(689.3) Novel Functional FOXC1 Variants in Familial and Sporadic Atrial Septal Defect

Poster Board Number: D60

Huan-Xin Chen (The Institute of Cardiovascular Diseases amp; Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Tianjin University amp; Chinese Academy of Medical Sciences), Hai-Tao Hou (The Institute of Cardiovascular Diseases amp; Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Tianjin University amp; Chinese Academy of Medical Sciences), Xiu-Li Wang (The Institute of Cardiovascular Diseases amp; Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Tianjin University amp; Chinese Academy of Medical Sciences), Qin Yang (The Institute of Cardiovascular Diseases amp; Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Tianjin University amp; Chinese Academy of Medical Sciences), Guo-Wei He (The Institute of Cardiovascular Diseases amp; Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Tianjin University amp; Chinese Academy of Medical Sciences, The Institute of Cardiovascular Diseases amp; Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Tianjin University amp; Chinese Academy of Medical Sciences, The Institute of Cardiovascular Diseases amp; Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Tianjin University amp; Chinese Academy of Medical Sciences)

Objective: Atrial septal defect (ASD) is one of the most common forms of congenital heart disease. Genetic defects play important roles in the pathogenesis of ASD but are complex and unclear. This study tries to discover the genetic pathogenesis in familial and sporadic ASD patients.

Methods: In Stage I, in a family with 30 members whole exome sequencing was performed in 4 ASD patients and the identified genetic variants were screened in the rest of the family members. In Stage II, 335 unrelated sporadic and isolated ASD patients were enrolled to test whether the genetic variants were involved in these patients. In Stage III, biological functions of the variants were elucidated at the cellular level and the CRISPR/Cas9 was used to construct variant-specific mutant mice in order to observe the abnormality of the heart structure.

Results: A novel heterozygous missense variant, FOXC1 c.518Ggt;A (p.R173H) was identified in the ASD family by whole exome sequencing. Subsequently, other 4 heterozygous variants in FOXC1, including 2 novel missense variants: c.556-558delAAG (p.K186del) and c.559Ggt;A (p.D187N) were identified in unrelated 335 sporadic ASD patients. In dual-luciferase reporter assay, the transcriptional activity of R173H decreased to almost 30% of the wild-type. In the Foxc1 R173H site-specific mutant mice, the atrial septum became very thin in tissue slices of the heart that was similar to the echocardiographic finding in the above family members.

Conclusion: Variants in FOXC1 likely cause cardiac anomaly, particularly ASD. These findings provide a new insight into genetic mechanisms and counseling of familial and sporadic ASD.

lt;igt;Supported by the National Natural Science Foundation of China [82170353 amp;amp; 81870288]; the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences [2020-PT310-007]; Tianjin Municipal Health Commission and Tianjin Binhai New Area Health Commission [KJ20071 amp;amp; 2019BWKY010 ]; Tianjin Science and Technology Project [18PTZWHZ00060];lt;/igt;lt;igt;TEDA International Cardiovascular Hospital[2021-ZX-002 amp;amp; 2019-TD-013]lt;/igt;