Autism sibling pair discordant for 22q11 microdeletion

Background:  

Autism is a complex genetic disorder.  The precise relationship between autism and 22q11 deletions (VCFS) is still under investigation.

Objectives:

We report the case of a sib-pair diagnosed with autistic disorder that were discordant for a 22q11 microdeletion upon genetic analysis. 

Methods:  

The siblings (one male, one female) met ADI-R and ADOS criteria for autism classification. They received a DSM IV best estimate diagnosis of Autistic Disorder using the ADI-R, ADOS, Vineland Scales and cognitive testing.  The affected female presented with facial dysmorphic features characteristic of VCFS.  This led to FISH testing using a probe corresponding to the VCFS region on chromosome 22.

Results:  

These studies revealed the loss of the VCFS critical region in this patient consistent with 46,XX.ish del(22)(q11.2q11.2)(TUPLE1-).  Array comparative genomic hybridization using a 19k human BAC microarray was performed on the proband, brother, and her parents and confirmed a deletion of 22q11.2 only in the female proband.

Conclusions:

Microdeletion discordance in this sib-pair is consistent with other recent reports of microdeletion in autism. As the 22q11 mutation was not inherited from a parent, but is de novo in the child, we would not expect to see concordance for the deletion, unless there was parental post-zygotic mosaicism.  If females have a higher dosage threshold for the development of autism then it’s feasible that the 22q11 del in our female patient is a variant that contributes to her phenotype being as severe as her brother, assuming that they shared other risk variants.  Alternatively, the siblings could have independent risk variants of major effect.  It is likely that the heterogeneity of autism will include common variants of weak effect and rare variants ranging from weak to strong effects.  It is also likely that many individuals and families will have combinations of such variants.