PCDF Research Forum #6: Genotype/Phenotype Relationships in PCD

Primary Ciliary Dyskinesia: Longitudinal Study of Lung Disease by Ultrastructure Defect and Genotype

Stephanie D. Davis et al.

Link to study abstract

Understanding and identifying the relationship between genotype (gene mutation) and phenotype (observable clinical traits) will be critical for advancing treatment of PCD. This paper by Davis, et al describes a review of longitudinal data collected through a multicenter study that included five of the North American Genetic Disorders of Mucociliary Clearance Consortium (GDMCC) sites. This review was conducted to determine the correlation between ultrastructural defects/genotype and effect on clinical phenotypes, including FEV1 and growth factors such as height and weight. Of the 171 participants in the reviewed data set, 137 had a confirmed PCD diagnosis through either genetics, electron microscopy (EM), or both and were included in this analysis. In addition, patients were grouped by ciliary defect, including: outer dynein arm (ODA), outer and inner dynein arm (ODA+IDA), inner dynein arm, central apparatus, microtubular disorganization (IDA/CA/MTD), normal ciliary structure, and ‘other’ defects that made up a small percentage of the study group.

Enrolled participants were 19 years and younger at the time of enrollment in the GDMCC study and were followed annually over five years. To be included in this longitudinal review, in addition to having confirmed PCD (as above) participants also had to have completed at least two annual visits over the five-year study period. Most had completed all six available visits—an entry visit, plus five annual follow up visits. FEV1 and FVC values were collected via spirometry at each visit, as well as growth measures of height and weight. In addition, patients provided a sputum sample to test for common respiratory pathogens.

The results of the longitudinal review showed that patients with IDA/CA/MTD defects, most of whom had defects in either CCDC39 or CCDC40, had consistently lower lung function and overall growth parameters compared to all other groups. These participants exhibited lower baseline lung function and greater decline in FEV1 over the five-year period than all other groups, including those with DNAH5 mutations. The IDA/CA/MTD group also had lower body mass index (BMI) with both lower heights and weights than the other groups. BMI has been shown to be correlated with lung function, with lower BMI associated with lower lung function. Interestingly, this group also tended to be diagnosed at an earlier age than the other groups, suggesting severity of disease in these mutations may lead to earlier diagnosis.

While it is not clear why individuals with IDA/CA/MTD defects appeared to have worse outcomes on the clinical measures analyzed, the authors suggested several possible, but unconfirmed, explanations. Ciliary beat function is significantly impaired in CCDC39 and CCDC40 mutations. However, it can also severely impaired in other defects, so this was not thought to likely be the only explanation. The authors also pointed to early research and one more recent paper that suggest neutrophil (white blood cells) motility and function may be impaired in individuals with PCD, making it more difficult to fight infection. However, neutrophil motility impairment was seen in other PCD ultrastructural defects, as well, and the role, if any, of this phenomenon is not clearly understood in PCD at this time.

For now, the explanation for the differences in clinical severity seen in PCD based on genotype is not clear, and the authors urged caution in drawing broad conclusions based on the small sample size of each defect group. Additionally, it was impossible to assess variations in care for individual participants who came to PCD expert centers annually for the GDMCC study but were followed for routine care in their local communities. (Please see the PCD Foundation Consensus document on PCD diagnosis and treatment for more information on best practices for PCD care).

This paper provides additional evidence to support the need for further clarification of PCD genotype/phenotype associations both to direct patient-specific care, as well as to guide the development of targeted therapies. For example, understanding the correlation between IDA/CA/MTD defects and BMI may encourage healthcare teams to be more aggressive with nutrition management in the care plan for these patients, and awareness of the association with lower FEV1 and FVC in these patients may prompt more frequent surveillance of lung function and earlier intervention to slow lung function decline.

This paper also demonstrates the need for more robust longitudinal (over a long period of time) data collection in larger populations of PCD patients to 1.) Overcome the problem of small sample sizes, 2.) Include data across all age groups and genotypes, and 3.) Allow for data collection in perpetuity so the experience of PCD patients over an entire lifespan can be analyzed. To address these needs, PCD registries have been or are being established by expert centers and patient advocacy groups around the world. PCD patient support for these efforts will be critical in allowing us to understand genotype/phenotype and expand on the important work represented in this paper by Davis, et al.

Billy Anton

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