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Peer-reviewedCC BY 4.0Cells

Re-Analysis on GRCh38 with the MANE Select Transcript Resolves Previously Undetected Biallelic ODAD4 Variants in Primary Ciliary Dyskinesia

  • Petra Pennekamp1
  • Marina Praprotnik2,3
  • Bernd Dworniczak1
  • Heymut Omran1
  • Rim Hjeij1
  1. 1Department of General Pediatrics, University Hospital Münster, 48149 Münster, Germany
  2. 2Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
  3. 3Department for Pulmonary Diseases, University Children’s Hospital Ljubljana, University Medical Center Ljubljana, 1000 Ljubljana, Slovenia
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Abstract

Molecular diagnosis is highly sensitive to the human genome assembly used in a bioinformatics pipeline. Panels designed on GRCh37 (hg19) inherit its exon annotation, whereas transcript standards and interpretation databases are anchored to GRCh38 (hg38); a coding exon absent from GRCh37 can therefore be neither targeted nor analyzed. We describe two unrelated individuals with primary ciliary dyskinesia (PCD) in whom first-line, GRCh37-based panel sequencing was non-diagnostic. Both were re-analyzed on GRCh38 against the Matched Annotation from NCBI and EMBL-EBI (MANE) Select transcript. In Patient 1 (OP-880 II1), trio whole-genome sequencing identified a homozygous frameshift variant (NM_031421.5:c.1157del, p.(Lys386ArgfsTer52)) in exon 9 of ODAD4 (previously TTC25), an exon not represented in GRCh37. In Patient 2 (OP-4121 II1), the panel detected only c.100C>T, p.(Gln34Ter); Sanger sequencing of exon 9 disclosed NM_031421.5:c.1273C>T, p.(Gln425Ter) in trans. Her cilia were immotile on high-speed video microscopy and lacked outer dynein arms on transmission electron microscopy. Two cases cannot establish frequency, but they identify a remediable failure mode: GRCh37-based pipelines miss GRCh38-defined exons, leaving a recessive genotype apparently monoallelic. Re-analysis on GRCh38 against MANE Select transcripts should be reflexive whenever a strong phenotype yields a negative or monoallelic result, including in previously tested individuals.

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Cite

BibTeXRIS
BibTeX
@article{pennekamp2026reanalysis,
  title = {{Re-Analysis on GRCh38 with the MANE Select Transcript Resolves Previously Undetected Biallelic ODAD4 Variants in Primary Ciliary Dyskinesia}},
  author = {Petra Pennekamp and Marina Praprotnik and Bernd Dworniczak and Heymut Omran and Rim Hjeij},
  journal = {Cells},
  year = {2026},
  month = oct,
  doi = {10.3390/cells15201893},
  url = {https://www.mdpi.com/2073-4409/15/20/1893},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Re-Analysis on GRCh38 with the MANE Select Transcript Resolves Previously Undetected Biallelic ODAD4 Variants in Primary Ciliary Dyskinesia
AU  - Petra Pennekamp
AU  - Marina Praprotnik
AU  - Bernd Dworniczak
AU  - Heymut Omran
AU  - Rim Hjeij
PY  - 2026
DA  - 2026/10/17
JO  - Cells
DO  - 10.3390/cells15201893
UR  - https://www.mdpi.com/2073-4409/15/20/1893
AB  - Molecular diagnosis is highly sensitive to the human genome assembly used in a bioinformatics pipeline. Panels designed on GRCh37 (hg19) inherit its exon annotation, whereas transcript standards and interpretation databases are anchored to GRCh38 (hg38); a coding exon absent from GRCh37 can therefore be neither targeted nor analyzed. We describe two unrelated individuals with primary ciliary dyskinesia (PCD) in whom first-line, GRCh37-based panel sequencing was non-diagnostic. Both were re-analyzed on GRCh38 against the Matched Annotation from NCBI and EMBL-EBI (MANE) Select transcript. In Patient 1 (OP-880 II1), trio whole-genome sequencing identified a homozygous frameshift variant (NM_031421.5:c.1157del, p.(Lys386ArgfsTer52)) in exon 9 of ODAD4 (previously TTC25), an exon not represented in GRCh37. In Patient 2 (OP-4121 II1), the panel detected only c.100C>T, p.(Gln34Ter); Sanger sequencing of exon 9 disclosed NM_031421.5:c.1273C>T, p.(Gln425Ter) in trans. Her cilia were immotile on high-speed video microscopy and lacked outer dynein arms on transmission electron microscopy. Two cases cannot establish frequency, but they identify a remediable failure mode: GRCh37-based pipelines miss GRCh38-defined exons, leaving a recessive genotype apparently monoallelic. Re-analysis on GRCh38 against MANE Select transcripts should be reflexive whenever a strong phenotype yields a negative or monoallelic result, including in previously tested individuals.
SN  - 2073-4409
ER  -