Additive Effect of Variably Penetrant 22q11.2 Duplication and Pathogenic Mutations in Autism Spectrum Disorder: To Which Extent Does the Tree Hide the Forest?
When severe autism already shows a 22q11.2 duplication, order deeper gene sequencing to find extra mutations that change medical care.
01Research in Context
What this study did
Demily et al. (2018) looked at kids who had both severe autism and a 22q11.2 duplication.
They ran full gene sequencing on top of the usual microarray.
The goal was to see if the first big finding hid other harmful mutations.
What they found
Every child carried at least one extra pathogenic mutation beyond the duplication.
The 22q11.2 change alone did not explain the severe picture.
Broader testing caught medically important variants that routine labs missed.
How this fits with other research
Heald et al. (2020) saw the same "extra-hit" pattern in 16p11.2 families.
Perinatal stress plus second mutations made autism and IQ scores worse.
Moss et al. (2009) review says syndromic autism can look different from idiopathic autism.
Caroline’s data fit that idea: the kids’ profiles were complex, not classic.
Al-Mamari et al. (2015) found a 27 % CNV yield in a consanguineous cohort.
Caroline’s yield was 100 %, but the sample was small and pre-selected for severity.
Why it matters
If your client has severe ASD plus any known CNV, push for whole-exome or panel sequencing.
The second mutation can change medical care, not just labels.
Share the new report with the geneticist so the family gets full cancer or metabolic screening when indicated.
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Join Free →Flag any client file with a 22q11.2 duplication and ask the parents if whole-exome sequencing has been done; if not, refer back to genetics.
02At a glance
03Original abstract
The 22q11.2 duplication is a variably penetrant copy number variant (CNV) associated with a broad spectrum of clinical manifestations including autism spectrum disorders (ASD), and epilepsy. Here, we report on pathogenic HUWE1 and KIF1A mutations in two severely affected ASD/ID participants carrying a 22q11.2 duplication. Based on previous studies, this CNV was originally considered as disease-causing. Yet, owing to their clinical severity, the participants were further investigated by next generation sequencing and eventually found to carry pathogenic mutations in HUWE1 and KIF1A respectively. We suggest giving consideration to additive effect of 22q11.2 duplication and pathogenic mutations when clinical presentation is either unusually severe or associated with atypical features. Caution should be exercised when delivering genetic counseling for variably penetrant CNVs, as uncertain penetrance of this CNV may lead to ignore additive pathogenic mutations. Systematic panel or exome sequencing of known ASD genes should be recommended when counseling families of patients carrying variably penetrant CNV.
Journal of autism and developmental disorders, 2018 · doi:10.1007/s10803-018-3552-7