DNAH9 – Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, autosomal recessive disorder of motile cilia function, characterized by chronic sinusitis, bronchiectasis, and situs inversus totalis in ~50% of cases. DNAH9 encodes an axonemal dynein β heavy chain located at 17p12, critical for outer dynein arm integrity. Defective DNAH9 disrupts ciliary motility, leading to recurrent respiratory infections and laterality defects.

In a Bahraini child with PCD and jejunal atresia, compound heterozygosity for c.7150G>A (p.Gly2384Arg) and c.11086C>T (p.His3696Tyr) in DNAH9 confirmed AR inheritance ([PMID:36712782]). A 52-year-old Han-Chinese patient with Kartagener syndrome harbored two rare DNAH9 variants, establishing this gene’s role across ethnicities ([PMID:35770021]).

Untargeted whole-exome sequencing in 48 patients with suspected PCD achieved a 94% diagnostic yield, identifying bi-allelic variants in DNAH9 among 34 confirmed cases, supporting DNAH9’s inclusion in diagnostic panels ([PMID:33447612]).

In a cohort of eight Chinese patients with laterality defects and complex congenital heart disease, compound heterozygous DNAH9 mutations led to exon skipping and mRNA downregulation. TEM demonstrated outer dynein arm defects, and dnah9 knockdown in zebrafish disturbed left–right patterning, while Dnah9 knockout mice showed compromised cardiac function, mirroring human phenotypes ([PMID:35050399]).

Despite early candidate-gene analyses excluding DNAH9 in two PCD families ([PMID:11247663]), accumulating case, segregation, and functional data solidify its pathogenic role in AR PCD.

Collectively, genetic and experimental evidence supports a strong clinical validity for DNAH9 in PCD, with moderate functional data. DNAH9 should be part of PCD gene panels to enable early genetic diagnosis and guide management before irreversible lung damage.

Key Take-home: DNAH9 biallelic variants cause autosomal recessive PCD with classic respiratory and laterality features; testing expedites diagnosis and informs care.

References

• Cureus • 2022 • A Novel DNAH9 Gene Mutation Causing Primary Ciliary Dyskinesia With an Unusual Association of Jejunal Atresia in a Bahraini Child. PMID:36712782
• Frontiers in medicine • 2022 • Case Report: Rare Dynein Axonemal Heavy Chain 9 Mutations in a Han-Chinese Patient With Kartagener Syndrome. PMID:35770021
• ERJ open research • 2020 • Whole-exome sequencing accuracy in the diagnosis of primary ciliary dyskinesia. PMID:33447612
• Human genetics • 2022 • Biallelic DNAH9 mutations are identified in Chinese patients with defective left-right patterning and cilia-related complex congenital heart disease. PMID:35050399
• Genomics • 2001 • Axonemal beta heavy chain dynein DNAH9: cDNA sequence, genomic structure, and investigation of its role in primary ciliary dyskinesia. PMID:11247663

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