title: A case report of primary ciliary dyskinesia, laterality defects and developmental delay caused by the co-existence of a single gene and chromosome disorder.
abstract: BACKGROUND
  Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder characterised by abnormal ciliary motion and impaired mucociliary clearance, leading to recurrent respiratory infections, sinusitis, otitis media and male infertility. Some patients also have laterality defects. We recently reported the identification of three disease-causing PCD genes in the Irish Traveller population; RSPH4A, DYX1C1 and CCNO. We have since assessed an additional Irish Traveller family with a complex phenotype involving PCD who did not have any of the previously identified PCD mutations.
  
  
  METHODS
  In this study we report on a family with three children with PCD and various laterality defects. In addition, one child (V:1) has mild-to-moderate developmental delay and one child has speech delay (V:2). Developmental delay is not usually associated with PCD and is likely to be caused by an additional genetic abnormality. Transmission electron microscopy showed variable inner and outer dynein arm defects. Exome sequencing identified a homozygous missense variant in CCDC103 (c.461A > C; p.His154Pro) as the most likely cause of the PCD and laterality defects in this family. However, as mutation in CCDC103 would not account for the developmental delay, array comparative genomic hybridisation was undertaken and identified a maternally inherited gain of ~1.6 Mb (chr17:34,611,352-36,248,918). Gains at this locus are associated with 17q12 duplication syndrome which includes speech and language delay.
  
  
  CONCLUSIONS
  We report on a variable and complex phenotype caused by the co-inheritance of a single gene mutation in CCDC103 and a microduplication at 17q12, both on chromosome 17. The co-existence of a single gene and chromosome disorder is unusual but accounts for the spectrum of clinical features in this family. In addition, our study brings the total number of PCD genes in the Irish Traveller population to four and we suspect additional PCD genes are yet to be identified. Although, on a global scale, PCD is associated with extensive genetic heterogeneity, finding such a high number of causative PCD genes within the relatively small Irish Traveller population was unexpected.
authors.affiliation: Genetics Department, Temple Street Children's University Hospital, Dublin 1, Ireland. jillian.casey@ucd.ie.|UCD Academic Centre on Rare Diseases, School of Medicine and Medical Sciences, University College Dublin, Belfield, Dublin 4, Ireland. jillian.casey@ucd.ie.
authors.forename: Jillian P
authors.initials: JP
authors.lastname: Casey
authors.affiliation: Primary Ciliary Dyskinesia Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK. Patricia.Goggin@uhs.nhs.uk.
authors.forename: Patricia
authors.initials: P
authors.lastname: Goggin
authors.affiliation: National Centre for Medical Genetics, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland. Jennifer.McDaid@olchc.ie.
authors.forename: Jennifer
authors.initials: J
authors.lastname: McDaid
authors.affiliation: Neonatology, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland. mjmjwhite@gmail.com.
authors.forename: Martin
authors.initials: M
authors.lastname: White
authors.affiliation: UCD Academic Centre on Rare Diseases, School of Medicine and Medical Sciences, University College Dublin, Belfield, Dublin 4, Ireland. sean.ennis@ucd.ie.|Neonatology, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland. sean.ennis@ucd.ie.
authors.forename: Sean
authors.initials: S
authors.lastname: Ennis
authors.affiliation: National Centre for Medical Genetics, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland. David.Betts@olchc.ie.
authors.forename: David R
authors.initials: DR
authors.lastname: Betts
authors.affiliation: Primary Ciliary Dyskinesia Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK. jlucas1@soton.ac.uk.
authors.forename: Jane S
authors.initials: JS
authors.lastname: Lucas
authors.affiliation: Pediatric Respiratory Medicine, The Adelaide and Meath Hospital, Tallaght, Dublin 24, Ireland. Basil.Elnazir@amnch.ie.
authors.forename: Basil
authors.initials: B
authors.lastname: Elnazir
authors.affiliation: Genetics Department, Temple Street Children's University Hospital, Dublin 1, Ireland. sallyann.lynch@olchc.ie.|UCD Academic Centre on Rare Diseases, School of Medicine and Medical Sciences, University College Dublin, Belfield, Dublin 4, Ireland. sallyann.lynch@olchc.ie.|National Centre for Medical Genetics, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland. sallyann.lynch@olchc.ie.
authors.forename: Sally Ann
authors.initials: SA
authors.lastname: Lynch
mesh_terms: D002675:Child, Preschool; D058674:Chromosome Duplication; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D003241:Consanguinity; D002658:Developmental Disabilities / Q000150:complications / Q000235:genetics*; D005190:Family; D005260:Female; D018740:Genetic Heterogeneity; D059446:Heterotaxy Syndrome / Q000150:complications / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D007619:Kartagener Syndrome / Q000235:genetics*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D010375:Pedigree; D050497:Stillbirth
chemical_list: C000598212:CCDC103 protein, human; D008869:Microtubule-Associated Proteins