Sensory processing dysfunction (SPD) affects 5–16% of children and can contribute to long-term impairments in cognition, social development, and family well-being [1–3]. Additionally, hyper and hypo-sensitivity to sound and touch has recently been added to the symptom cluster for Autism Spectrum Disorders (ASD) in the most recent Diagnostic and Statistical Manual, DSM-5 [4]. We have recently shown that children with SPD, who do not meet criteria for ASD, have measurable differences in white matter microstructure predominantly in the posterior brain regions, which are critical to sensory perception and processing [5]. We have further demonstrated overlap between these brain findings in children with SPD and children with ASD, suggesting that there is not only a phenotypic overlap between SPD and ASD, but that there may be a mechanistic connection as well [6]. However, in our study, children with ASD have broader neural disruption, including key white matter tracts that subserve language, emotional memory, and processing. Approaches to address ASD mechanisms have included deep genetic analyses, including whole exome sequencing (WES), demonstrating that loss of function de novo mutations occur in genes that play important roles in neurodevelopmental pathophysiology. This type of rigorous approach to investigate the genetics of SPD remains to be undertaken, despite the growing recognition that SPD can present both as an isolated neurodevelopmental concern as well as a co-morbid condition for children who meet criteria for other behaviorally described conditions in the DSM-5 such as ASD, attention deficit disorders, and anxiety [7–10].

There are, however, some suggestions as to the genetic architecture of SPD. Numerous genetically mediated neurodevelopmental disorders have been reported to show increased sensory sensitivity, including triplet repeat disorders (e.g. Fragile X), chromosomal copy number variations (e.g. Williams syndrome), and single gene disorders (e.g. ARHGEF9) [11–13]. In addition, large population-based twin studies suggest that sensory over-responsivity (SOR) shows moderate heritability across sensory domain with 38% of auditory SOR and 52% of tactile SOR attributed to genetic factors [14].

The search for genes that explain the observed heritability in cognitive and behavioral disorders has been challenging. Despite that, recent WES with large ASD cohorts have shown that loss of function mutations in certain genes occur in 10–15% of patients with a frequency that provides strong statistical evidence for causality in ASD [15]. There is also evidence that ASD patients carry an oligogenic or polygenic combination of variations in “high-risk” neurodevelopment genes, each variant making either a large or small contribution to the phenotype [16, 17]. In fact, it is now posited that as many as 1000 genes can confer risk for ASD [18].

WES technology allows for the investigation of both de novo mutations and inherited risk polymorphisms when sequencing is performed for the index patient and his/her parents. In cohorts of children with intellectual disability or global developmental delay, the diagnostic rate using WES for de novo single gene etiologies was estimated to be 33% [19]. In an initial study of 238 families where only one member has autism, Sanders, et al. 2012 identified 16 loss of function mutations in probands, including nonsense, splice site and frame shift mutations [20]. In a follow up study, integrating both copy number variations and de novo loss of function mutations from WES, Sanders, et al. 2015 report 65 high-risk autism genes which show enrichment in protein-protein interactions and suggest two main sub-networks: chromatin regulation and synaptic control [21]. In this preliminary study, we sought to identify de novo loss of function mutations in children who presented with SPD to investigate monogenic etiologies. We further aimed to test whether there is an increased burden of inherited (or transmitted) rare Single Nucleotide Variants (rSNV) in high- and moderate- risk ASD genes when compared to non-transmitted rare variants in both our preliminary SPD cohort and in the larger ASD family cohort from the Simons Simplex Collection. We hypothesize that, as there are phenotypic and brain structure similarities in children with ASD or SPD, there may also be an overlap in genetic etiologies.

This genetic cohort study aims to establish the occurrence of de novo missense and loss of function mutations in children with community diagnosed SPD. We further aimed to determine if there is a higher burden of transmitted rSNV in children with SPD and their parents in high and moderate-risk genes associated with ASD.

There is growing interest in the etiology of sensory processing dysfunction for individuals with social communication challenges meeting DSM-5 criteria for ASD. This stems in part from the fact that in the current version of the DSM, “hyper- or hyporeactivity to sensory input or unusual interests in sensory aspects of the environment” is now included in the ASD phenotypic criteria. There are, however, many individuals who are over-responsive to sensory input but do not have the degree of social or communication challenges that meet an ASD label. These individuals are currently being lumped under the category of Sensory Processing Disorder or SPD. With an estimated 10–15% of children with an ASD label currently being reported to have disease associated variants identified via WES, we sought to investigate the occurrence of de novo missense/nonsense mutations in ASD candidate genes in children with SPD. Furthermore, we sought to investigate whether children with SPD and their parents would show an increased burden of deleterious rSNV in high and moderate-risk ASD candidate genes. Herein, we report that 18% of our sample has a pathogenic de novo missense/nonsense mutation in genes previously associated with neurodevelopmental disorders. We further show that there is an enhanced rate of rare inherited variants in high-risk ASD genes transmitted from parent to affected child in SPD and ASD patients, but not in unaffected ASD siblings.

