CITED2 was first reported in relation to autosomal dominant congenital heart disease in 2012 (Chen et al., PMID 23082118). At least 10 rare variants (9 missense, 1 splice variant in the non-canonical gene) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. CITED2 has been noted to be associated with the following disease entities: atrial septal defect and ventricular septal defect (OMIM 614431 and 614433). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism and inheritance pattern. Therefore, these disease entities have been lumped into one disease entity, Autosomal Dominant CITED2-related Congenital Heart Disorders. Variants in this gene have been reported in at least 10 probands in 10 publications (PMIDs 23082118, 24848765, 24456003, 28436679, 28687891, 31515672), using an allele frequency threshold of 1x10-5. This gene-disease relationship is supported by animal models, expression studies, and functional assays. Expression studies confirmed that CITED2 is expressed early in chick and mouse embryogenesis (PMIDs 11044621, 11823447, 15750185, 17133411). Fetal human tissues from hearts affected by ventricular septal defects had decreased CITED2 expression (PMID 23899608). Loss of CITED resulted in impaired mesoderm and cardiomyocyte differentiation from mouse embryonic stem cells (PMIDs 22761414, 31378782), while overexpression led to increased cardiac differentiation (PMID 27818139). Mouse models demonstrated that deficiency of CITED led to cardiac malformations as well as neural tube defects (PMIDs 15475956, 12149478, 11694877, 15750185, 18440989, 21224256, 22504313). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 9/5/23 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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