Laboratoire de Bioinformatique des Génomes et des Réseaux (BiGRe), Université Libre de Bruxelles (ULB), Brussels, Belgium.
J Med Genet. 2013 Sep;50(9):585-92. doi: 10.1136/jmedgenet-2013-101603. Epub 2013 Jun 28.
Harstfield 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.
We 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.
We 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.
Dominant 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.
哈斯菲尔德综合征是一种罕见且独特的前脑无裂畸形（HPE）和并指（趾）畸形的关联，伴有或不伴有唇腭裂，并伴有不同的其他特征。所有报道的病例均为散发性发生。尽管已经鉴定出 HPE 和并指（趾）畸形的几个致病基因，但哈斯菲尔德综合征的遗传原因仍不清楚。我们假设单个关键发育基因可能是 HPE 和并指（趾）畸形共发生的基础。
我们使用全外显子组测序对包括一例先证者-父母三体外的四例孤立病例进行研究，并对另外三例病例进行直接 Sanger 测序，以研究哈斯菲尔德综合征的致病变异。
我们在 7 例患者中的 6 例中发现了一种新的 FGFR1 突变。受影响的残基高度保守，位于受体的细胞外结合域（两个纯合突变）或细胞内酪氨酸激酶域（四个新生杂合缺失变异）。引人注目的是，在 6 个新突变中，有 3 个位于与 ATP 的磷酸或配位镁相邻的位置，一个位置对激酶活性是必需的，还有 3 个与已知的与卡尔曼综合征和其他发育异常相关的突变相邻。
FGFR1 显性或隐性突变负责哈斯菲尔德综合征，这与 FGFR1 在脊椎动物胚胎发生中的已知作用以及条件性 Fgfr1 缺陷小鼠一致。我们的研究表明，在人类中，缺乏准确的 FGFR1 激活会破坏大脑和手/脚中线的发育，并且 FGFR1 功能丧失突变负责的临床异常谱比以前认为的更广泛，从看似孤立的促性腺激素缺乏性性腺功能减退症，到伴有或不伴有其他特征的卡尔曼综合征，再到哈斯菲尔德综合征最严重的程度。
