RSPH4A – Primary Ciliary Dyskinesia

Autosomal recessive mutations in RSPH4A underlie primary ciliary dyskinesia (PCD), characterized by chronic oto-sino-pulmonary disease, bronchiectasis, infertility, and anosmia. Reported pathogenic variants include novel missense, splice-site, and frameshift alleles across diverse populations. Inheritance is autosomal recessive with biallelic loss-of-function or hypomorphic alleles.

A novel homozygous missense variant c.1321T>C (p.Trp441Arg) was identified in a Puerto Rican family, segregating with PCD in the proband and her sister (PMID:38818043). The founder splice-site mutation c.921+3_921+6del (intronic) occurs homozygously in up to 13 individuals from 11 unrelated Puerto Rican families, presenting PCD without laterality defects and bronchiectasis (PMID:33670432; PMID:23798057). In a Japanese cohort, targeted NGS detected RSPH4A mutations in one of 46 suspected PCD patients, confirming global allelic heterogeneity (PMID:28939216).

Across studies, at least 25 independent probands from ≥7 unrelated families harbor biallelic RSPH4A variants with segregation in affected sibships and carrier parents. Founder and recurrent alleles (c.921+3_921+6del, c.1321T>C) have defined population-specific risk, with a carrier frequency of ~13% among Puerto Rican PCD cases (PMID:35626283).

Functional assays demonstrate that RSPH4A loss disrupts radial spoke head assembly: immunofluorescence in 21 individuals shows absence of RSPH4A and secondary loss of RSPH1/RSPH9 in respiratory cilia (PMID:25789548). Zebrafish knockdown of Rsph4a produces central-pair agenesis and motility defects, rescued by human RSPH4A expression (PMID:19200523).

No conflicting evidence has been reported; all variants are concordant with an autosomal recessive, loss-of-function mechanism. Exome and panel sequencing streamline diagnosis across populations.

Integrated evidence supports a Strong clinical validity: multiple unrelated families, segregation, functional concordance, and population founder effects. Genetic testing for RSPH4A variants informs early PCD diagnosis, guiding management of chronic respiratory disease and infertility.

Key Take-home: Biallelic RSPH4A pathogenic variants cause autosomal recessive PCD; molecular confirmation enables precise diagnosis and tailored clinical care.

References

• Frontiers in Genetics • 2024 • A novel homozygous RSPH4A variant in a family with primary ciliary dyskinesia and literature review. PMID:38818043
• Human Mutation • 2013 • Founder mutation in RSPH4A identified in patients of Hispanic descent with primary ciliary dyskinesia. PMID:23798057
• Diagnostics (Basel, Switzerland) • 2021 • Primary Ciliary Dyskinesia Diagnostic Challenges: Understanding the Clinical Phenotype of the Puerto Rican RSPH4A Founder Mutation. PMID:33670432
• Auris, Nasus, Larynx • 2018 • A targeted next-generation sequencing panel reveals novel mutations in Japanese patients with primary ciliary dyskinesia. PMID:28939216
• Diagnostics (Basel, Switzerland) • 2022 • The Genetics of Primary Ciliary Dyskinesia in Puerto Rico. PMID:35626283
• American Journal of Respiratory Cell and Molecular Biology • 2015 • Immunofluorescence Analysis and Diagnosis of Primary Ciliary Dyskinesia with Radial Spoke Defects. PMID:25789548
• American Journal of Human Genetics • 2009 • Mutations in radial spoke head protein genes RSPH9 and RSPH4A cause primary ciliary dyskinesia with central-microtubular-pair abnormalities. PMID:19200523

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