Primary Ciliary Dyskinesia as a common cause of
bronchiectasis in the Canadian Inuit population
Deborah J. Morris-Rosendahl, PhD1,2
Clinical Genetics and Genomics Laboratory, Royal Brompton and
Harefield Clinical Group, Guy’s and St. Thomas’ NHS Foundation Trust,
London, UK
National Heart and Lung Institute, Imperial College London, London, UK
Increased rates of upper and lower respiratory tract illness and otitis
media in Inuit children have been known for a long
time.1 An increased prevalence of non-CF
bronchiectasis later in life has also been reported.2The reasons for this are not fully understood and are likely to be
multifactorial, however the findings of Hunter-Schouela et
al.3 in this issue of the journal may provide a
missing link. They report a novel, pathogenic, possible founder DNA
variant causing Primary Ciliary Dyskinesia (PCD) in Inuit patients from
different geographical areas of the Nunavut (Qikiqtaaluk region, Baffin
Island) and Nunavik (Northern Qebec) regions in Canada, which may well
be a contributing factor to the finding of increased bronchiectasis in
this population. The DNA variant, c.4095+2C>A in theDNAH11 gene, was found in 7 Inuit patients with PCD, from four
families, by genetic testing in three different Canadian centers. All
affected individuals were homozygous for the variant and although its
effect has not yet been confirmed at the RNA level, the variant is not
present in the gnomAD database (www.gnomad.org), nor has it previously
been reported and it is strongly predicted to have an effect on
splicing.
Previous estimates of bronchiectasis in Inuit children in the
Qikiqtaaluk Nunavut region are as high as 1/5002 and
based on the finding of five affected PCD patients in an approximate
population size of 16,000 Inuits, Hunter-Schouela et al. have
roughly estimated that the DNAH11 variant may have a carrier
frequency as high as 1/19 individuals. The age at genetic diagnosis in
the patients varied from 4 to 59 years, partly due to late clinical
diagnosis, but also due to varying severity. Four patients had
laterality defects, whereas the other 3 had situs solitus. Other
clinical findings were typical of PCD, including neonatal respiratory
distress, bronchiectasis, chronic atelectasis, chronic rhinitis and
chronic otitis media. DNAH11 encodes one member of the axonemal
dynein heavy chain protein family4 that contributes to
the assembly of respiratory cilia. It is also one of the causes of PCD
that is not well diagnosed by routine cilia diagnostics, such as
standard transmission electron microscopy (TEM). Hence the respiratory
cilia appeared to be normal in 5 of the patients in this study for whom
this was investigated, which delayed the recognition of PCD.
Although PCD is a rare disease, recent calculations predict that it is
more common than previously assumed, with the minimum global prevalence
now estimated to be at least 1/75505. More than 50
genes have been identified as being causative of PCD which is
characterized by allelic as well as genetic heterogeneity with many
different pathogenic variants described in each of the genes.DNAH11 is one of, if not the most common cause of PCD in world
populations5.
Although much of the research on PCD and most diagnostic tests have been
performed on North American and European patients, this is not the first
study highlighting that the prevalence of PCD may be higher in
non-European populations. Hannah et al5.highlighted from their study of pathogenic PCD variants in the gnomAD
database, that the prevalence of carrying two disease-causing alleles in
a PCD gene is generally higher in individuals of African descent than in
most other populations. Their data suggested that patients of
non-European ancestry might specifically be in need of PCD workup.
Founder variants in other PCD genes have been previously reported in
different populations7,8,9,10,11. In many cases these
findings have enabled a more targeted approach to genetic testing, with
analysis of the founder variant being the first line of testing before
going on to a more expensive and time-consuming next-generation gene
panel, whole exome or whole genome sequencing to screen all known PCD
genes12.
Genomic medicine and genetic testing have historically been relatively
inaccessible to indigenous and isolated populations13,
for manifold reasons including the lack of access to genetic services
and diagnostic laboratories, as well as the expense of genetic testing.
Fortunately this is changing, with a steady reduction in the cost of
diagnostics and an appreciation of the clinical utility of
“mainstreaming” genomics, bringing genetic testing in line with other
laboratory and clinical investigations. Early and accurate diagnosis of
inherited conditions generally leads to better medical care for patients
and their families, with improved knowledge of the natural history of
the condition and early intervention. It is therefore essential that
equitable access to such testing is established for indigenous and
isolated populations, in order to further narrow the health disparity
gap. Although supported by funding from a few sources, this study
signals a success for the Silent Genomes Project, with one of the cases
having been identified by whole genome sequencing within that project,
after negative whole exome sequencing. Furthermore the study has
potential life-changing clinical consequences and provides starting
points for possible interventions for respiratory medicine in the Inuit
population. These include increased awareness of the possibility of PCD
in patients presenting with neonatal respiratory distress,
bronchiectasis or otitis media leading to early intervention; and in
conjunction with Inuit organizations and public health officials,
targeted analysis of the DNAH11 variant in the population with
the possible introduction of newborn screening for PCD.