FOXC1 haploinsufficiency due to 6p25 deletion in a patient with rapidly progressing aortic valve disease

6p25 deletion is a rare but well‐known entity. The main clinical features include an abnormal facial appearance, developmental delay, and ocular anomalies. Cardiac anomalies are frequently seen but remain poorly delineated. We describe a 4‐year‐old girl with 6p25.3 deletion, which includes the FOXC1 gene, typical dysmorphic features associated with developmental delay and oculo‐motor anomalies. Aortic valve dysplasia was diagnosed early in life. The cardiac lesion progressed very rapidly between the age of 3 and 4 years requiring aortic valve replacement. Genomic analysis of blood and excised valve tissue showed down‐regulation of FOXC1 but also FOXC2 expression in the diseased aortic valve. This allows us to speculate on the potential role of FOXC1 in aortic valve anomalies.

[1]  C. Stumpel,et al.  The 6p25 deletion syndrome: An update on a rare neurocristopathy , 2017, Ophthalmic genetics.

[2]  R. Redon,et al.  Search for Rare Copy-Number Variants in Congenital Heart Defects Identifies Novel Candidate Genes and a Potential Role for FOXC1 in Patients With Coarctation of the Aorta , 2016, Circulation. Cardiovascular genetics.

[3]  K. Xia,et al.  A Novel Mutation of FOXC1 (R127L) in an Axenfeld–Rieger Syndrome Family with Glaucoma and Multiple Congenital Heart Diseases , 2014, Ophthalmic genetics.

[4]  B. Keavney,et al.  Functionally Significant, Rare Transcription Factor Variants in Tetralogy of Fallot , 2014, PloS one.

[5]  K. Gripp,et al.  Cardiac anomalies in Axenfeld–Rieger syndrome due to a novel FOXC1 mutation , 2013, American journal of medical genetics. Part A.

[6]  T. Kume.  The cooperative roles of Foxc1 and Foxc2 in cardiovascular development. , 2009, Advances in experimental medicine and biology.

[7]  Tsutomu Kume,et al.  Forkhead transcription factors, Foxc1 and Foxc2, are required for the morphogenesis of the cardiac outflow tract. , 2006, Developmental biology.

[8]  Hideo Fujita,et al.  The forkhead transcription factors, Foxc1 and Foxc2, are required for arterial specification and lymphatic sprouting during vascular development. , 2006, Developmental biology.

[9]  R. Ritch,et al.  Phenotypic and molecular assessment of seven patients with 6p25 deletion syndrome: Relevance to ocular dysgenesis and hearing impairment , 2004, BMC Medical Genetics.

[10]  B. Hogan,et al.  The murine winged helix transcription factors, Foxc1 and Foxc2, are both required for cardiovascular development and somitogenesis. , 2001, Genes & development.

[11]  B. Hogan,et al.  Roles for the winged helix transcription factors MF1 and MFH1 in cardiovascular development revealed by nonallelic noncomplementation of null alleles. , 1999, Developmental biology.

[12]  T. Sugiyama,et al.  Essential roles of the winged helix transcription factor MFH-1 in aortic arch patterning and skeletogenesis. , 1997, Development.