COL27A1 – Steel syndrome

Steel syndrome is an autosomal recessive osteochondrodysplasia characterized by congenital bilateral hip dysplasia, carpal coalition, dislocated radial heads, short stature, scoliosis and facial dysmorphism (MONDO:0014061). Onset is in early childhood with progressive skeletal manifestations that often require surgical intervention.

Pathogenic biallelic COL27A1 variants have been described in 29 families (20 Puerto Rican, 9 non-Puerto Rican) and 51 patients (PMID:35568358). A recurrent founder missense allele c.2089G>C (p.Gly697Arg) was first reported in a non-consanguineous Puerto Rican kindred (PMID:24986830) and subsequently identified in multiple additional probands. Compound heterozygous and homozygous loss-of-function alleles (nonsense, frameshift, splice-site) have been observed across diverse populations.

Variant spectrum includes canonical splice-site mutations such as c.3556-2A>G (PMID:28322503) and the founder missense c.2089G>C (p.Gly697Arg) (PMID:32376988). Null alleles (e.g., c.521_528del (p.Cys174fs)) and novel missense changes (e.g., c.295G>A (p.Ala99Thr), c.2521G>A (p.Gly841Arg)) have been documented, supporting a loss-of-function mechanism.

Segregation analysis demonstrates autosomal recessive inheritance with at least five additional affected relatives in founder pedigrees and consistent carrier status in parents (PMID:32376988). All reported COL27A1 alleles segregate faithfully with disease in both consanguineous and non-consanguineous families.

Functional studies corroborate pathogenicity: orthologous p.Gly697Arg in murine Col27a1 recapitulates reduced body length, scoliosis and cranial shape anomalies, and reveals disorganized growth plate architecture (PMID:32376988). Affected individuals with c.3556-2A>G exhibit aberrant mRNA splicing and marked reduction of COL27A1 transcript levels in patient fibroblasts (PMID:28322503).

No studies dispute the COL27A1–Steel syndrome association. The cumulative genetic and experimental evidence establishes a definitive gene–disease relationship. Molecular testing of COL27A1 is clinically actionable for diagnosis, family counseling, and population screening, particularly in at-risk ancestries.

Key take-home: Biallelic COL27A1 loss-of-function and founder missense variants cause autosomal recessive Steel syndrome, supporting targeted genetic testing and early intervention.

References

• European journal of human genetics • 2015 • Mutations in COL27A1 cause Steel syndrome and suggest a founder mutation effect in the Puerto Rican population. PMID:24986830
• Clinical genetics • 2017 • Second family provides further evidence for causation of Steel syndrome by biallelic mutations in COL27A1. PMID:28276056
• American journal of medical genetics. Part A • 2017 • A novel aberrant splice site mutation in COL27A1 is responsible for Steel syndrome and extension of the phenotype to include hearing loss. PMID:28322503
• European journal of human genetics • 2020 • Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide. PMID:32376988
• European journal of medical genetics • 2022 • Steel syndrome: Report of three patients, including monozygotic twins and review of clinical and mutation profiles. PMID:35568358

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