De novo variants in SIAH1, encoding an E3 ubiquitin ligase, are associated with developmental delay, hypotonia and dysmorphic features.

BACKGROUND: Ubiquitination has a central role in numerous biological processes, including cell development, stress responses and ageing. Perturbed ubiquitination has been implicated in human diseases ranging from cancer to neurodegenerative diseases. SIAH1 encodes a RING-type E3 ubiquitin ligase involved in protein ubiquitination. Among numerous other roles, SIAH1 regulates metabotropic glutamate receptor signalling and affects neural cell fate. Moreover, SIAH1 positively regulates Wnt signalling through ubiquitin-mediated degradation of Axin and accumulation of ß-catenin. METHODS: Trio exome sequencing followed by Sanger validation was undertaken in five individuals with syndromic developmental delay. Three-dimensional structural modelling was used to predict pathogenicity of affected residues. Wnt stimulatory activity was measured by luciferase reporter assays and Axin degradation assays in HEK293 cells transfected with wild-type and mutant SIAH1 expression plasmids. RESULTS: We report five unrelated individuals with shared features of developmental delay, infantile hypotonia, dysmorphic features and laryngomalacia, in whom exome sequencing identified de novo monoallelic variants in SIAH1. In silico protein modelling suggested alteration of conserved functional sites. In vitro experiments demonstrated loss of Wnt stimulatory activity with the SIAH1 mutants, suggesting variant pathogenicity. CONCLUSION: Our results lend support to SIAH1 as a candidate Mendelian disease gene for a recognisable syndrome, further strengthening the connection between SIAH1 and neurodevelopmental disorders. Furthermore, the results suggest that dysregulation of the Wnt/ß-catenin pathway may be involved in the pathogenesis.

Genetic counselors' attitudes toward and practice related to psychiatric genetic counseling.

Despite the high demand for psychiatric genetic counseling among people with psychiatric conditions (>90%), surveys show that genetic counselors rarely receive primary referrals for psychiatric cases. The purpose of this study was to further investigate potential barriers to the provision of psychiatric genetic counseling services, focusing specifically on the prevalence and impact of psychiatric stigmatization among genetic counselors. Board-certified, practicing genetic counselors were invited to participate in an anonymous survey via the National Society of Genetic Counselors. Survey measures included a validated psychiatric stigmatization scale (OMS-HC) and questions assaying genetic counselors' experiences with and opinions of psychiatric genetic counseling. Associations between psychiatric stigmatization and attitudes toward and practice related to psychiatric genetic counseling were computed using Pearson's correlation. The majority of respondents believed that psychiatric genetic counseling is of value to families (94%) and that it is indicated if there is a relevant personal or family history (90.3%), but only 44.6% reported providing this service. On average, respondents scored neutrally on psychiatric stigma scales; however, higher stigma levels were associated with less frequent psychiatric discussions (p = .05), less counselor comfort and perceived qualification (p = .003) and perceptions of having insufficient psychiatric genetic data (p < .02), resources (p < .02) and time (p < .03). This study suggests that the limits of psychiatric genetics research and unavailability of genetic testing lead many genetic counselors to doubt the utility of psychiatric genetic counseling. Should this mindset persist, without the intervention of psychiatric education and training, the field of genetic counseling risks continuing to inadequately serve a historically underserved population.