FLVCR2 – Fowler syndrome

FLVCR2 is implicated in Fowler syndrome, a rare autosomal recessive disorder characterized by severe neurologic impairment, brain vascular anomalies, and a spectrum of developmental defects. Multiple independent studies have identified pathogenic variants in FLVCR2 in patients presenting with clinical features such as seizures, intellectual disability, ventriculomegaly, and cerebral calcifications (PMID:25677735).

Comprehensive genetic analyses across several families have revealed a heterogeneous spectrum of variants in FLVCR2. For example, one study reported a homozygous mutation, c.1289C>T (p.Thr430Met), in affected siblings, which supports the role of this gene in the disease etiology (PMID:25677735). Such findings, confirmed by targeted and exome‑wide sequencing approaches, underscore the critical contribution of FLVCR2 variants to the disease phenotype.

The autosomal recessive inheritance pattern is further supported by the presence of segregating mutations in multiple unrelated families. In one series, nearly 45 cases from 27 families were documented, with consistent identification of biallelic pathogenic alleles accompanied by clear familial segregation (PMID:29500860) and additional evidence from other cohorts (PMID:20206334). This breadth of genetic evidence robustly supports a strong gene-disease association.

Complementary functional studies have provided moderate but important experimental evidence linking FLVCR2 to the disease mechanism. In vitro assays and animal models have demonstrated that FLVCR2 mutations lead to impaired choline transport at the blood-brain barrier, decreased heme import, and resultant cellular dysfunction (PMID:37873173; PMID:38302740). These observations help explain the vascular and neurologic abnormalities observed in patients with Fowler syndrome.

In summary, the integration of robust genetic data and functional assays across multiple studies provides strong evidence for the association between FLVCR2 and Fowler syndrome. Notably, the convergence of clinical, segregation, and experimental data emphasizes the clinical utility of FLVCR2 testing in patients suspected of having Fowler syndrome. The assembled evidence supports diagnostic decision‑making, commercial application, and further publication in the field.

Key take‑home sentence: FLVCR2 genetic testing is critical for accurate diagnosis and management of Fowler syndrome, guiding prognosis and potential therapeutic interventions.

References

• Clinical genetics • 2016 • Mutations in FLVCR2 associated with Fowler syndrome and survival beyond infancy PMID:25677735
• Molecular genetics & genomic medicine • 2018 • Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome or Fowler syndrome: Report of a family and insight into the disease's mechanism PMID:29500860
• Human mutation • 2010 • Mutations in FLVCR2 are associated with proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (Fowler syndrome) PMID:20206334
• European journal of human genetics • 2025 • A hypomorphic FLVCR2 variant resulting in moderate transport deficiency causes hydranencephaly syndrome with brain calcifications PMID:40133703
• bioRxiv • 2023 • Structural and molecular basis of choline uptake into the brain by FLVCR2 PMID:37873173
• Cell research • 2024 • MFSD7c functions as a transporter of choline at the blood-brain barrier PMID:38302740

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