Pfeiffer syndrome: genes and variants

Genes linked to Pfeiffer syndrome

• FGFR1: Fibroblast growth factor receptor 1

  Its fibroblast-growth-factor signaling controls proliferation, differentiation, migration, and developmental patterning in many tissues. Germline pathogenic variants can cause hypogonadotropic hypogonadism or craniosynostosis syndromes, while fusions and other activating alterations drive selected cancers.

  18 disease-causing and 252 uncertain variants in FGFR1 are linked to Pfeiffer syndrome.

• FGFR2: Fibroblast growth factor receptor 2

  Its fibroblast-growth-factor signaling regulates proliferation, differentiation, and developmental patterning across multiple tissues. Germline activating variants cause several craniosynostosis syndromes, while somatic mutations, amplification, or fusions can drive cancer.

  13 disease-causing and 13 uncertain variants in FGFR2 are linked to Pfeiffer syndrome.

Weakly linked (only a few uncertain records): MDM4.

Where Pfeiffer syndrome variants cluster

• FGFR2 Ig-like C2-type 3 (positions 256–358): 8 of 13 disease-causing changes, 4.9× more than its size predicts.
• FGFR1 Ig-like C2-type 1 (positions 25–119): 4 of 18 disease-causing changes, 1.9× more than its size predicts.

Known disease-causing variants in Pfeiffer syndrome

Which prediction tools work for Pfeiffer syndrome

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• PolyPhen-2: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 94 out of 100

Same protein, different disease

• Hypogonadotropic hypogonadism 2 with or without anosmia is also caused by FGFR1 variants; they fall mostly in different places as the Pfeiffer syndrome variants (55 disease-causing).
• Hartsfield-Bixler-Demyer syndrome is also caused by FGFR1 variants; they fall mostly in different places as the Pfeiffer syndrome variants (13 disease-causing).
• Jackson-Weiss syndrome is also caused by FGFR1 variants; they fall mostly in different places as the Pfeiffer syndrome variants (5 disease-causing).
• Osteoglophonic dysplasia is also caused by FGFR1 variants; they fall mostly in different places as the Pfeiffer syndrome variants (5 disease-causing).
• Hypogonadotropic hypogonadism 7 with or without anosmia is also caused by FGFR1 variants; they fall mostly in different places as the Pfeiffer syndrome variants (3 disease-causing).
• FGFR2-related craniosynostosis is also caused by FGFR2 variants; they fall partly in the same places as the Pfeiffer syndrome variants (54 disease-causing).
• Crouzon syndrome is also caused by FGFR2 variants; they fall mostly in different places as the Pfeiffer syndrome variants (22 disease-causing).
• Acrocephalosyndactyly type I is also caused by FGFR2 variants; they fall mostly in different places as the Pfeiffer syndrome variants (6 disease-causing).
• Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis is also caused by FGFR2 variants; they fall in the same places as the Pfeiffer syndrome variants (5 disease-causing).
• Common craniosynostosis syndromes is also caused by FGFR2 variants; they fall in the same places as the Pfeiffer syndrome variants (5 disease-causing).

Diseases related to Pfeiffer syndrome

• Colorectal cancer, also linked to FGFR1 and FGFR2
• Jackson-Weiss syndrome, also linked to FGFR1 and FGFR2
• Craniosynostosis syndrome, also linked to FGFR1 and FGFR2
• Hypogonadotropic hypogonadism 2 with or without anosmia, also linked to FGFR1
• FGFR2-related craniosynostosis, also linked to FGFR2
• Crouzon syndrome, also linked to FGFR2
• Gastric cancer, also linked to FGFR2
• Non-small cell lung carcinoma, also linked to FGFR1
• Idiopathic pulmonary fibrosis, also linked to FGFR1
• Hartsfield-Bixler-Demyer syndrome, also linked to FGFR1
• Bilateral sensorineural hearing impairment, also linked to FGFR2
• Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis, also linked to FGFR2

Frequently asked questions

Which genes are linked to Pfeiffer syndrome?

In CATVariant, Pfeiffer syndrome is linked to 2 analyzed proteins: FGFR1 (Fibroblast growth factor receptor 1) and FGFR2 (Fibroblast growth factor receptor 2).

How many genetic variants are linked to Pfeiffer syndrome?

327 variants: 31 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 266 are of uncertain significance or have conflicting reports.

Which uncertain variants in Pfeiffer syndrome look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Pfeiffer syndrome?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.94, based on 23 disease-causing and 34 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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