BICRA – Coffin-Siris syndrome 12

The BICRA gene has been implicated in autosomal dominant Coffin-Siris syndrome 12 (Coffin-Siris syndrome 12) through two unrelated de novo loss-of-function variants. A first proband presented with language developmental delay, hypotonia (HP:0001252), and mild gastrointestinal features; trio WES identified a heterozygous nonsense variant c.1666C>T (p.Gln556Ter) in exon 6, absent from gnomAD and classified pathogenic (PMID:37485815). A second case exhibited low birth weight (HP:0001518), microcephaly (HP:0000252), visual impairment (HP:0000505), and craniofacial dysmorphism (HP:0000271); a novel de novo variant c.535C>T (p.Gln179Ter) was similarly confirmed by Sanger sequencing (PMID:36437209).

These two independent de novo truncating variants support a limited level of clinical validity for BICRA haploinsufficiency in CSS12. No functional assays directly assess BICRA’s role in neurodevelopment, and segregation data are lacking. Further studies are needed to define the full phenotypic spectrum and molecular mechanism. Key take-home: consider BICRA sequencing in patients with neurodevelopmental delay and hypotonia when CSS12 is suspected.

References

• Molecular Genetics & Genomic Medicine • 2023 • A de novo variant of BICRA results in Coffin-Siris syndrome 12. PMID:37485815
• SPATIALLY UNDEFINED • Title Unavailable • Year Unavailable PMID:36437209

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