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Using Whole Exome Sequencing to Investigate the Genetics of Sensory Processing Disorders
While genetic causes of Autism Spectrum Disorders (ASD) have been extensively investigated, there has yet to be a focus on the genetics of Sensory Processing Disorders (SPD), either as a part of the ASD phenotype or in isolation. Heritability rates for sensory sensitivity have been estimated to be as high as 54% for tactile sensitivity and 38% for auditory sensitivity. In addition, there are several genetically mediated neurodevelopmental disorders with evidence of sensory sensitivity such as Fragile X and 16p11.2 deletion syndrome.
Objectives:
Firstly: to determine whether de novo pathogenic mutations are found in candidate neurodevelopmental genes in a small SPD cohort (N=11). Our second objective is to determine if in this SPD cohort there is a higher prevalence of rare potentially pathogenic variants in ASD associated genes than in the overall pool of genes interrogated by exome sequencing.
Methods:
We enrolled 11 children (ages 8-16 years) with SPD, but who do not meet clinical criteria for ASD, and their biological parents from the UCSF Sensory Neurodevelopment and Autism Program Registry. Probands and their biologic parents underwent sensory assessments and genetic testing using whole exome sequencing using the Agilent sure select platform and an in house analytic pipeline based on the current GATK best practices workflow (https://www.broadinstitute.org/gatk/guide/best-practices). Missense, nonsense, splice site, frameshift and indel mutations that were not present in dbSNP or the exome variant server (http://evs.gs.washington.edu/EVS/) were included in the downstream analysis of both de novo and inherited mutations. Mutations in ASD-linked genes were tested for association with the SPD phenotype through analysis of a bionomial distribution, accounting for gene length and correcting for multiple comparisons using Bonferroni.ASD linked genes were selected from the SFARI gene collection (genes.sfari.org).
Results:
First, our analysis identified a de novo premature stop codon mutation in the MBD5 gene of a single female child in our cohort. MBD5, located at 2q23.1 has previously been implicated in mental retardation autosomal dominant type 1. Affected individuals are reported to have microcephaly, intellectual disabilities, severe speech impairment, ASD and seizures but there is no mention of sensory processing differences. Second, inherited mutations in genes repeatedly linked to ASD are found in children with SPD more frequently than would be expected in a random model. However, given our small sample size, this finding only reached trend level (p=0.068).
Conclusions:
While further studies with a larger sample size are required, this preliminary study showing that both de novo and inherited ASD related mutations are found in an SPD only cohort suggests that SPD is mediated by similar deficits as ASD and that a similar clinical genetic investigation is warranted for children with SPD who may not meet other DSM based labels.