FGFR1 – Hartsfield-Bixler-Demyer syndrome

Hartsfield-Bixler-Demyer syndrome is an ultrarare developmental disorder defined by the combination of holoprosencephaly, ectrodactyly and cleft lip/palate. Since the initial report of de novo FGFR1 variants in 2014, monoallelic and occasionally biallelic FGFR1 mutations have been repeatedly identified in unrelated patients, establishing a robust gene-disease link (PMID:24888332). The hallmark features overlap holoprosencephaly (HP:0001360), ectrodactyly (HP:0100257) and orofacial cleft (HP:0000202).

Inheritance is predominately autosomal dominant with de novo occurrence, although gonadal mosaicism explains recurrence in sibships. Two siblings with an identical FGFR1 c.1880G>C (p.Arg627Thr) variant illustrate familial transmission via parental gonadal mosaicism (PMID:24888332). To date, 37 affected individuals from ≥10 families have been reported (PMID:35338003), including both sporadic de novo and mosaic cases.

The variant spectrum in HS comprises at least eight distinct FGFR1 coding changes, primarily missense substitutions clustering in kinase and extracellular domains. Notable examples include c.1880G>C (p.Arg627Thr) and c.759A>C (p.His253Pro) (PMID:27790375). These variants disrupt ligand binding or kinase activity, consistent with a dominant-negative mechanism.

Functional assays in zebrafish and cellular models demonstrate that kinase domain mutants behave as dominant-negative alleles. In overexpression assays, five of nine HS-associated FGFR1 mutations show impaired rescue of fgfr1 morphant phenotypes in zebrafish (PMID:26931467). Biochemical studies reveal that the p.Ala645Val substitution perturbs FGF2-mediated RAS/ERK1/2 signaling and autophagy regulation in human cell lines (PMID:30787447).

Genotype-phenotype correlations highlight that mutations in both extracellular and kinase domains produce the full HS triad, whereas extracellular variants may also associate with hypogonadotropic hypogonadism (PMID:27790375). Mosaicism occurs in ~9% of families, guiding recurrence risk counseling (PMID:35338003).

Together, the genetic and experimental evidence attests to a Strong clinical validity for FGFR1 in Hartsfield-Bixler-Demyer syndrome. Molecular testing for FGFR1 variants is critical for diagnosis, prognostic assessment and family planning. Key take-home: FGFR1 dominant-negative variants cause HS through disruption of FGF signaling, supporting targeted genetic diagnosis and counseling.

References

• American journal of medical genetics. Part A • 2014 • Novel de novo heterozygous FGFR1 mutation in two siblings with Hartsfield syndrome: a case of gonadal mosaicism. PMID:24888332
• Human genome variation • 2016 • Novel heterozygous mutation in the extracellular domain of FGFR1 associated with Hartsfield syndrome. PMID:27790375
• Human molecular genetics • 2016 • Dominant-negative kinase domain mutations in FGFR1 can explain the clinical severity of Hartsfield syndrome. PMID:26931467
• European journal of human genetics : EJHG • 2019 • A novel dominant-negative FGFR1 variant causes Hartsfield syndrome by deregulating RAS/ERK1/2 pathway. PMID:30787447
• European journal of medical genetics • 2022 • Mosaicism in Hartsfield syndrome. PMID:35338003
• Prenatal diagnosis • 2023 • Prenatal diagnosis of Hartsfield syndrome with a novel genetic variant. PMID:38013637

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