Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by a core set of atypical behaviors in social‐communicative and repetitive‐motor domains. Individual profiles are widely heterogeneous and include language skills ranging from nonverbal to hyperlexic. The causal mechanisms underlying ASD remain poorly understood but appear to include a complex combination of polygenic and environmental risk factors. SHANK3 (SH3 and multiple ankyrin repeat domains 3) is one of a subset of well‐replicated ASD‐risk genes (i.e., genes demonstrating ASD associations in multiple studies), with haploinsufficiency of SHANK3 following deletion or de novo mutation seen in about 1% of non‐syndromic ASD. SHANK3 is a synaptic scaffolding protein enriched in the postsynaptic density of excitatory synapses. In order to more closely evaluate the contribution of SHANK3 to neurodevelopmental expression of ASD, a knockout mouse model with a mutation in the PDZ domain was developed. Initial research showed compulsive/repetitive behaviors and impaired social interactions in these mice, replicating two core ASD features. The current study was designed to further examine Shank3B heterozygous and homozygous knockout mice for behaviors that might map onto atypical language in ASD (e.g., auditory processing, and learning/memory). We report findings of repetitive and atypical aggressive social behaviors (replicating prior reports), novel evidence that Shank3B KO mice have atypical auditory processing (low‐level enhancements that might have a direct relationship with heightened pitch discrimination seen in ASD), as well as robust learning impairments.

Language development builds upon a complex network of interacting subservient systems. It therefore follows that variations in, and subclinical disruptions of, these systems may have secondary effects on emergent language. In this paper, we consider the relationship between genetic variants, hearing, auditory processing and language development. We employ whole genome sequencing in a discovery family to target association and gene x environment interaction analyses in two large population cohorts; the Avon Longitudinal Study of Parents and Children (ALSPAC) and UK10K. These investigations indicate that USH2A variants are associated with altered low-frequency sound perception which, in turn, increases the risk of developmental language disorder. We further show that Ush2a heterozygote mice have lowlevel hearing impairments, persistent higher-order acoustic processing deficits and altered vocalizations. These findings provide new insights into the complexity of genetic mechanisms serving language development and disorders and the relationships between developmental auditory and neural systems.

Background Albright hereditary osteodystrophy (AHO) is caused by heterozygous inactivating mutations in GNAS. Patients with maternally-inherited mutations develop pseudohypoparathyroidism type 1A (PHP1A) with multi-hormone resistance and aberrant craniofacial and skeletal development among other abnormalities. Chiari malformation type 1 (CM1), a condition in which brain tissue extends into the spinal canal when the skull is too small, has been reported in isolated cases of PHP1A. It has been hypothesized to be associated with growth hormone (GH) deficiency. Given the adverse clinical sequelae that can occur if CM1 goes unrecognized, we investigated the previously undetermined prevalence of CM1, as well as any potential correlations with GH status, given the known increased prevalence of GH deficiency in PHP1A. We also investigated these metrics for low lying cerebellar tonsils (LLCT), defined as tonsillar descent less than 5 mm below the foramen magnum. In addition, we investigated possible correlations of CM1/LLCT with advanced hand/wrist bone ages and craniofacial abnormalities known to occur in PHP1A to determine whether premature chondrocyte differentiation and/or aberrant craniofacial development could be potential etiologies of CM1/LLCT through both human studies and investigations of our AHO mouse model. Methods We examined patients with PHP1A in our clinic and noticed CM1 more frequently than expected. Therefore, we set out to determine the true prevalence of CM1 and LLCT in a cohort of 54 mutation-confirmed PHP1A participants who had clinically-indicated brain imaging. We examined potential correlations with GH status, clinical features, biological sex, genotype, and hand/wrist bone age determinations. In addition, we investigated the craniofacial development in our mouse model of AHO (Gnas E1+/-m) by histologic analyses, dynamic histomorphometry, and micro-computerized tomographic imaging (MCT) in order to determine potential etiologies of CM1/LLCT in PHP1A. Results In our cohort of PHP1A, the prevalence of CM1 is 10.8%, which is at least 10-fold higher than in the general population. If LLCT is included, the prevalence increases to 21.7%. We found no correlation with GH status, biological sex, genotype, or hand/wrist bone age. Through investigations of our Gnas E1+/-m mice, the correlate to PHP1A, we identified a smaller cranial vault and increased cranial dome angle with evidence of hyperostosis due to increased osteogenesis. We also demonstrated that there was premature closure of the spheno-occipital synchondrosis (SOS), a cartilaginous structure essential to the development of the cranial base. These findings lead to craniofacial abnormalities and could contribute to CM1 and LLCT development in PHP1A. Conclusion The prevalence of CM1 is at least 10-fold higher in PHP1A compared to the general population and 20-fold higher when including LLCT. This is independent of the GH deficiency that is found in approximately two-thirds of patients with PHP1A. In light of potential serious consequences of CM1, clinicians should have a low threshold for brain imaging. Investigations of our AHO mouse model revealed aberrant cranial formation including a smaller cranium, increased cranial dome angle, hyperostosis, and premature SOS closure rates, providing a potential etiology for the increased prevalence of CM1 and LLCT in PHP1A.