De novo coding variants in the AGO1 gene cause a neurodevelopmental disorder with intellectual disability.

BACKGROUND: High-impact pathogenic variants in more than a thousand genes are involved in Mendelian forms of neurodevelopmental disorders (NDD). METHODS: This study describes the molecular and clinical characterisation of 28 probands with NDD harbouring heterozygous AGO1 coding variants, occurring de novo for all those whose transmission could have been verified (26/28). RESULTS: A total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Recurrently identified variants were present in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del). AGO1 encodes the Argonaute 1 protein, which functions in gene-silencing pathways mediated by small non-coding RNAs. Three-dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linker domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behaviour and additional behavioural manifestations. CONCLUSION: Our study establishes that de novo coding variants in AGO1 are involved in a novel monogenic form of NDD, highly similar to the recently reported AGO2-related NDD.

Associations between psychosocial wellbeing and experience of gender-based violence at community, household, and intimate-partner levels among a cross-sectional cohort of young people living with and without HIV during COVID-19 in Cape Town, South Africa.

BACKGROUND: Growing evidence indicates that gender-based violence (GBV) increased during COVID-19. We investigated self-reported impact of the pandemic on GBV at community, household and intimate partner (IPV) levels among young people and its associations with psychosocial wellbeing, i.e., COVID-related stressors and mental health. METHODS: Cross-sectional data were drawn from a survey with young people ages 13-24 (N = 536) living with HIV (YPLWH) and without HIV (YPLWoH), in peri-urban Cape Town, South Africa. The survey, conducted February-October 2021, examined the impact of the initial lockdown on experience and perceived changes in GBV at each level, and pandemic-related psychosocial wellbeing. Descriptive statistics and binomial and multinomial regression analyses were conducted to illustrate exposure and perceived changes in GBV since lockdown, and their association with COVID-related stress factors (e.g., social isolation, anxiety about COVID), mental health (e.g., depression, anxiety), and other risk factors (e.g., age, gender, socioeconomic status) by HIV status. RESULTS: Participants were 70% women with mean age 19 years; 40% were living with HIV. Since lockdown, YPLWoH were significantly more likely than YPLWH to perceive community violence as increasing (45% vs. 28%, p < 0.001), and to report household violence (37% vs. 23%, p = 0.006) and perceive it as increasing (56% vs. 27%, p = 0.002) (ref: decreasing violence). YPLWoH were also more likely to report IPV experience (19% vs. 15%, p = 0.41) and perception of IPV increasing (15% vs. 8%, p = 0.92). In adjusted models, COVID-related stressors and common mental health disorders were only associated with household violence. However, indicators of economic status such as living in informal housing (RRR = 2.07; 95% CI = 1.12-3.83) and food insecurity (Community violence: RRR = 1.79; 95% CI = 1.00-3.20; Household violence: RRR = 1.72; 95% CI = 1.15-2.60) emerged as significant risk factors for exposure to increased GBV particularly among YPLWoH. CONCLUSIONS: Findings suggest that for young people in this setting, GBV at community and household levels was more prevalent during COVID-19 compared to IPV, especially for YPLWoH. While we found limited associations between COVID-related stressors and GBV, the perceived increases in GBV since lockdown in a setting where GBV is endemic, and the association of household violence with mental health, is a concern for future pandemic responses and should be longitudinally assessed.

Access to sexual and reproductive health services among South African young people living with and without HIV during the COVID-19 pandemic.

OBJECTIVE: To examine sexual and reproductive health (SRH) service access among South African young people during the COVID-19 pandemic. STUDY DESIGN: We utilized cross-sectional data collected from February to October 2021 in Cape Town among young people 13-24 years of age living with and without HIV. RESULTS: Two hundred and fifteen young people living with HIV (YPLWH) and 320 young people living without HIV were included. Young people reported an unmet need for SRH services during COVID-19, and 28% of YPLWH reported missing an HIV care appointment during the COVID-19 lockdowns. CONCLUSIONS: Expanding access to SRH services for young people during disruptive events is critical to reduce disparities in HIV and other SRH outcomes.