In this report, WES has identified a stop codon mutation in MBD5 that likely causes premature truncation and nonsense mediated decay of the protein from one of the two alleles leading to haploinsufficiency. Methyl-CpG-binding domain 5 (MBD5) is a gene located at 2q23.1. This gene, reviewed by Mullegama, et al. 2016, is believed to contribute to DNA methylation and through that to potentially be involved in cell division, growth, and differentiation however further research is indicated to better understand the role of this protein [32]. Haploinsufficiency is believed to impact the expression of downstream genes such as upregulation of CF4 and UBE3A, and down regulation of MEF2C, EHMT1, RAI1 in a dose sensitive fashion [33]. Loss of function mutations in MBD5 are highly likely to be pathogenic given that the probability of loss of function intolerance is 1.00 [34].

MBD5, also referred to as mental retardation autosomal dominant 1 and now given the name MBD5-Associated Neurodevelopmental Disorder (MAND), was originally described in the context of the 2q23.1 microdeletion syndrome thought to be an Angelman Syndrome mimic. Clinically, affected individuals are variably affected by intellectual disability, motor delay, and severe speech impairment. The language deficits, social challenges and stereotypies seen in affected individuals can result in the affected child meeting criteria for autism [35, 36]. Additionally, children may have seizures, sleep disorders, and attentional challenge and some individuals will show mild craniofacial and skeletal anomalies [33, 37]. In the review article by Hodge et al. 2014, they summarize the phenotype for individuals in the literature with either point mutations in the MBD5 gene or microdeletions containing MBD5. In their summary table, they include reports of sensory integration disorder (SID) which is a label frequently used in the occupational therapy community. In children with MBD5 point mutations, there is no comment on SID, however SID is reported in 2/3 (66%) children with 2q23.1 microdeletions [33]. So while, sensory over-responsivity to either sound or touch was a key clinical inclusion phenotype in our cohort, it is not always considered in the current genetic literature and thus difficult to know the extent to which it affects children with single gene disorders.

The female patient in this study first presented to our SNAP clinic at age 11 years due to prominent sensory dysfunction affecting her auditory, vestibular, visual, tactile, and oral systems (classified as 2 standard deviations below average on the Sensory Profile [38]). On evaluation by a pediatric geneticist, no dysmorphic features were noted and she is normocephalic with a head circumference at the 44th percentile. On evaluation by a licensed community pediatric neuropsychologist (L.D.) using the Wechsler Intelligence Scale for Children-4th edition (WISC IV), she had a verbal comprehension index of 121, Perceptual Reasoning Index of 86, and a working memory index of 99. These scores are all in the average to above average range but highlight a relative challenge in the perceptual measures. While verbal conceptual skills are a strength, multiple aspects of motor control are a significant concern with poor articulation and dysgraphia leading to severe school based challenges. In addition, while socially alert, interested and driven, she has challenges with interpretation of non-verbal social cues as well as heightened distractibility affecting sustained focus and selective attention. Specifically, she meets cut-off criteria for combined Inattentive/Hyperactive subtype on the Vanderbilt ADHD Diagnostic Parent Rating Scale [39]. These challenges contribute to a lack of social finesse that has led to difficulty with maintaining age appropriate friendships. However on evaluation in the lab, in the community, and at school, she did not meet the social communication criteria for an autism spectrum disorder.

Of the nine genes with missense mutation leading to amino acid substitution, six were considered potentially damaging to the protein structure: FMN2, DNAH9, KLHL33, MCM2, PFDN6, SLCO2B1. Of these genes, only Formin 2 (FMN2) has been previously reported to be associated with neurodevelopmental impairment. FMN2, located at chromosome 1q43, is one of 15 members of the formin homology protein family and is thought to play a role in actin cytoskeleton organization and cellular polarity. FMN2 has received the designation: mental retardation, autosomal recessive 47. In addition to the literature implicating mutations of FMN2 with autosomal recessive inheritance, there are reports of heterozygous deletion involving FMN2 in two additional reports in patients with neurodevelopmental impairment [40, 41]. Law, et al. 2014 reports that FMN2 localizes to the dendrites and likely alters synaptic density in a mouse model that has demonstrated challenges with fear-learning [42]. Affected patients were reported to have challenges with cognition and speech out of proportion to their motor difficulties. In the existing literature, there is no report of associated dysmorphic features and in one family there were rare complex partial seizures. There is no mention of sensory processing ability or challenges in the extant literature.

The male patient in this study with the FMN2 missense mutation first presented to SNAP research at 9 years of age. The patient had sensory dysfunction affecting his auditory, vestibular, tactile, multisensory and oral systems (classified as 2 standard deviations below average on the Sensory Profile [38]). The patient had a verbal comprehension index of 116, Perceptual Reasoning Index of 115, and a working memory index of 94 as assed using the WISC IV. He did not meet ASD cut-off scoring using the ADOS Assessment. Finding these two, highly penetrant de novo mutations in SPD patients who do not meet criteria for ASD suggests that de novo mutations may be found as the primary etiology in a significant percentage (up to 18%) of children with a sensory-first presentation.

