Frequency of Sex Chromosome Involvement in a Large Cohort of Subjects with Two Copy Number Variants.

Copy number variants (CNVs) are a common finding in the clinical setting and contribute to both genetic variation and disease. Studies have described the accumulation of multiple CNVs as a disease-modifying mechanism. While it has been described how additional CNVs may play a role in phenotype, in which ways and to what extent sex chromosomes are involved in dual CNV scenario has not been fully defined. To describe the distribution of CNVs, a secondary data analysis using the DECIPHER database on 2,273 de-identified individuals with two CNVs was performed. CNVs were designated larger and secondary based on size and characteristics. We found that the X chromosome was observed to be the most common chromosome involved in secondary CNVs. Further analysis showed CNVs on the sex chromosome have significant differences compared to autosomes when comparing median size (p = 0.013), pathogenicity groups (p < 0.001), and variant classification (p = 0.001). Lastly, we identified chromosome combinations for larger and secondary CNVs and observed the plurality of secondary CNVs fell in the same chromosome as the larger. The observations of this study provide additional information on sex chromosome CNV involvement in a variety of indications.

The first reported case of Loeys-Dietz syndrome in a patient with biallelic SMAD3 variants.

Loeys-Dietz syndrome (LDS), a connective tissue disorder characterized by its vascular, skeletal, craniofacial, and cutaneous manifestations is caused by mutations in one of six genes (TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2, and TGFB3). Until recently, all reported cases of LDS have been attributed to heterozygous pathogenic variants in these genes. Here, we report the first case of Loeys-Dietz syndrome due to SMAD3 biallelic likely pathogenic variants in a 15-year-old male with classic Loeys-Dietz features, including dysmorphic facial features, significant scoliosis, and pectus excavatum, arachnodactyly, severe aortic root dilation, and diffuse arterial tortuosity. His parents are each heterozygous for the likely pathogenic variant and are more mildly affected. To our knowledge, this represents the first reported case of biallelic SMAD3-related Loeys-Dietz syndrome and the third case in the literature of biallelic LDS, indicating that there are multiple genetic modes of inheritance underlying this disorder.