Submission Details

The TP73 gene encodes a transcription factor belonging to the p53 family and controls cell proliferation and cell death, as well as the architecture and homeostasis of various tissues (PMID: 34368167). TP73 has been reported as an essential positive regulator of lung ciliated cell differentiation (PMID: 34077761) as well as an activator of FOXJ1 expression (PMID: 26988441). TP73 was first reported as a candidate gene linked to primary ciliary dyskinesia 47 and lissencephaly in 2021 (Wallmeier et al., PMID: 34077761). The specific disease entity, primary ciliary dyskinesia 47 and lissencephaly (CILD47, MONDO:0030346, OMIM#: 619466), is part of a larger group of more than 40 forms of primary ciliary dyskinesia (PCD) with a monogenic etiology. Autosomal-recessive motile ciliopathy is triggered by loss-of-function variants in TP73 leading to impaired differentiation of multiciliated cells (MCC). This defect is the underlying cause of a severe, chronic, and destructive pulmonary disease, as well as abnormalities in the development of the cerebral cortex.

The 2021 study described seven patients from five non-related families with a history of consanguinity who experienced chronic respiratory conditions affecting both upper and lower airways, characterized by repeated infections, a productive cough, persistent rhinitis, and frequent otitis media (PMID: 34077761). Some patients exhibited these symptoms very early on, with onset in the neonatal period necessitating respiratory support. One patient required medical intervention at two months old due to respiratory failure complications. Chest radiographs indicated conditions such as atelectasis, mucus obstruction, and bronchiectasis. However, there was no occurrence of situs inversus among these individuals. Additionally, these patients had brain irregularities that closely resembled patterns of anterior focused lissencephaly, often accompanied by a thin, poorly developed, or completely absent corpus callosum. These neurological abnormalities were associated with a spectrum of intellectual disabilities, central hypotonia, and evidence of increased seizure susceptibility (PMID: 34077761). Respiratory epithelial cells from patient samples harboring TP73 variants were cultured under an air-liquid interface (ALI) and showed a reduced number of FOXJ1- and RFX2-positive multi-ciliated cells, a reduction in ciliary length, a severe defect in differentiation, and an inability to transport particles by ciliary beating in vitro (PMID 34077761).

Five suspected disease-causing variants have been scored as part of this curation (one multi-exon deletion, one frameshift, two nonsense, and one canonical splice site disruption introducing a premature stop codon). These variants have been collectively reported in five probands in one publication, all of whom were homozygous for their respective variants (PMID: 34077761). The parents of these individuals were found to be heterozygous carriers of the respective variants.

This gene-disease relationship is also supported by experimental evidence. TP73 expression in humans is found in ciliated-related organ tissue such as the lung and testis (PMID: 24309898). A pooling-based genome-wide association study reported a link between p73 and chronic rhinosinusitis in a human population (PMID: 20211107). Animal models have shown that mice functionally deficient in p73 exhibited profound neurological defects, hydrocephalus, chronic infections, and inflammation. Histologically, the p73-/- mice developed severe rhinitis and purulent otitis media, and massive neutrophil infiltrates of these sites were evident at the earliest ages and persisted through adulthood when greater than 80% of p73-/- mice exhibited chronic, bilateral rhinitis, otitis, periorbital edema, and conjunctivitis (PMID:10716451). The same finding was replicated by Nemajerova et al., 2016 (PMID: 27257214) with similar upper and lower airway phenotypes. A separate mouse model was created, demonstrating that mice deficient in p73 display pronounced airway abnormalities including epithelial hyperplasia, loss of epithelial integrity, and the absence of multiciliated cells (MCC). Additionally, these mice showed clear signs of lung infection and inflammation, including the accumulation of debris, mucus, and inflammatory cells within the bronchioles, leading to crystalline pneumonia (PMID: 26947080). Isolated murine tracheal epithelial cells (MTECs) from these mice demonstrated a significant change in the cellular composition of epithelium from murine tracheas and bronchioles and reduced ciliated cells compared to the wild-type controls. p73 regulates Foxj1 as a transcriptional regulator in multi-ciliogenesis (PMID: 26947080). Finally, a mouse model has recapitulated the neurological feature of immature and aberrant multi-ciliated ependymal cells that persist in adulthood (PMID: 26482843).

In summary, TP73 is strongly associated with primary ciliary dyskinesia 47 and lissencephaly. This has been demonstrated in both clinical diagnostic and research settings without the emergence of contradictory evidence, leading to a strong classification. Replication over a longer period will be required to reach a more definitive gene-disease association. The ClinGen Motile Ciliopathy GCEP approved this classification on September 14, 2023 (SOP Version 10).