitive stereotypic activities. Evidence from twin and family studies strongly suggest that genetic factors play a significant role in the etiology of autism. The factors involved in the development of autism are also thought to underlie related pervasive developmental disorders (PDD). The affected sib-pair method was used to screen nine autosomal candidate loci in 18 families, each of which have two or more children with autism or a related PDD. Candidate loci were selected on the basis that: (1) the locus is near genetic disorders or chromosomal abnormalities found to co-occur with autism; and/or (2) the gene encodes a protein which has been speculated to play a role in the pathophysiology of autism. Genotypes of the affected children and their parents were determined for the following microsatellite markers which are tightly linked to the candidate genes/regions: 13S118, DRD2, TH, HRAS-1, 22S343, D15S11, GABRB3, 16S291, and DBH. No significant concordance between affected siblings was observed for any of the loci tested. During the study, however, many of the families were found to be uninformative at the dopamine beta hydroxylase (DBH) microsatellite locus. A comparsion of DBH allele frequencies observed in the parents to published British values revealed a significant difference between the two groups (L2=13.16, df=5, p<0.05). Given this finding, and the knowledge that serum DBH activity is largely under the control of DNA sequences in or close to the DBH gene, serum DBH activities were measured in the parents and in an adult control group. Mean serum DBH activity was found to be significantly lower in parents with two autistic/PDD children compared to an adult control group (Student's t=-1.71, df=60, p<0.05). DBH alleles are defined by a polymorphic dinucleotide repeat and the presence or absence of a 19 bp sequence. Upon further analysis the frequency of alleles in which the 19 bp sequence is deleted was found to be significantly increased in the mothers with two autistic/PDD children, compared to both published frequencies (L2=11.99, df=1, p<0.001) and to a Canadian control group (L2=6.96, df=1, p<0.01). Subsequent investigation revealed that deletion of the 19 bp sequence is associated with lower mean serum DBH enzyme activity (nondeletion homozygotes 44.5±28.6 iu/L; heterozygotes 30.4±16.0 iu/L; and deletion homozygotes 20.5±15.3 iu/L; F=5.45, df=59, p<0.01). Based on these findings it is proposed that lowered maternal serum DBH activity provides a uterine environment which, in conjunction with genotypic susceptiblity of a fetus, results in autism or a related PDD.