Analysis of the genetic contribution to thoracic aortic aneurysm or dissection in a prospective cohort of patients with familial and sporadic cases in East China

Table 4 Pathogenic or likely pathogenic variants identified by the IMPATT assay

No.	Age, Sex	Gene affected	Variant	MAF in Exac		Evidence-based ACMG	Aortic pathology	Clinical diagnosis	Classification	Previously reported?	Family history
No.	Age, Sex	Gene affected	Variant	Worldwide	East Asian	Evidence-based ACMG	Aortic pathology	Clinical diagnosis	Classification	Previously reported?	Family history
TAAD_6	13,M	FBN1	c.114delA p.Ala39fs	0.0000%	0.0000%	PVS	Aortic root aneurysm	Marfan	Pathologic	No	No
TAAD_81	20,M	FBN1	c.1285 C > T p.Arg429*	0.0000%	0.0000%	PVS	Aortic root aneurysm	Marfan	Pathologic	No	Yes
TAAD_89	50,M	MYLK	c.2736delG p.Lys913fs	0.0000%	0.0000%	PVS	Ascending aortic aneurysm	N/A	Pathologic	No	No
TAAD_90	47,M	SMAD3	c.139 C > T p.Gln47*	0.0000%	0.0000%	PVS	Ascending aortic aneurysm	N/A	Pathologic	No	No
TAAD_98	33,M	MYH11	c.3787_3789delAAG p.Lys1263del	0.0006%	0.0012%	PS3 + PM4 + PP1	Type A aortic dissection	N/A	Likely Pathologic¹	No	No
TAAD_102	30,M	FBN1	c.7988G > C p.Cys2663Ser	0.0000%	0.0000%	PS1 + PM2 + PP2 + PP3	Type A aortic dissection	Marfan	Pathologic	No	No

Note:
¹ The variant MYH11 c.3787_3789delAAG p. Lys1263del was categorized as likely pathogenic for the following reasons: (i) The variant had been proven to decrease the MYH11 level by RT‒qPCR and Western blot (PS3 evidence; we downgraded PM3 into PS3 because the report failed to directly confirm the harmful effect of protein function (PMID: 28,074,631)). (ii) The variant resulted in a change in the length of MYH11 (PM4 evidence). (iii) The variant and TAAD were cosegregated in several family members (PMID: 22,968,129, 26,056,961) (PP1 evidence). (iv) In the ClinVar database, vcv000180420.16 described the variant as likely pathogenic in 1 and a variant of uncertain significance in 7 among 8 submitters, In addition, this variant has been reported in several unrelated individuals affected with thoracic aortic aneurysm and aortic dissection (PMID: 25,907,466, 28,074,631, 28,391,405, 29,510,914, 30,675,029), as well as in two individuals referred for aortopathy genetic testing (PMID: 25,944,730). Finally (v) the protein level was found to be relatively decreased in the surgical specimen (data not shown)

ISSN: 1750-1172