COL11A1 – Marshall syndrome

Marshall syndrome is an autosomal dominant connective tissue disorder characterized by midfacial hypoplasia, high myopia, cataracts, and early‐onset bilateral sensorineural hearing loss. Heterozygous COL11A1 variants, particularly splice‐site mutations and glycine substitutions in the triple‐helical domain, underlie disease by perturbing collagen XI assembly and fibrillogenesis (PMID:10889003; PMID:30020262). Clinical otologic and vestibular evaluations demonstrate cochlear origin of hearing loss and subclinical vestibular dysfunction without bony labyrinth malformations, implicating direct effects on the membranous labyrinth (PMID:10889003).

Genetic studies report at least 17 unrelated probands with Marshall syndrome due to heterozygous COL11A1 variants, including recurrent c.3816+1G>A splice‐donor mutations and missense changes such as c.2702G>A (p.Gly901Glu), co‐segregating in six additional affected relatives (PMID:10889003; PMID:30020262; PMID:25073711; PMID:17236192). Variants include splice‐site (majority), missense glycine substitutions, and small in‐frame deletions, consistent with a dominant‐negative mechanism.

Inheritance is autosomal dominant, with segregation demonstrated in multiple multigenerational pedigrees. Case series encompass three affected in a pedigree with progressive sensorineural hearing loss (PMID:10889003) and a family harboring heterozygous c.3816+1G>A with bilateral hearing impairment of variable severity (PMID:30020262).

Functional evidence includes radiologic and audiologic data showing normal temporal bone morphology but disrupted membranous labyrinth function, supporting a collagen XI‐dependent mechanism in auditory structures. Alternative splicing assays in analogous collagen‐XI disorders confirm that splice‐site variants induce exon skipping and aberrant triple‐helix formation, consistent with dominant‐negative effects in the extracellular matrix.

No studies dispute the association; phenotypic overlap with Stickler syndrome is distinguished by more pronounced facial features and early‐onset sensorineural hearing loss in Marshall syndrome. Additional functional work in cell and animal models could further elucidate collagen XI roles in inner ear development.

Key take-home: Heterozygous COL11A1 splice‐site and glycine‐substitution mutations have a definitive role in Marshall syndrome, guiding molecular diagnosis and enabling tailored audiologic surveillance.

References

• Archives of Otolaryngology–Head & Neck Surgery • 2000 • Audiovestibular phenotype associated with a COL11A1 mutation in Marshall syndrome. PMID:10889003
• Otology & Neurotology • 2018 • Audiologic Manifestations of Marshall Syndrome. PMID:30020262
• American Journal of Medical Genetics Part A • 2014 • Marshall syndrome: further evidence of a distinct phenotypic entity and report of new findings. PMID:25073711
• American Journal of Medical Genetics Part A • 2007 • A report on 10 new patients with heterozygous mutations in the COL11A1 gene and a review of genotype-phenotype correlations in type XI collagenopathies. PMID:17236192

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