BCS1L – Bjornstad syndrome

Bjornstad syndrome is an autosomal recessive disorder characterized by pili torti and sensorineural hearing impairment, resulting from pathogenic variants in BCS1L (BCS1L; Bjornstad syndrome). Patients present with twisted hair shafts and progressive auditory deficits without multisystemic features of complex III deficiency or GRACILE syndrome. The inheritance follows an autosomal recessive pattern with compound heterozygous or homozygous variants disrupting BCS1L function.

Genetic evidence includes two Italian siblings with compound heterozygous mutations c.133C>T (p.Arg45Cys) and c.703G>C (p.Gly235Arg) segregating with disease in a consanguineous family (PMID:28322498) and independent identification of BCS1L missense mutations in additional families (PMID:17314340). Affected relatives: 2. Reported variant spectrum in Bjornstad syndrome comprises missense substitutions at highly conserved residues involved in complex III assembly.

Functional studies demonstrate that BCS1L missense mutations impair assembly of mitochondrial complex III, reduce electron transport chain activity, and increase reactive oxygen species in cellular models and yeast complementation assays (PMID:17314340). The pathogenic mechanism involves loss of BCS1L chaperone function, leading to defective insertion of the Rieske iron–sulfur protein and destabilization of respirasomes.

Phenotypic correlation indicates that mutations affecting protein–protein interaction surfaces result in the restricted hair and hearing phenotype of Bjornstad syndrome, whereas variants disrupting ATP-binding cause more severe metabolic disorders. This spectrum underscores tissue-specific thresholds for mitochondrial complex III activity in auditory and hair follicle cells.

In conclusion, biallelic BCS1L variants are causative for Bjornstad syndrome with robust genetic and functional evidence supporting a Moderate clinical validity classification. BCS1L gene testing is indicated in individuals with pili torti and sensorineural hearing loss to enable accurate diagnosis and genetic counseling.

Key take-home: BCS1L variant analysis informs diagnosis of Bjornstad syndrome in patients with pili torti and hearing impairment.

References

• American journal of medical genetics. Part A • 2017 • Novel compound heterozygous mutations in BCS1L gene causing Bjornstad syndrome in two siblings. PMID:28322498
• The New England journal of medicine • 2007 • Missense mutations in the BCS1L gene as a cause of the Björnstad syndrome PMID:17314340

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