Relationship Between Genotype and Laterality Defects in Primary Ciliary Dyskinesia

Relationship Between Genotype and Laterality Defects in Primary Ciliary Dyskinesia AT Barber1, AJ Shapiro2, SD Davis1, TW Ferkol3, JJ Atkinson3, SD Sagel4, SD Dell5, KN Olivier6, CE Milla7, M Rosenfeld8, L Li1, F Lin1, KM Sullivan1, M Zariwala1, MR Knowles1, MW Leigh1 1. University of North Carolina at Chapel Hill, 2. Montreal Children’s Hospital, 3. Washington University School of Medicine, 4. University of Colorado School of Medicine, 5. BC Children’s Hospital, 6. National Heart, Lung, and Blood Institute, 7. Stanford University, 8. Seattle Children’s Hospital

Background Results Discussion

❖ Primary Ciliary Dyskinesia (PCD) is a rare, Laterality ❖ Individuals with mutations resulting in normal/near genetically heterogeneous disease of motile cilia Ciliary ultrastructure normal ciliary ultrastructure almost exclusively have SS SIT SA SS. The 3 individuals in this group with SIT had ❖ Common features of PCD include neonatal mutations in FOXJ1 and OFD1, both of which are respiratory distress, chronic sino-oto-pulmonary ODA (n = 242) known to be associated with laterality defects. disease, infertility, and organ laterality defects ❖ 559 total ARMC4, CCDC103, CCDC114, DNAH5, DNAI1, 96 (40%) 112 (46%) 34 (14%) DNAI2 ❖ There is a greater likelihood of a laterality defect in ❖ Normal organ arrangement (situs solitus, SS) is ❖ SS – 286 (51.2%) individuals with mutations causing ODA defects present in ~50%, mirror image organ arrangement compared to individuals with mutations causing (situs inversus totalis, SIT) is present in ~40%, and ❖ SIT – 214 (38.3%) ODA/IDA (n = 96) IDA/CA/MTD defects. other laterality defects within that spectrum (situs CFAP298, CFAP300, DNAAF1, DNAAF2, DNAAF3, 40 (42%) 43 (45%) 13 (14%) ❖ SA – 59 (10.6%) DNAAF4, DNAAF5, LRRC6, PIH1D3, SPAG1, ambiguus, SA) are present in ~10% of individuals ZMYND10 ❖ Individuals with mutations causing IDA/CA/MTD defects are known to have more severe lung ❖ Little is known about the association between ❖ Median age 11 years, range 1 month – 82 years disease. The decrease in prevalence of laterality genotype and prevalence/type of laterality defects IDA/CA/MTD (n = 96) 52 (54%) 36 (38%) 8 (8%) CCDC39, CCDC40 defects in this group may be partially explained by in PCD ❖ 44% male, 56% female selection bias, as these individuals may be more likely to be diagnosed with PCD in the absence of a Normal/near normal (n = 82) laterality defect. CCNO, CCDC65, CCDC164, CFAP57, CFAP221, 79 (96%) 3 (4%) 0 Methods FOXJ1, GAS2L2, HYDIN, NEK10, OFD1, RPGR, RSPH1, RSPH3, RSPH4A, RSPH9 Conclusions ❖ Prospective study at 9 sites across North America within the Genetic Disorders of Mucociliary DNAH11 (n = 43) 19 (44%) 20 (47%) 4 (9%) ❖ Prevalence of laterality defects in PCD varies by Clearance Consortium (GDMCC) ciliary ultrastructural defect ❖ Included subjects with a definitive diagnosis of PCD Acknowledgements based on either genetic testing and/or hallmark Likelihood of a laterality defect (SIT+SA) defects in ciliary ultrastructure on transmission electron microscopy (TEM) This research was supported by: ❖ Sorted individuals into 1 of 5 groups based on Ultrastructure (vs IDA/CA/MTD) Odds Ratio 95% Confidence Interval P-value 1. NIH - The Genetic Disorders of Mucociliary genotype and expected ultrastructural defect: Clearance Consortium (U54HL096458) is part of the National Center for Advancing Translational Sciences ❖ Outer dynein arm defect (ODA) ODA (n = 242) 1.8 1.12 – 2.91 0.02 (NCATS) Rare Diseases Clinical Research Network ❖ Outer and inner dynein arm defect (ODA/IDA) (RDCRN) and supported by the RDCRN Data ❖ Inner dynein arm and central apparatus defect ODA/IDA (n = 96) 1.66 0.94 – 2.94 0.08 Management and Coordinating Center (DMCC) with microtubular disorganization (IDA/CA/MTD) (U2CTR002818). RDCRN is an initiative of the Office of Rare Diseases Research (ORDR) funded through a ❖ Normal/near normal ultrastructure Normal/near normal (n = 82) 0.05 0.01 – 0.15 <0.01 collaboration between NCATS and National Heart, ❖ DNAH11 Lung, and Blood Institute (NHLBI). ❖ Reviewed imaging studies and assigned each DNAH11 (n = 43) 1.48 0.72 – 3.06 0.29 2. The Carolina for the Kids Grant Program at UNC individual a laterality status (SS, SIT, or SA) Health Children’s