Heterozygous loss-of-function SMC3 variants are associated with variable growth and developmental features.

Heterozygous missense variants and in-frame indels in SMC3 are a cause of Cornelia de Lange syndrome (CdLS), marked by intellectual disability, growth deficiency, and dysmorphism, via an apparent dominant-negative mechanism. However, the spectrum of manifestations associated with SMC3 loss-of-function variants has not been reported, leading to hypotheses of alternative phenotypes or even developmental lethality. We used matchmaking servers, patient registries, and other resources to identify individuals with heterozygous, predicted loss-of-function (pLoF) variants in SMC3, and analyzed population databases to characterize mutational intolerance in this gene. Here, we show that SMC3 behaves as an archetypal haploinsufficient gene: it is highly constrained against pLoF variants, strongly depleted for missense variants, and pLoF variants are associated with a range of developmental phenotypes. Among 14 individuals with SMC3 pLoF variants, phenotypes were variable but coalesced on low growth parameters, developmental delay/intellectual disability, and dysmorphism, reminiscent of atypical CdLS. Comparisons to individuals with SMC3 missense/in-frame indel variants demonstrated an overall milder presentation in pLoF carriers. Furthermore, several individuals harboring pLoF variants in SMC3 were nonpenetrant for growth, developmental, and/or dysmorphic features, and some had alternative symptomatologies with rational biological links to SMC3. Analyses of tumor and model system transcriptomic data and epigenetic data in a subset of cases suggest that SMC3 pLoF variants reduce SMC3 expression but do not strongly support clustering with functional genomic signatures of typical CdLS. Our finding of substantial population-scale LoF intolerance in concert with variable growth and developmental features in subjects with SMC3 pLoF variants expands the scope of cohesinopathies, informs on their allelic architecture, and suggests the existence of additional clearly LoF-constrained genes whose disease links will be confirmed only by multilayered genomic data paired with careful phenotyping.

Racial and Ethnic Disparities in Food Insufficiency in Families with Children During the COVID-19 Pandemic: the Role of Risk and Protective Factors.

BACKGROUND: Black and Hispanic households are at elevated risk of food insecurity and insufficiency-correlates of adverse outcomes in areas such as health and mental health-relative to White households in the USA. The COVID-19 pandemic and its economic shock threatened to further exacerbate these issues. Research has identified a number of risk and protective factors for food insecurity and insufficiency. These could relate to racial and ethnic disparities in two ways-through aggregate differences in the distribution of characteristics such as educational attainment and employment or through differences in the degree of risk or protection associated with a factor. We examined the relationship between four factors-household head age, educational attainment, single mother household composition, and employment-and disparities in food insufficiency between White, Black, and Hispanic households with children during the COVID-19 pandemic to consider these pathways. METHODS: We analyzed data from the Census Bureau's Household Pulse Survey using bivariate statistics, multivariable regression, and decomposition methods to understand differences in the prevalence and consequences of underlying risk and protective factors for food insufficiency in households with children. RESULTS: Consistent with prior literature, we documented higher rates of food insufficiency among Black and Hispanic households compared to White households. Differences in the distributions of education and employment accounted for a substantial fraction of the disparities in risk. Both the distribution and degree of risk associated with single mother household composition also related to disparities, but these differences were muted after accounting for economic resources. Much, though not all, of the relationship between the distributions of education and disparate risk of food insufficiency were also captured by differences in economic resources. CONCLUSION: This study provides insight into the structure underlying racial and ethnic disparities in food insufficiency during the COVID-19 pandemic, highlighting the importance of human capital, income, and assets.