Unexpected genetic heterogeneity for primary ciliary dyskinesia in the Irish Traveller population.
We present a study of five children from three unrelated Irish Traveller families presenting with primary ciliary dyskinesia (PCD). As previously characterized disorders in the Irish Traveller population are caused by common homozygous mutations, we hypothesised that all three PCD families shared the same recessive mutation. However, exome sequencing showed that there was no pathogenic homozygous mutation common to all families. This finding was supported by histology, which showed that each family has a different type of ciliary defect; transposition defect (family A), nude epithelium (family B) and absence of inner and outer dynein arms (family C). Therefore, each family was analysed independently using homozygosity mapping and exome sequencing. The affected siblings in family A share a novel 1 bp duplication in RSPH4A (NM_001161664.1:c.166dup; p.Arg56Profs*11), a radial-spoke head protein involved in ciliary movement. In family B, we identified three candidate genes (CCNO, KCNN3 and CDKN1C), with a 5-bp duplication in CCNO (NM_021147.3:c.258_262dup; p.Gln88Argfs*8) being the most likely cause of ciliary aplasia. This is the first study to implicate CCNO, a DNA repair gene reported to be involved in multiciliogenesis, in PCD. In family C, we identified a ∼3.5-kb deletion in DYX1C1, a neuronal migration gene previously associated with PCD. This is the first report of a disorder in the relatively small Irish Traveller population to be caused by >1 disease gene. Our study identified at least three different PCD genes in the Irish Traveller population, highlighting that one cannot always assume genetic homogeneity, even in small consanguineous populations.
1] National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland [2] Genetics Department, Temple Street Children's University Hospital, Dublin 1, Ireland [3] Academic Centre on Rare Diseases, School of Medicine and Medical Sciences, University College Dublin, Belfield, Dublin 4, Ireland.
Jillian P
JP
Casey
1] Academic Centre on Rare Diseases, School of Medicine and Medical Sciences, University College Dublin, Belfield, Dublin 4, Ireland [2] UCD School of Agriculture, Food Science and Veterinary Medicine, University College Dublin, Dublin 4, Ireland.
Paul A
PA
McGettigan
Respiratory Department, Temple Street Children's University Hospital, Dublin 1, Ireland.
Fiona
F
Healy
Paediatric Respiratory Department, Royal Brompton Hospital, London, UK.
Claire
C
Hogg
Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
Alison
A
Reynolds
1] Academic Centre on Rare Diseases, School of Medicine and Medical Sciences, University College Dublin, Belfield, Dublin 4, Ireland [2] Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
Breandan N
BN
Kennedy
1] Academic Centre on Rare Diseases, School of Medicine and Medical Sciences, University College Dublin, Belfield, Dublin 4, Ireland [2] National Centre for Medical Genetics, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland.
Sean
S
Ennis
1] Respiratory Department, Temple Street Children's University Hospital, Dublin 1, Ireland [2] School of Medicine and Medical Sciences, University College Dublin, Belfield, Dublin 4, Ireland.
Dubhfeasa
D
Slattery
1] Genetics Department, Temple Street Children's University Hospital, Dublin 1, Ireland [2] Academic Centre on Rare Diseases, School of Medicine and Medical Sciences, University College Dublin, Belfield, Dublin 4, Ireland [3] National Centre for Medical Genetics, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland.
Sally A
SA
Lynch
D002648:Child; D002925:Ciliary Motility Disorders / Q000175:diagnosis / Q000235:genetics*; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics; D003598:Cytoskeletal Proteins; D045647:DNA Glycosylases / Q000235:genetics; D004848:Epithelium / Q000473:pathology; D005260:Female; D018740:Genetic Heterogeneity; D006720:Homozygote; D006801:Humans; D007494:Ireland; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D011506:Proteins / Q000235:genetics; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000235:genetics
C493964:CDKN1C protein, human; D050761:Cyclin-Dependent Kinase Inhibitor p57; D003598:Cytoskeletal Proteins; C478878:DNAAF4 protein, human; C406328:KCNN3 protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011506:Proteins; C000589692:RSPH4A protein, human; D051640:Small-Conductance Calcium-Activated Potassium Channels; C492570:CCNO protein, human; D045647:DNA Glycosylases