The DNAL1 gene was first reported in relation to primary ciliary dyskinesia (PCD) in 2011 (PMID: 21496787). PCD is a condition of impaired ciliary function characterized by neonates with respiratory distress, recurrent chest infections, cough and/or pneumonia. Heterotaxy is present with approximately 50% penetrance, most often in the form of situs inversus totalis. Immotile sperm and female infertility are also reported for some affected patients. DNAL1 was evaluated for gene-disease association with PCD because it encodes the ortholog to Chlamydomonas axonemal dynein light chain 1, which is an outer dynein arm component that assists cilia movement (PMID: 21496787).
At the time of this review, at least eight probands with phenotypes consistent with PCD and variants in DNAL1 consistent with an expected autosomal recessive inheritance pattern have been identified in the literature. Of these variants, 1 was reported to have variant level functional evidence and was identified as homozygous in the patient (PMID: 21496787, PMID: 30300419, PMID: 36841509, PMID: 33479112). Supporting experimental data have been reported from a study of the Chlamydomonas ortholog, in which RNAi-based silencing of the gene resulted in non-flagellate, non-motile zoospores (PMID: 20451645).
In summary, DNAL1 has a Definitive association with primary ciliary dyskinesia 16. This classification has been clearly demonstrated and confirmed through both experimental and genetic evidence and has been upheld over time without the emergence of conflicting evidence. This classification was approved by the ClinGen Motile Ciliopathy GCEP on April 8th, 2024 (SOP Version 10).
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