A Portuguese family was evaluated to characterize two compound heterozygous DNAH5 variants — a missense variant of uncertain significance (VUS) c.5290T>C p.(Ser1764Pro) and a pathogenic truncating variant c.4237C>T p.(Gln1413*) — in two brothers diagnosed with primary ciliary dyskinesia (PCD), using nasal nitric oxide, high-speed videomicroscopy (HSVM), transmission electron microscopy (TEM), whole-exome sequencing, immunofluorescence, and protein structural modeling.
Both brothers carried compound heterozygous DNAH5 variants in trans; the proband (diagnosed at age 44) showed nasal nitric oxide of 30 nL/min, ciliary beat frequency of 0.66 Hz, 62.5% total ciliary immotility, class-1 ODA defects on TEM, and markedly reduced DNAH5 expression on immunofluorescence (p<0.0001). The brother (diagnosed at 48) had a similar phenotype including oligoasthenoteratozoospermia. Protein structural modeling showed the Ser1764Pro substitution destabilizes the Link3–4 β-sheet of the DNAH5 linker domain, supporting reclassification of c.5290T>C p.(Ser1764Pro) from VUS to pathogenic.
- Very small family cohort (2 affected brothers + 2 carrier parents); findings may not generalize broadly. - TEM and detailed semen analysis were not performed in the brother or parents, limiting full phenotypic comparison. - Protein structural analysis is predictive (in silico/structural models) rather than confirmed by functional rescue experiments.
When a DNAH5 VUS co-segregates in trans with a known pathogenic variant and both brothers show reduced DNAH5 immunofluorescence and classic PCD findings, integrate structural modeling and family immunofluorescence to support reclassification — this can enable inclusion in diagnostic panels and guide counseling. Consider PCD even with a low PICADAR score (≤5) and adult-onset presentation, as diagnosis may be delayed by decades.
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