ArticleJournal of medical genetics2013
FGFR1 mutations cause Hartsfield syndrome, the unique association of holoprosencephaly and ectrodactyly.
Article in Journal of medical genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers, 3 of them syntheses that pooled it.
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Who cites it
46 citing papers in PubMed, 3 syntheses or guidelines pooled it, 95 citations in OpenAlex.
- Syndromes associated with holoprosencephaly.American journal of medical genetics. Part C, Seminars in medical genetics · 2018Pooled it
- Molecular testing in holoprosencephaly.American journal of medical genetics. Part C, Seminars in medical genetics · 2018Pooled it
- Tooth agenesis and orofacial clefting: genetic brothers in arms?Human genetics · 2016Pooled it
- Confirmation of frameshift variants in the last exon of FGFR1 as a cause of multiple epiphyseal dysplasia.European journal of human genetics : EJHG · 2026Article
- Evidence-based classification of genes implicated in craniosynostosis disorders using the ClinGen curation framework.Genetics in medicine : official journal of the American College of Medical Genetics · 2026Article
- Pleiotropic genes linking congenital hypogonadotropic hypogonadism and cleft lip/palate: evidence from a genomic CHH cohort study.European journal of human genetics : EJHG · 2026Article
- Malformation Pattern and Molecular Findings in theMedical sciences (Basel, Switzerland) · 2025Review
- Novel Missense Variant in the FGFR1 Gene Associated With Prenatal Diagnosis of Hartsfield Syndrome.Prenatal diagnosis · 2025Article
- Recent advances in the diagnosis and molecular pathogenesis of holoprosencephaly: a review.Journal of applied genetics · 2025Article
- Exome Sequencing to Identify Novel Susceptibility Genes for Nonsyndromic Split-Hand/Ft Malformation: A Report From the National Birth Defects Prevention Study.Birth defects research · 2025Article
- Intrafamilial Phenotypic Variability of theGenes · 2025Review
- Solitary median maxillary central incisor syndrome caused by 22q11.2 microdeletion.Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology · 2025Article
- Midline defect with corpus callosum agenesis, vermian hypoplasia and median cleft lip palate.Case reports in perinatal medicine · 2025Article
- Reverse repurposing: Potential utility of cancer drugs in nonmalignant illnesses.Med (New York, N.Y.) · 2024Review
- Prenatal whole-exome sequencing for fetal structural anomalies: a retrospective analysis of 145 Chinese cases.BMC medical genomics · 2023Article
- DECIPHER: Improving Genetic Diagnosis Through Dynamic Integration of Genomic and Clinical Data.Annual review of genomics and human genetics · 2023Review
- Mendelian inheritance revisited: dominance and recessiveness in medical genetics.Nature reviews. Genetics · 2023Review
- Holoprosencephaly: Review of Embryology, Clinical Phenotypes, Etiology and Management.Children (Basel, Switzerland) · 2023Review
- Adar-mediated A-to-I editing is required for embryonic patterning and innate immune response regulation in zebrafish.Nature communications · 2022Article
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Corrections and comments
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Authors and funding
16 authors at 9 institutions in 5 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.