This multiplex family was one of the first to be collected as part of the IMGSAC cohort used for linkage analysis.13, 14
In this family, the proband and his two maternal half-brothers have all been diagnosed with autism. This family structure () means that recessive susceptibility factors are less likely to be involved in this pedigree, with the most likely inheritance pattern being a maternal dominant risk factor. Consistent with this suggestion, whole-genome CNV analysis identified a 15q13.3 microdeletion that was transmitted to all affected children from their mother. The absence of this deletion from the DGV, together with the segregation seen in this generation of the pedigree, suggests that it may be a rare variant involved in autism pathogenesis. In view of the gender bias seen for autism, it is interesting to note that all the affected offspring are male, whereas the mother harbouring the same deletion appears phenotypically normal.
This 15q13.3 microdeletion was described recently in association with MR.8
The nine published MR cases harbouring the microdeletion were described as having mild-to-moderate MR, with reported IQs ranging from 34 to 62, with one individual having ‘mild autism'. By contrast, the three individuals described here are less severely affected in terms of intelligence, but all have been diagnosed with autism using the ADI-R/ADOS. Sharp et al8
also report that the majority of individuals in their study presented with mild face and hand dysmorphologies, whereas no such abnormalities were documented in the family described here. Autism is associated with increased head circumference in approximately 17% of cases.22
Two of the three individuals described here had a head circumference of >97th centile, whereas only one of the individuals reported by Sharp et al8
showed this feature ().
The mechanism by which this deletion might lead to autism can only be speculated upon. Haploinsufficiency of one or more of the seven genes contained in this critical region is likely to be a key factor. One of the genes (CHRNA7
) encodes a synaptic ion channel that in mouse knockouts is associated with an abnormal EEG.23
This gene is therefore a good candidate to explain the epilepsy or abnormal EEG results observed in seven out of nine of the Sharp et al8
cases (although this phenotype was not present in our study). Alternatively, the microdeletion may also cause changes in chromatin structure that upregulate nearby genes, thereby following the same underlying mechanism as the 15q11–13 duplication.
None of the individuals described here had other associated psychiatric problems at the age of assessment (16 years for case 1, 14 years for case 2 and 10 years for case 3). Nevertheless, two recent studies reported the same deletion to be recurrent in schizophrenia cohorts.24, 25
In the larger of these studies, an Icelandic group found this deletion in 7 out of 4213 (0.17%) affected individuals, compared with 8 out of 39
800 (0.02%) controls. Interestingly, 299 of the controls screened were in fact autistic, and one of these autistic control samples harboured the 15q13.3 microdeletion.24
In addition, while this paper was under review, Miller et al26
reported this microdeletion in two cases of pervasive developmental disorder – not otherwise specified – from a total of 262 autism spectrum disorder (ASD) and PDD cases referred to Children's Hospital Boston and in 0 out of 751 families from the Autism Genetic Resource Exchange. Together with the individual with milder autism described by Sharp et al8
and the autistic ‘control', our family is therefore the forth independent report of this rare microdeletion in individuals with ASD and the first to demonstrate segregation in a multiplex family with narrowly defined autism.
It is becoming increasingly apparent that CNVs can span the boundaries of clinical diagnosis. We believe that the 15q13.3 deletion acts in concert with modifier genes, other contributing CNVs or even environmental exposures, which may determine why it causes MR in some individuals, autism in others and schizophrenia in yet more.
Although this microdeletion is rare, its association with autism susceptibility should be further assessed. Studies have shown that the occurrence of de novo
CNVs is decreased in multiplex families compared with singleton families;6, 27, 28
so it is therefore important to screen increased numbers of singleton families for this rare variant.