FGFR1mutations cause Hartsfield syndrome, the unique association of holoprosencephaly and ectrodactyly

Abstract

BackgroundHarstfield syndrome is the rare and unique association of holoprosencephaly (HPE) and ectrodactyly, with or without cleft lip and palate, and variable additional features. All the reported cases occurred sporadically. Although several causal genes of HPE and ectrodactyly have been identified, the genetic cause of Hartsfield syndrome remains unknown. We hypothesised that a single key developmental gene may underlie the co-occurrence of HPE and ectrodactyly.MethodsWe used whole exome sequencing in four isolated cases including one case-parents trio, and direct Sanger sequencing of three additional cases, to investigate the causative variants in Hartsfield syndrome.ResultsWe identified a novel FGFR1 mutation in six out of seven patients. Affected residues are highly conserved and are located in the extracellular binding domain of the receptor (two homozygous mutations) or the intracellular tyrosine kinase domain (four heterozygous de novo variants). Strikingly, among the six novel mutations, three are located in close proximity to the ATP's phosphates or the coordinating magnesium, with one position required for kinase activity, and three are adjacent to known mutations involved in Kallmann syndrome plus other developmental anomalies.ConclusionsDominant or recessive FGFR1 mutations are responsible for Hartsfield syndrome, consistent with the known roles of FGFR1 in vertebrate ontogeny and conditional Fgfr1-deficient mice. Our study shows that, in humans, lack of accurate FGFR1 activation can disrupt both brain and hand/foot midline development, and that FGFR1 loss-of-function mutations are responsible for a wider spectrum of clinical anomalies than previously thought, ranging in severity from seemingly isolated hypogonadotropic hypogonadism, through Kallmann syndrome with or without additional features, to Hartsfield syndrome at its most severe end.

Six3 dosage mediates the pathogenesis of holoprosencephaly

“…The Fgf signaling pathway has also been suggested to promote ventral telencephalic specification independently of Shh (Gutin et al, 2006). Mutations in FGF8 and FGFR1 have been identified in human patients with HPE (McCabe et al, 2011;Simonis et al, 2013). Fgf signaling is both necessary and sufficient for Foxg1 expression in the ANE (Paek et al, 2009;Shimamura and Rubenstein, 1997).…”

Genetic insights into the mechanisms of Fgf signaling

“…This is evident by the striking phenotypic similarities between human congenital disorders caused by alterations in Fgf signaling and their corresponding mouse models. Conserved developmental requirements have been demonstrated in skeletal growth, palate closure, limb patterning, ear development, cranial suture ossification, neural development, and the hair cycle (Hebert et al 1994;Rousseau et al 1994;Shiang et al 1994;Wilkie et al 1995;Partanen et al 1998;Chen et al 1999;Li et al 1999;Wang et al 1999Wang et al , 2005Dode et al 2003;Tsai et al 2005;Gill and Tsai 2006;Mason 2007;Riley et al 2007;Falardeau et al 2008;Mansour et al 2009;Stanier and Pauws 2012;Simonis et al 2013;Higgins et al 2014;Ornitz and Marie 2015). These conserved developmental functions and accessible genetics make the mouse an excellent model for studying the mechanisms that Fgf signaling uses in vivo, which we discuss in this review.…”

Homozygous Mutation of the <b><i>FGFR1</i></b> Gene Associated with Congenital Heart Disease and 46,XY Disorder of Sex Development

“…The cardinal features of the latter consist of holoprosencephaly and ectrodactyly with variable features including hyper-or hypotelorism, abnormalities of ear morphology, cryptorchidism, and micropenis [Simonis et al, 2013]. Both homozygous and heterozygous mutations can contribute to Hartsfield syndrome [Simonis et al, 2013]. The novel homozygous mutation p.Arg473Gln in FGFR1 in the patient described here is located between the transmembrane domain and the first tyrosine kinase domain of the protein.…”

“…Mutations in the FGFR1 gene are associated with a wide range of clinical phenotypes, ranging from isolated hypogonadotropic hypogonadism to the more severe Hartsfield syndrome [Dodé et al, 2003;Sato et al, 2004;Simonis et al, 2013]. The cardinal features of the latter consist of holoprosencephaly and ectrodactyly with variable features including hyper-or hypotelorism, abnormalities of ear morphology, cryptorchidism, and micropenis [Simonis et al, 2013]. Both homozygous and heterozygous mutations can contribute to Hartsfield syndrome [Simonis et al, 2013].…”

“…It also plays an important role in the developing of the genital tubercle [Satoh et al, 2004] and it is involved in outflow tract septation, positioning of the heart within the thorax, development of the pulmonary vasculature, and ventricular myocardial proliferation and maturation [Beiman et al, 1996;Partanen et al, 1998;Abu-Issa et al, 2002;Marguerie et al, 2006]. Mutations in the FGFR1 gene are associated with a wide range of clinical phenotypes, ranging from isolated hypogonadotropic hypogonadism to the more severe Hartsfield syndrome [Dodé et al, 2003;Sato et al, 2004;Simonis et al, 2013]. The cardinal features of the latter consist of holoprosencephaly and ectrodactyly with variable features including hyper-or hypotelorism, abnormalities of ear morphology, cryptorchidism, and micropenis [Simonis et al, 2013].…”