BCAP31 – Severe Motor and Intellectual Disabilities–Sensorineural Deafness–Dystonia Syndrome

BCAP31, located on Xq28, has been implicated in an X-linked disorder characterized by severe motor and intellectual disabilities, sensorineural deafness, dystonia, and cerebral hypomyelination, collectively described as DDCH (MONDO:0010334). Affected males typically present in early childhood with profound developmental delay and multisystem involvement, while carrier females are asymptomatic due to skewed X-inactivation in rare de novo cases.

Three unrelated probands have been reported: a three-year-old male with a de novo frameshift deletion c.709_721del (p.Leu122HisfsTer12) (PMID:31330203), an eight-year-old male with a recurrent nonsense variant c.97C>T (p.Gln33Ter) (PMID:31953925), and the first female case harboring c.92G>A (p.Arg31Lys) accompanied by skewed inactivation of the maternal X chromosome (PMID:32652807).

Inheritance follows an X-linked recessive pattern with no additional affected relatives reported. All three probands carry hemizygous or functionally hemizygous loss-of-function variants in BCAP31, consistent with haploinsufficiency.

Variant spectrum in DDCH is dominated by frameshift and nonsense changes leading to truncated proteins. The recurrent c.97C>T variant has been observed in multiple families, suggesting a mutational hotspot in exon 2, while larger exon 8 deletions appear de novo.

Functional studies support a loss-of-function mechanism: Bap31 knockdown in N2a cells reduces valosin-containing protein (VCP) expression via altered Elf2 regulation (PMID:30504720); patient fibroblasts exhibit complex I mitochondrial deficiency (PMID:31953925); and Bap31-deficient microglia demonstrate increased superoxide production and neuroinflammation (PMID:33777312).

In summary, hemizygous loss-of-function variants in BCAP31 produce a consistent DDCH phenotype through disrupted ER-associated processes and mitochondrial dysfunction. Genetic testing for BCAP31 LoF variants enables definitive diagnosis and informs carrier screening.

Key Take-home: BCAP31 LoF variants cause an X-linked DDCH syndrome amenable to molecular diagnosis and genetic counseling.

References

• European journal of medical genetics • 2020 • BCAP31-related syndrome: The first de novo report. PMID:31330203
• Molecular genetics & genomic medicine • 2020 • Possible mitochondrial dysfunction in a patient with deafness, dystonia, and cerebral hypomyelination (DDCH) due to BCAP31 Mutation. PMID:31953925
• Human mutation • 2020 • De novo mutation and skewed X-inactivation in girl with BCAP31-related syndrome. PMID:32652807
• Cellular physiology and biochemistry • 2018 • B-Cell Receptor-Associated Protein 31 Regulates the Expression of Valosin-Containing Protein Through Elf2. PMID:30504720
• Oxidative medicine and cellular longevity • 2021 • Regulation of Superoxide by BAP31 through Its Effect on p22phox and Keap1/Nrf2/HO-1 Signaling Pathway in Microglia. PMID:33777312

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