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Item Heterozygous loss-of-function SMC3 variants are associated with variable and incompletely penetrant growth and developmental features(medRxiv, 2023-09-28) Ansari, Morad; Faour, Kamli N. W.; Shimamura, Akiko; Grimes, Graeme; Kao, Emeline M.; Denhoff, Erica R.; Blatnik, Ana; Ben-Isvy, Daniel; Wang, Lily; Helm, Benjamin M.; Firth, Helen; Breman, Amy M.; Bijlsma, Emilia K.; Iwata-Otsubo, Aiko; de Ravel, Thomy J. L.; Fusaro, Vincent; Fryer, Alan; Nykamp, Keith; Stühn, Lara G.; Haack, Tobias B.; Korenke, G. Christoph; Constantinou, Panayiotis; Bujakowska, Kinga M.; Low, Karen J.; Place, Emily; Humberson, Jennifer; Napier, Melanie P.; Hoffman, Jessica; Juusola, Jane; Deardorff, Matthew A.; Shao, Wanqing; Rockowitz, Shira; Krantz, Ian; Kaur, Maninder; Raible, Sarah; Kliesch, Sabine; Singer-Berk, Moriel; Groopman, Emily; DiTroia, Stephanie; Ballal, Sonia; Srivastava, Siddharth; Rothfelder, Kathrin; Biskup, Saskia; Rzasa, Jessica; Kerkhof, Jennifer; McConkey, Haley; O'Donnell-Luria, Anne; Sadikovic, Bekim; Hilton, Sarah; Banka, Siddharth; Tüttelmann, Frank; Conrad, Donald; Talkowski, Michael E.; FitzPatrick, David R.; Boone, Philip M.; Medical and Molecular Genetics, School of MedicineHeterozygous 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 13 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 a milder presentation in pLoF carriers. Furthermore, several individuals harboring pLoF variants in SMC3 were nonpenetrant for growth, developmental, and/or dysmorphic features, some instead having intriguing symptomatologies with rational biological links to SMC3 including bone marrow failure, acute myeloid leukemia, and Coats retinal vasculopathy. Analyses of transcriptomic and epigenetic data suggest that SMC3 pLoF variants reduce SMC3 expression but do not result in a blood DNA methylation signature clustering with that of CdLS, and that the global transcriptional signature of SMC3 loss is model-dependent. Our finding of substantial population-scale LoF intolerance in concert with variable penetrance 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 multi-layered genomic data paired with careful phenotyping.Item Heterozygous loss-of-function SMC3 variants are associated with variable growth and developmental features(Elsevier, 2024) Ansari, Morad; Faour, Kamli N. W.; Shimamura, Akiko; Grimes, Graeme; Kao, Emeline M.; Denhoff, Erica R.; Blatnik, Ana; Ben-Isvy, Daniel; Wang, Lily; Helm, Benjamin M.; Firth, Helen; Breman, Amy M.; Bijlsma, Emilia K.; Iwata-Otsubo, Aiko; de Ravel, Thomy J. L.; Fusaro, Vincent; Fryer, Alan; Nykamp, Keith; Stühn, Lara G.; Haack, Tobias B.; Korenke, G. Christoph; Constantinou, Panayiotis; Bujakowska, Kinga M.; Low, Karen J.; Place, Emily; Humberson, Jennifer; Napier, Melanie P.; Hoffman, Jessica; Juusola, Jane; Deardorff, Matthew A.; Shao, Wanqing; Rockowitz, Shira; Krantz, Ian; Kaur, Maninder; Raible, Sarah; Dortenzio, Victoria; Kliesch, Sabine; Singer-Berk, Moriel; Groopman, Emily; DiTroia, Stephanie; Ballal, Sonia; Srivastava, Siddharth; Rothfelder, Kathrin; Biskup, Saskia; Rzasa, Jessica; Kerkhof, Jennifer; McConkey, Haley; Sadikovic, Bekim; Hilton, Sarah; Banka, Siddharth; Tüttelmann, Frank; Conrad, Donald F.; O'Donnell-Luria, Anne; Talkowski, Michael E.; FitzPatrick, David R.; Boone, Philip M.; Medical and Molecular Genetics, School of MedicineHeterozygous 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.Item The global prevalence and ethnic heterogeneity of primary ciliary dyskinesia gene variants: a genetic database analysis(Elsevier, 2022) Hannah, William B.; Seifert, Bryce A.; Truty, Rebecca; Zariwala, Maimoona A.; Ameel, Kristen; Zhao, Yi; Nykamp, Keith; Gaston, Benjamin; Biostatistics and Health Data Science, School of MedicineBackground: Primary ciliary dyskinesia (PCD) is a motile ciliopathy characterised by otosinopulmonary infections. Inheritance is commonly autosomal recessive, with extensive locus and allelic heterogeneity. The prevalence is uncertain. Most genetic studies have been done in North America or Europe. The aim of the study was to estimate the worldwide prevalence and ethnic heterogeneity of PCD. Methods: We calculated the allele frequency of disease-causing variants in 29 PCD genes associated with autosomal recessive inheritance in 182 681 unique individuals to estimate the global prevalence of PCD in seven ethnicities (African or African American, Latino, Ashkenazi Jewish, Finnish, non-Finnish European, east Asian, and south Asian). We began by aggregating variants that had been interpreted by Invitae, San Francisco, CA, USA, a genetics laboratory with PCD expertise. We then determined the allele frequency of each variant (pathogenic, likely pathogenic, or variant of uncertain significance [VUS]) in the Genome Aggregation Database (gnomAD), a publicly available next-generation sequencing database that aggregates exome and genome sequencing information from a wide variety of large-scale projects and stratifies allele counts by ethnicity. Using the Hardy-Weinberg equilibrium equation, we were able to calculate a lower-end prevalence of PCD for each ethnicity by including only pathogenic and likely pathogenic variants; and upper-end prevalence by also including VUS. This approach was similar to previous work on Li-Fraumeni (TP53 variants) prevalence. We were not diagnosing PCD, but rather estimating prevalence based on known variants. Findings: The overall minimum global prevalence of PCD is calculated to be at least one in 7554 individuals, although this is likely to be an underestimate because some variants currently classified as VUS might be disease-causing and some pathogenic variants might not be detected by our methods. In the overall cohort, Invitae data could be included for variants without gnomAD data for a primary ethnicity. When using only gnomAD allele frequencies to calculate prevalence in individual ethnicities, the estimated prevalence of PCD was lower in each ethnicity compared with the overall cohort. This is because the overall cohort includes additional data from the Invitae database such as copy number variants and other variants not present in gnomAD. With gnomAD we found the expected PCD frequency to be higher in individuals of African ancestry than in most other populations (excluding VUS: 1 in 9906 in African or African American vs 1 in 10 388 in non-Finnish European vs 1 in 14 606 in east Asian vs 1 in 16 309 in Latino; including VUS: 1 in 106 in African or African American vs 1 in 178 in non-Finnish European vs 1 in 196 in Latino vs 1 in 188 in east Asian). In addition, we found that the top 5 genes most commonly implicated in PCD differed across ethnic ancestries and contrasted commonly published findings. Interpretation: PCD appears to be more common than has been recognised, particularly in individuals of African ancestry. We identified gene distributions that differ from those in previous European and North American studies. These results could have an international impact on case identification. Our analytic approach can be expanded as more PCD loci are identified, and could be adapted to study the prevalence of other inherited diseases.