RNA sequencing significantly improves HYDIN diagnosis and defines the effects of common deletions in primary ciliary dyskinesia.

HYDIN

Biallelic HYDIN variants, including a recurrent 10 kb deletion (intron 17 to intron 18) causing complex aberrant splicing; 98% homologous pseudogene HYDIN2

Diagnosing HYDIN-related primary ciliary dyskinesia (PCD) is complicated by a 98% homologous pseudogene (HYDIN2) and by the lack of ultrastructural defects visible on electron microscopy. The authors performed RNA-seq on nasal epithelium cultured for 21 days at the air-liquid interface in 13 patients with strong clinical suspicion, normal electron microscopy and inconclusive genetics, 11 of whom carried a single pathogenic or likely pathogenic HYDIN variant. RNA-seq resolved 11 of 13 cases (85%). The same complex aberrant splicing event, found in seven unrelated patients, is caused by a 10 kb deletion spanning intron 17 to intron 18, which the authors now include in their routine PCD genomic testing.

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

A very concrete example of what the transcriptome adds when only one variant is found in a recessive gene: 11 of 13 cases resolved, in a gene where the pseudogene complicates short-read alignment. The recurrent intron 17–intron 18 deletion deserves active searching in PCD exomes and genomes with a single HYDIN variant, even before turning to RNA. Limitation: 21-day air-liquid interface culture remains an expert-centre technique.

Analysis by Dr Thibaut Benquey