Novel synonymous and missense variants in FGFR1 causing Hartsfield syndrome

Am J Med Genet A. 2019 Dec;179(12):2447-2453. doi: 10.1002/ajmg.a.61354. Epub 2019 Sep 11.


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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cleft Lip / diagnosis*
  • Cleft Lip / genetics*
  • Cleft Palate / diagnosis*
  • Cleft Palate / genetics*
  • DNA Mutational Analysis
  • Female
  • Fingers / abnormalities*
  • Genetic Association Studies* / methods
  • Genetic Predisposition to Disease*
  • Hand Deformities, Congenital / diagnosis*
  • Hand Deformities, Congenital / genetics*
  • Holoprosencephaly / diagnosis*
  • Holoprosencephaly / genetics*
  • Humans
  • Intellectual Disability / diagnosis*
  • Intellectual Disability / genetics*
  • Male
  • Mutation, Missense*
  • Pedigree
  • Phenotype
  • Receptor, Fibroblast Growth Factor, Type 1 / genetics*
  • Silent Mutation*


  • FGFR1 protein, human
  • Receptor, Fibroblast Growth Factor, Type 1

Supplementary concepts

  • Holoprosencephaly, Ectrodactyly, and Bilateral Cleft Lip-Palate