Homozygous missense variants in CACNB4 underlie autosomal recessive epilepsy in two unrelated Pakistani consanguineous families.

Two homozygous missense variants in CACNB4 affecting highly conserved residues; 3D modelling predicts slower stabilisation, increased structural flexibility and a central cavity enlarged by about 10 Å.

The authors assessed the diagnostic utility of exome sequencing in two consanguineous families with epilepsy and neurological manifestations segregating in an autosomal recessive manner, sequencing two affected members of family 1 and one affected member of family 2. Family 1 carried a novel, presumably deleterious homozygous missense variant in CACNB4 (NM_000726.3, c.839T>C; p.(Ile280Thr)), and family 2 another novel homozygous missense variant, c.1199G>A; p.(Arg400His), both affecting highly conserved residues, with co-segregation checked by bidirectional Sanger sequencing. 3D modelling and several in silico tools indicated that the mutant proteins took longer to stabilise, showed increased structural flexibility and formed less compact structures with a central cavity enlarged by about 10 Å. To the authors' knowledge, this is the second report of autosomal recessive epilepsy associated with biallelic CACNB4 variants.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The value of this work is to consolidate a still fragile gene-disease relationship: a second independent report moves biallelic CACNB4 from an isolated observation to an acceptable hypothesis in recessive epilepsy in a consanguineous setting. The demonstration nevertheless stops at modelling — no electrophysiology, no functional assay on the channel — and three patients from two families cannot define a phenotypic spectrum or a genotype-phenotype correlation. In practice, a homozygous CACNB4 variant on an exome deserves discussion with the clinician and submission to matchmaking, not reporting as an established diagnosis.

Analysis by Dr Thibaut Benquey