An example for potentially underrated causes of recessive disease in the Greater Middle East: integrative long-read genome and transcriptome sequencing pinpoint a deep-intronic homozygous HEXB candidate founder variant in GM2-gangliosidosis

Background Consanguinity provides shortcuts to identify homozygous recessive mutations. However, deep-intronic variants escape standard sequencing (panel; exome/WES), and their pathogenicity cannot be inferred from genomic data. We applied WES, long-read genome and long-read-RNA-sequencing (LR-WGS, LR-RNA-Seq) in a Syrian patient with biochemically evident GM2-gangliosidosis. Results No exonic HEXA , HEXB and GM2A mutations were found. LR-WGS/LR-RNA-Seq revealed a homozygous HEXB variant, c.771 + 985G > A, activating a 97 bp pseudo-exon. Conclusions Integrative genome and transcriptome sequencing unlocked a deep-intronic, database-annotated HEXB mutation and proved causality. This illustrates the diagnostic challenges in patients from the Middle East with its prevalent consanguinity and hidden (candidate founder) mutations which are potential targets for splice-modulating therapies.