SERPINF1 – Osteogenesis Imperfecta Type VI

SERPINF1 (HGNC:8824) encodes pigment epithelium-derived factor (PEDF), a secreted glycoprotein essential for bone mineralization. Biallelic pathogenic variants in SERPINF1 cause osteogenesis imperfecta type VI (MONDO:0013515), an autosomal recessive disorder marked by moderate to severe bone fragility, osteomalacia, and recurrent fractures.

OI type VI exhibits strict autosomal recessive inheritance. To date, at least 11 probands from six unrelated families have been reported: one with a novel in-frame duplication (PMID:22528245), two siblings homozygous for c.787-10C>G (PMID:26815784), four individuals carrying splice or truncating variants including c.283+2T>G and c.1152_1170del (PMID:37839784), and four patients with frameshift variants such as c.992_993insCA (p.Glu331AspfsTer3) (PMID:40649977).

The variant spectrum spans loss-of-function alleles (nonsense, frameshift, splice: c.992_993insCA [PMID:40649977], c.283+2T>G [PMID:37839784], c.787-10C>G [PMID:26815784]), in-frame deletions (c.1152_1170del (p.Val384_Gln390del)), and missense changes (c.185G>T (p.Gly62Val)). A recurrent founder duplication c.261_265dup (p.Leu89ArgfsTer26) shows a carrier frequency of 0.44% in a Tuvinian cohort, indicating allelic enrichment (PMID:40649977).

Family segregation analyses demonstrate cosegregation of biallelic SERPINF1 variants with OI type VI and absence of bone fragility in heterozygous carriers (PMID:25127091). No dominant-negative effects have been described, consistent with loss-of-function mechanism.

Functional studies in patient fibroblasts and osteoblastic models show markedly reduced SERPINF1 transcript and PEDF secretion, intracellular retention of mutant PEDF and a stress response in the endoplasmic reticulum, and impaired type I collagen deposition and mineralization (PMID:25868797, PMID:30283904). These findings align with the human phenotype of osteomalacia and fractures, supporting haploinsufficiency of PEDF as the pathogenic mechanism.

There is no compelling conflicting evidence. Heterozygous carriers remain phenotypically normal. Overall, the genetic, segregation, and functional data support a Strong clinical validity classification for the SERPINF1–OI type VI association.

Key Take-home: SERPINF1 biallelic pathogenic variants cause autosomal recessive OI type VI; targeted sequencing of SERPINF1 is recommended in patients with unexplained bone fragility and osteomalacia.

References

• American journal of medical genetics. Part A | 2012 | A co-occurrence of osteogenesis imperfecta type VI and cystinosis. PMID:22528245
• Calcified tissue international | 2016 | Osteogenesis Imperfecta Type VI in Individuals from Northern Canada. PMID:26815784
• Bone | 2015 | The effect of SERPINF1 in-frame mutations in osteogenesis imperfecta type VI. PMID:25868797
• JBMR plus | 2018 | Whole-Exome Sequencing Identifies an Intronic Cryptic Splice Site in SERPINF1 Causing Osteogenesis Imperfecta Type VI. PMID:30283904
• European journal of medical genetics | 2023 | Characterization of three adults and an adolescent with Osteogenesis Imperfecta type VI and a novel founder SERPINF1 variant. PMID:37839784
• International journal of molecular sciences | 2025 | Molecular and Clinical Aspects of Osteogenesis Imperfecta Type VI: A Case Series with Novel SERPINF1 Gene Variants. PMID:40649977
• The Journal of clinical endocrinology and metabolism | 2014 | Normal bone density and fat mass in heterozygous SERPINF1 mutation carriers. PMID:25127091

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