Compound heterozygous RSPH4A variants associated with suspected primary ciliary dyskinesia in a Chinese family: a case report and literature review.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder caused by defects in ciliary structure and function, leading to impaired mucociliary clearance and chronic respiratory tract infections. The radial spoke head protein 4 homolog A (RSPH4A) gene is one of over 50 genes responsible for causing PCD. The diagnosis of PCD is challenging because symptoms are nonspecific and overlap with common respiratory diseases, such as asthma and recurrent bronchitis, while definitive diagnosis requires specialized and not widely available techniques, such as transmission electron microscopy (TEM) and genetic testing, with test results being not always positive.

CASE DESCRIPTION: The female proband, of 11-year-old, presented chronic cough, recurrent pneumonia, bronchiectasis. Her nasal nitric oxide (nNO) level was 5 ppb, which is markedly below the age-specific reference threshold of 113 ppb for an 11-year-old child. Genetic testing revealed two novel compound heterozygous variants in the RSPH4A gene: a nonsense variant c.658A>T (p.Lys220Ter) and a synonymous variant c.1764G>T (p.Gly588=), both of which were confirmed by Sanger sequencing. Family segregation analysis demonstrated that the proband inherited the two variants from her asymptomatic father and mother, respectively, confirming compound heterozygosity. Although cough symptoms improved following treatment with antibiotics, bronchoscopy secretions aspiration, and inhaled corticosteroids, the follow-up at 3 months revealed persistent moderate obstructive ventilatory dysfunction with no significant improvement.

CONCLUSIONS: This case expands the mutational spectrum of RSPH4A-associated PCD and highlights that synonymous variants should not be routinely excluded from pathogenicity assessment in patients with a compatible PCD phenotype.