A Novel Mutation in FOXC1 in a Lebanese Family with Congenital Heart Disease and Anterior Segment Dysgenesis: Potential Roles for NFATC1 and DPT in the Phenotypic Variations

Abstract

Congenital heart diseases (CHDs) are still the leading cause of death in neonates. Anterior segment dysgenesis is a broad clinical phenotype that affects the normal development of the eye, leading in most of the cases to glaucoma which is still a major cause of blindness for children and adolescents. Despite tremendous insights gained from genetic studies, a clear genotype-phenotype correlation is still difficult to draw. In Lebanon, a small country with still a high rate of consanguineous marriages, there are little data on the epidemiology of glaucoma amongst children with or without CHD. We carried out whole exome sequencing (WES) on a family with anterior segment dysgenesis, and CHD composed of three affected children with glaucoma, two of them with structural cardiac defects and three healthy siblings. The results unravel a novel mutation in FOXC1 (p. R127H) segregating with the phenotype and inherited from the mother, who did not develop glaucoma. We propose a digenic model for glaucoma in this family by combining the FOXC1 variant with a missense variant inherited from the father in the dermatopontin (DPT) gene. We also unravel a novel NFATC1 missense mutation predicted to be deleterious and present only in the patient with a severe ocular and cardiac phenotype. This is the first report on FOXC1 using WES to genetically characterize a family with both ocular and cardiac malformations. Our results support the usage of such technology to have a better genotype-phenotype picture for Mendelian-inherited diseases for which expressivity and penetrance are still not answered.

Keywords: anterior segment dysgenesis; congenital heart disease; digenic; forkhead box c1; whole exome sequencing.

Figure 1

Glaucoma and congenital heart disease in a Lebanese family. The pedigree shows a two-generations family (roman numbers): circles and squares for females and males, respectively. Primary glaucoma and aniridia () or glaucoma, aniridia, and congenital heart defects (). Double lines indicate first degree cousin marriages. Death is represented with an oblique black line.

Figure 2

Sequencing results for the FOXC1 variant p.R127C. (A) Integrative genomics viewer visualization of whole exome sequencing shows a novel heterozygous variant (blue for the normal “C” allele and red for the variant “T” allele) in FOXC1 gene in family members I.2, II.3, II.2, and II.6. (B) Sanger sequencing of the FOXC1 gene confirmed the C>T variant (boxed), in the affected individuals represented in the lower panel versus the normal individuals in the upper panel.

Figure 3

Sequencing results for the DSG2 variant p.W51*. (A) Location and description of the DSG2 variant using the Illumina Variant Studio show that the variant on chr18:290099836 G>A leads to a premature stop codon at position 51 of the transcript with an overall allele frequency of O in the Exome databases (EVS). (B) Integrative genomics viewer visualization of whole exome sequencing shows a novel heterozygous variant (brown for the normal “G” allele and green for the variant “A” allele) in DSG2 in the father (I.1), the three affected children (II.3, II.4, and II.6) and in their healthy sister (II.1).