BCORL1 – Shukla-Vernon syndrome

BCORL1 encodes BCL-6 corepressor-like protein 1, an X-linked transcriptional corepressor critical for neurodevelopment. Shukla-Vernon syndrome is an extremely rare neurodevelopmental disorder characterized by global developmental delay, intellectual disability, seizures, and dysmorphic craniofacial features. Pathogenic variants in BCORL1 have been identified as the molecular cause and segregate in an X-linked recessive pattern.

In the second published family, whole exome sequencing of an Indian pedigree revealed a novel hemizygous missense variant c.3793C>T (p.Arg1265Cys) in two affected male siblings ([PMID:33810051]). Segregation analysis confirmed carrier status in the mother and absence in unaffected relatives, supporting pathogenicity in an X-linked recessive inheritance model. This report replicates the association first described previously, strengthening the genetic link.

To date, all BCORL1 variants reported in Shukla-Vernon syndrome are missense substitutions clustering in functional domains of the protein. The only variant described in this family, c.3793C>T (p.Arg1265Cys), replaces a highly conserved arginine residue and is absent from population databases. No loss-of-function or splice variants have been reported for this syndrome.

Affected individuals present with global developmental delay (HP:0001263), intellectual disability (HP:0001249), kyphosis (HP:0002808), seizures (HP:0001250), and strabismus (HP:0000486), along with dysmorphic eyebrows, beaked nose, and protuberant mandible. The consistent phenotype across independent families highlights core clinical features.

No functional studies have directly assessed the impact of BCORL1 missense variants in patient cells or model organisms. Consequently, mechanistic understanding of how p.Arg1265Cys impairs transcriptional repression remains to be established.

Taken together, two independent families with hemizygous BCORL1 missense variants and consistent neurodevelopmental phenotypes provide limited but reproducible evidence for BCORL1 as the causative gene in Shukla-Vernon syndrome. BCORL1 gene testing should be considered in male patients with unexplained intellectual disability, developmental delay, seizures, and characteristic dysmorphic features.

References

• Genes • 2021 • Shukla-Vernon Syndrome: A Second Family with a Novel Variant in the BCORL1 Gene. PMID:33810051

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