Genetic testing of 10 patients with features of loeys-dietz syndrome

Genetic profiling and cardiovascular phenotypic spectrum in a Chinese cohort of Loeys-Dietz syndrome patients

“…Upon a detailed examination of the father's cardiac structure and arterial tree, there were no apparent abnormalities except for a slight decrease in left ventricular diastolic function. Considering that LDS was a dominant disorder with full penetrance expected at an early age and that the variant was also observed in the patient's healthy father, this variant was finally downgraded into VUS [11] with conflicting evidence (BS2). When we reanalyzed this case after half a year, we noted that the unequal peak heights suggested probable mosaicism.…”

“…Note: NA not available; MAF in ExAC was the maximal allele frequency from the public version (20160423), and MAF in gnomAD was the maximal allele frequency from gnomAD v2.1.1; P, pathogenic; LP, likely pathogenic; VUS, variant of uncertain significance; a , reported in our previous article [11]; b This variant was previously classified as VUS, and then upgraded into pathogenic after the father was confirmed to carry a mosaic mutation in the same site; $ This variant was confirmed to be de novo in patient AD1413's mother we performed deep sequencing (5000×) at this location, and the results showed that the father indeed had a mosaic mutation (Fig. 2), which convincingly explained his lack of LDS symptoms.…”

“…Except that her youngest brother had pectus carinatum and scoliosis, other family members had no obvious skeletal deformities. A 15-gene panel [9] testing revealed that she Note: NA not available; MAF in ExAC was the maximal allele frequency from the public version (20160423), and MAF in gnomAD was the maximal allele frequency from gnomAD v2.1.1; P, pathogenic; LP, likely pathogenic; VUS, variant of uncertain significance; a , reported in our previous article [11]; b This variant was previously misclassified as likely pathogenic [11], and now corrected into VUS carried a TGFBR2 mutation (c.1254G > T, p.Gln418His), which was inherited from her mother, who suffered an aortic dissection at age 42. Therefore, she was highly suspected to be LDS.…”

Features of multiple self‐healing squamous epithelioma and Loeys‐Dietz syndrome in a patient with a novel TGFBR1 variant

“…Pathogenic missense variants in or near the TGFBR1 kinase domain (encoded by Exons 4–9) are established to cause LDS (Loeys et al, ; Luo et al, ; Figure ). The mechanism of disease is complex: Transfected cell cultures exhibit reduced TGF‐β signaling (suggesting loss of function), but mouse models demonstrate paradoxically increased TGF‐β signaling in their aortic wall (Cardoso, Robertson, & Daniel, ; Gallo et al, ).…”

“…Loeys‐Dietz syndrome (LDS) is similarly associated with pathogenic variants in the TGFBR1 gene though it is clinically distinct [OMIM #609192, #610168]. Variants causing LDS are primarily missense variants found in the kinase domain (Loeys et al, ; Luo et al, ). LDS can also be caused by pathogenic variants in TGFBR2 (Loeys et al, ).…”