Novel synonymous and missense variants in FGFR1 causing Hartsfield syndrome

Carolina Courage 1 2 , Christopher B Jackson 3 , Marta Owczarek-Lipska 4 , Aleksander Jamsheer 5 6 , Anna Sowińska-Seidler 5 , Małgorzata Piotrowicz 7 , Lucjusz Jakubowski 7 , Fanny Dallèves 2 , Erik Riesch 8 , John Neidhardt 4 , Johannes R Lemke 9

  1. Folkhälsan Research Center, Helsinki, Finland.
  2. Division of Human Genetics, Department of Pediatrics, Inselspital, University of Bern, Bern, Switzerland.
  3. Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
  4. Human Genetics, Faculty of Medicine and Health Sciences, University of Oldenburg, Oldenburg, Germany.
  5. Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland.
  6. Centers for Medical Genetics GENESIS, Poznan, Poland.
  7. Department of Genetics, Polish Mother’s Memorial Hospital Research Institute, Poland.
  8. CeGaT GmbH-Center for Genomics and Transcriptomics, Tübingen, Germany.
  9. Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.


Hartsfield syndrome is a rare clinical entity characterized by holoprosencephaly and ectrodactyly with the variable feature of cleft lip/palate. In addition to these symptoms patients with Hartsfield syndrome can show developmental delay of variable severity, isolated hypogonadotropic hypogonadism, central diabetes insipidus, vertebral anomalies, eye anomalies, and cardiac malformations. Pathogenic variants in FGFR1 have been described to cause phenotypically different FGFR1-related disorders such as Hartsfield syndrome, hypogonadotropic hypogonadism with or without anosmia, Jackson-Weiss syndrome, osteoglophonic dysplasia, Pfeiffer syndrome, and trigonocephaly Type 1. Here, we report three patients with Hartsfield syndrome from two unrelated families. Exome sequencing revealed two siblings harboring a novel de novo heterozygous synonymous variant c.1029G>A, p.Ala343Ala causing a cryptic splice donor site in exon 8 of FGFR1 likely due to gonadal mosaicism in one parent. The third case was a sporadic patient with a novel de novo heterozygous missense variant c.1868A>G, p.(Asp623Gly).

Keywords: FGFR1; Hartsfield syndrome; fibroblast growth factor receptor 1; gonadal mosaicism; holoprosencephaly.