A Homozygous Deep Intronic SNX14 Variant Activates Pseudo-Exon Inclusion in a Patient with SCAR20

SNX14 (homozygous deep intronic variant)

Homozygous deep intronic SNX14 variant → pseudo-exon inclusion → intronic sequence inserted in mRNA → loss of function; undetectable by exome alone, requires WGS

Identification of a homozygous deep intronic SNX14 variant as the cause of SCAR20 in a patient with a negative exome. The variant activates pseudo-exon inclusion in SNX14 mRNA, leading to loss of function. This case illustrates the underestimation of deep intronic variants in the etiology of Mendelian diseases: they contribute to the differential diagnostic yield of WGS over exome, estimated at 2-15% across cohorts. Functional validation by RNA-seq confirms the transcriptional impact.

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

This case strengthens the argument for first-tier WGS in recessive cerebellar ataxias unresolved after exome. SNX14 is the causal gene for SCAR20 — a syndrome of ataxia + psychomotor delay + distinctive facies — and deep intronic variants in this gene should not be overlooked in secondary WGS interpretation.

exemplary deep intronic mechanism +3; biallelic AR +2; diagnostic yield impact WGS vs exome +2; Genes (MDPI) +1