While it has long been recognized that triplet repeat and single gene disorders, such as Fragile X or SHANK2, and more recently copy number variation disorders, such as 16p11.2 deletion, are associated with neurodevelopmental conditions; there has also been substantial interest in whether a cumulative burden of rare single nucleotide variants, either inherited or de novo, can result in a clinical condition such as ASD or SPD. In this study, we looked first at our SPD pediatric cohort with the hypothesis that these affected children would have a higher burden of inherited rSNV in high- or moderate-risk ASD genes relative to the expected mutation rate. We found that, despite the small number of individuals in this pilot SPD cohort, there was indeed a trend level increase in transmitted rSNV in high-risk ASD candidate genes but not moderate-risk ASD genes. This result has two main implications. This finding suggests, first, that the SPD phenotype and the ASD phenotype may have shared genetic underpinnings in a “high value” gene set, as of now only 76 genes. Second, the phenotype may also result from an accumulation of multiple changes each with a smaller effect size, hence polygenic (and thus inherited from parents). Given that in the ASD literature, parents have been reported to show an increase in sensory processing behavioral differences, we investigated the burden of rSNV in the parents of our probands with SPD [43, 44].

Despite the small number of individuals in the cohort, there was a robust increase in the transmitted high risk ASD gene rSNV for parents of children with SPD. There was no increase in rSNV for either transmitted or non-transmitted moderate-risk ASD genes. This finding supports the importance of investigating the role of variant burden in SPD with a large effect in a small sample, and also highlights a potential difference in causality between the high and moderate-risk candidate genes. This robust increase in burden of variants in the parents is interesting given that the ASD literature suggests increased sensory differences in parents of affected individuals. In this SPD cohort, there are a couple of explanations that merit further exploration. First, it is possible that SPD parents themselves are affected by sensory processing dysfunction that is similar to their children’s. Second, one must consider that the probands have additional variants contributing to their clinical symptomatology that we are not measuring in the exonic DNA meriting a whole genome approach. Finally, it may not be simply the additive burden of the variants but rather a particular combination of variants in specific genes that may work in an epistatic fashion to contribute to sensory processing dysfunction.

We chose to further investigate the relationship between rSNV burden in affected children with SPD and their parents by applying this analysis to a cohort of children also known to have an increased prevalence of sensory difference, those with ASD. In the SSC ASD family cohort, we were also able to increase our statistical power both by the sheer number of ASD families and by the inclusion of an unaffected sibling in the family cluster. We thus investigated whether children with ASD from the SSC and their unaffected siblings and parents have a higher burden of rSNV that were transmitted to the identified proband with ASD. As predicted, the affected child when compared to his or her parents, but not the unaffected sibling, shows an increase in transmitted rSNV from the high-risk ASD gene set. After stringent Bonferroni correction, neither the unaffected siblings nor the parents showed a significant burden of non-transmitted rSNV. These findings underscore the importance of inherited variants in ASD, even in families recruited for an increased likelihood of de novo variants. In one recent genome-wide ASD study, children with ASD show a “nominal difference” in rare inherited nonsense/splice site mutations when compared to their unaffected siblings [45]. Similarly, a study including 3871 ASD cases investigating the interplay of common and rare variants, reports that 5% of the ASD cohort has de novo loss of function mutation in a set of 107 autosomal genes involved in synaptic formation, transcriptional regulation, and chromatin remodeling pathways. However, this study did not show an association for inherited missense variants, so these variants were not included in their Transmission And De novo Associated (TADA) analysis [46]. De Rubeis et al., 2014 suggest that while the de novo loss of function (LOF) mutations confer the largest effect on risk, by including de novo missense SNV and transmitted LOF variants, they were able to double their gene discovery rate and suggest that ASD genes show “a strong constraint against variation.” Future genetic investigation to determine whether there are genes specific to sensory challenges, specifically SOR, and genes more specific to language and social differences would greatly contribute to our understanding of neurodevelopment and neurodevelopmental disorders.

There are limitations to this work, which bear mentioning. This work needs to be replicated in a much larger independent sample, despite the provocative findings in this initial cohort. In future investigations, direct assessment of auditory and tactile SOR phenotype in parents and children with isolated SPD and ASD/SPD is warranted. Finally, bringing direct sensory phenotyping in a broader cohort of children with neurodevelopmental concerns with their parents and siblings in conjunction with genetic investigation will deepen our understanding of the contributing genetic variations, both monogenic and polygenic.

In this study, we find a rough estimate of 18% de novo, disease-associated, single gene mutations in a cohort of children identified on the basis of a sensory processing dysfunction. Furthermore, we find that this pediatric sensory cohort and their parents, similar to an autism cohort, show an enrichment of rare single nucleotide variants in genes previously reported to be associated with autism and neurodevelopmental delay. This small-scale study suggests that SPD results from genetically coded, brain based differences, with monogenic and polygenic contributions. It highlights the need for additional genetic research in SPD and the importance of a thorough genetic evaluation in children presenting with sensory processing dysfunctions, regardless of the additional neurodevelopmental concerns.