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To the Editor: Zhang et al. (Dec. 10 issue) 1 report the prevalence of mutations in predisposition genes among children and adolescents with cancer. One of their main conclusions is that family history does not predict the presence of an underlying germline mutation. However, it is not clear how the authors obtained information about family history. There are important differences between an in-depth interview by a clinical geneticist and a query about additional cancer in the family by a pediatrician. Moreover, information on family history was available in only 58 patients (61%) and missing in the remaining 37 patients (39%); selection . . .

Myocardin (MYOCD) is the founding member of a class of transcriptional coactivators that bind the serum-response factor to activate gene expression programs critical in smooth muscle (SM) and cardiac muscle development. Insights into the molecular functions of MYOCD have been obtained from cell culture studies, and to date, knowledge about in vivo roles of MYOCD comes exclusively from experimental animals. Here, we defined an often lethal congenital human disease associated with inheritance of pathogenic MYOCD variants. This disease manifested as a massively dilated urinary bladder, or megabladder, with disrupted SM in its wall. We provided evidence that monoallelic loss-of-function variants in MYOCD caused congenital megabladder in males only, whereas biallelic variants were associated with disease in both sexes, with a phenotype additionally involving the cardiovascular system. These results were supported by cosegregation of MYOCD variants with the phenotype in 4 unrelated families by in vitro transactivation studies in which pathogenic variants resulted in abrogated SM gene expression and by the finding of megabladder in 2 distinct mouse models with reduced Myocd activity. In conclusion, we have demonstrated that variants in MYOCD result in human disease, and the collective findings highlight a vital role for MYOCD in mammalian organogenesis.

Background Pathogenic variants in FBN1 cause autosomal dominant Marfan syndrome but can also be found in patients presenting with apparently isolated features of Marfan syndrome. Moreover, several families with autosomal recessive Marfan syndrome caused by pathogenic variants in FBN1 have been described. The aim of this report was to underline the clinical variability that can be associated with the pathogenic variant c.1453C>T, p.(Arg485Cys) in FBN1. Methods We provide the clinical details of two autosomal dominant families with this specific FBN1 variant, which was previously associated with autosomal recessive Marfan syndrome. Results Clinical data of 14 individuals carrying this variant from these two families were collected retrospectively. In both families, the diagnosis of autosomal dominant Marfan syndrome was established based on the characteristics of the variant and the phenotype which includes aortic aneurysms and dissections. Of interest, in one of the families, multiple relatives were diagnosed with early onset abdominal aortic aneurysms. Conclusion In conclusion, FBN1 variant c.1453C>T, p.(Arg485Cys) is a pathogenic variant that can cause autosomal dominant Marfan syndrome characterized by a high degree of clinical variability and apparently isolated early onset familial abdominal aortic aneurysms. This study corroborates the high degree of clinical variability associated with variants in FBN1 and provides novel insights into the pattern of inheritance of FBN1 variant c.1453C>T, p.(Arg485Cys). Homozygosity for this variant was previously reported to cause autosomal recessive Marfan syndrome (MFS) in a consanguineous family. As illustrated by these two pedigrees, we provide the clinical details of two autosomal dominant families with MFS with this specific FBN1 variant.

Pathogenic loss-of-function variants in BGN, an X-linked gene encoding biglycan, are associated with Meester-Loeys syndrome (MRLS), a thoracic aortic aneurysm/dissection syndrome. Since the initial publication of five probands in 2017, we have considerably expanded our MRLS cohort to a total of 18 probands (16 males and 2 females). Segregation analyses identified 36 additional BGN variant-harboring family members (9 males and 27 females). The identified BGN variants were shown to lead to loss-of-function by cDNA and Western Blot analyses of skin fibroblasts or were strongly predicted to lead to loss-of-function based on the nature of the variant. No (likely) pathogenic missense variants without additional (predicted) splice effects were identified. Interestingly, a male proband with a deletion spanning the coding sequence of BGN and the 5’ untranslated region of the downstream gene (ATP2B3) presented with a more severe skeletal phenotype. This may possibly be explained by expressional activation of the downstream ATPase ATP2B3 (normally repressed in skin fibroblasts) driven by the remnant BGN promotor. This study highlights that aneurysms and dissections in MRLS extend beyond the thoracic aorta, affecting the entire arterial tree, and cardiovascular symptoms may coincide with non-specific connective tissue features. Furthermore, the clinical presentation is more severe and penetrant in males compared to females. Extensive analysis at RNA, cDNA, and/or protein level is recommended to prove a loss-of-function effect before determining the pathogenicity of identified BGN missense and non-canonical splice variants. In conclusion, distinct mechanisms may underlie the wide phenotypic spectrum of MRLS patients carrying loss-of-function variants in BGN.