|SEN, PARTHA - Children'S Nutrition Research Center (CNRC)|
|GERYCHOVA, ROMANA - Masaryk University|
|JANKU, PETR - Masaryk University|
|JEZOVA, MARTA - Masaryk University|
|VALASKOVA, IVETA - Masaryk University|
|NAVARRO, COLBY - Baylor College Of Medicine|
|SILVA, IRIS - Baylor College Of Medicine|
|LANGSTON, CLAIRE - Baylor College Of Medicine|
|WELTY, STEPHEN - Baylor College Of Medicine|
|BELMONT, JOHN - Children'S Nutrition Research Center (CNRC)|
|STANKIEWICZ, PAWEL - Baylor College Of Medicine|
Submitted to: European Journal of Human Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/13/2012
Publication Date: 4/1/2013
Citation: Sen, P., Gerychova, R., Janku, P., Jezova, M., Valaskova, I., Navarro, C., Silva, I., Langston, C., Welty, S., Belmont, J., Stankiewicz, P. 2013. A familial case of alveolar capillary dysplasia with misalignment of pulmonary veins supports paternal imprinting of FOXF1 in human. European Journal of Human Genetics. 21(4):474-477.
Interpretive Summary: We have learned about a handful of extremely rare diseases that cause problems in lung development. Alveolar capillary dysplasia (ACD), one of the most severe of these conditions, is 100% lethal in the first few weeks of life. Fortunately, ACD typically does not run in families because it is caused by a new mutation in a gene called FOXF1. These mutations are not present in either parent. We used several modern methods of genetic analysis to demonstrate that the ACD mutations always happen on the chromosome inherited from the father. This parent-specific pattern of mutation shows that FOXF1 is "imprinted". This adds to a short list of human genes that are both imprinted and required for normal body development. At other genes, imprinting may be altered by nutrition. It is possible that FOXF1 could be influenced by nutritional factors and explain part of the known connection between nutrition and human birth defects.
Technical Abstract: Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare developmental lung disorder that is uniformly lethal. Affected infants die within the first few weeks of their life despite aggressive treatment, although a few cases of late manifestation and longer survival have been reported. We have shown previously that mutations and deletions in FOXF1 are a cause of this disorder. Although most of the cases of ACD/MPV are sporadic, there have been infrequent reports of familial cases. We present a family with five out of six children affected with ACD/MPV. DNA analysis identified a missense mutation (c.416G>T; p.Arg139Leu) in the FOXF1 gene that segregated in the three affected siblings tested. The same variant is also present as a de novo mutation in the mother and arose on her paternally derived chromosome 16. The two tested affected siblings share the same chromosome 16 haplotype inherited from their maternal grandfather. Their single healthy sibling has a different chromosome 16 haplotype inherited from the maternal grandmother. The results are consistent with paternal imprinting of FOXF1 in human.