Genetic testing of 248 Chinese aortopathy patients using a panel assay

Abstract

Inherited aortopathy, which is characterized by a high risk of fatal aortic aneurysms/dissections, can occur secondarily to several syndromes. To identify genetic mutations and help make a precise diagnosis, we designed a gene panel containing 15 genes responsible for inherited aortopathy and tested 248 probands with aortic disease or Marfan syndrome. The results showed that 92 individuals (37.1%) tested positive for a (likely) pathogenic mutation, most of which were FBN1 mutations. We found that patients with a FBN1 truncating or splicing mutation were more prone to developing severe aortic disease or valvular disease. To date, this is the largest reported cohort of Chinese patients with aortic disease who have undergone genetic testing. Therefore, it can serve as a considerable dataset of next generation sequencing data analysis of Chinese population with inherited aortopathy. Additionally, according to the accumulated data, we optimized the analysis pipeline by adding quality control steps and lowering the false positive rate.

Patient with Marfan Syndrome and a Novel Variant in FBN1 Presenting with Bilateral Popliteal Artery Aneurysm

“…Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders [ 2 ]. Furthermore, other missense variants at the same residue (C1958Y, C1958R) have also been reported in published literature in association with FBN1-related disorders, including assumed de novo occurrences for both variants, supporting the functional significance of this residue [ 15 – 17 ]. Finally, this variant has not been observed in large population cohorts such as the ExAC (Exome Aggregation Consortium) database [ 18 – 20 ].…”

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

“…More than 900 patients with aortic disease and/or diagnosed or suspected MFS had been referred from the Aortic Surgery Department to the Center for Molecular Diagnosis at Fuwai Hospital and had undergone panel testing involving 15 genes (ACTA2, COL3A1, FBN1, FBN2, MYH11, MYLK, NOTCH1, PRKG1, SKI, SLC2A10, SMAD3, SMAD4, TGFB2, TGFBR1, TGFBR2) since Feb 2014 [9]. Furthermore, more than 200 aortopathy patients were performed whole exome sequencing.…”

“…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.…”

NGS Technologies as a Turning Point in Rare Disease Research , Diagnosis and Treatment

“…Several studies in which gene panels have been used for clinical diagnosis have reported varying rates of diagnosis. Just some of the diseases studied to date are epilepsy [ 134 , 135 ], metabolic disorders [ 31 , 45 , 136 , 137 ], orodental diseases [ 138 ], neuromuscular disorders [ 139 - 142 ], hereditary immunodeficiencies [ 143 - 144 ], hereditary motor neuropathies [ 145 - 147 ], amyotrophic lateral sclerosis [ 148 ], intellectual disability [ 149 ], hematologic diseases [ 150 , 151 ], skeletal dysplasias [ 152 ], cardiovascular disorders [ 153 - 155 ], hearing loss [ 156 - 157 ], retinal disorders [ 158 - 163 ], sex development [ 164 - 165 ], maturity onset diabetes of the young [ 166 ], ichthyosis [ 167 ], cystic kidney diseases [ 168 ], and aortopathies [ 169 ].…”