@article {608, title = {Primary Ciliary Dyskinesia: Longitudinal Study of Lung Disease by Ultrastructure Defect and Genotype.}, journal = {Am J Respir Crit Care Med}, volume = {199}, year = {2019}, month = {2019 01 15}, pages = {190-198}, abstract = {

RATIONALE: In primary ciliary dyskinesia, factors leading to disease heterogeneity are poorly understood.

OBJECTIVES: To describe early lung disease progression in primary ciliary dyskinesia and identify associations between ultrastructural defects and genotypes with clinical phenotype.

METHODS: This was a prospective, longitudinal (5 yr), multicenter, observational study. Inclusion criteria were less than 19 years at enrollment and greater than or equal to two annual study visits. Linear mixed effects models including random slope and random intercept were used to evaluate longitudinal associations between the ciliary defect group (or genotype group) and clinical features (percent predicted FEV and weight and height z-scores).

MEASUREMENTS AND MAIN RESULTS: A total of 137 participants completed 732 visits. The group with absent inner dynein arm, central apparatus defects, and microtubular disorganization (IDA/CA/MTD) (n = 41) were significantly younger at diagnosis and in mixed effects models had significantly lower percent predicted FEV and weight and height z-scores than the isolated outer dynein arm defect (n = 55) group. Participants with CCDC39 or CCDC40 mutations (n = 34) had lower percent predicted FEV and weight and height z-scores than those with DNAH5 mutations (n = 36). For the entire cohort, percent predicted FEV decline was heterogeneous with a mean (SE) decline of 0.57 (0.25) percent predicted/yr. Rate of decline was different from zero only in the IDA/MTD/CA group (mean [SE], -1.11 [0.48] percent predicted/yr; P = 0.02).

CONCLUSIONS: Participants with IDA/MTD/CA defects, which included individuals with CCDC39 or CCDC40 mutations, had worse lung function and growth indices compared with those with outer dynein arm defects and DNAH5 mutations, respectively. The only group with a significant lung function decline over time were participants with IDA/MTD/CA defects.

}, keywords = {Child, Cilia, Cohort Studies, Female, Genotype, Humans, Kartagener Syndrome, Longitudinal Studies, Lung, Male, Mutation, Phenotype, Prospective Studies, Respiratory Function Tests}, issn = {1535-4970}, doi = {10.1164/rccm.201803-0548OC}, author = {Davis, Stephanie D and Rosenfeld, Margaret and Lee, Hye-Seung and Ferkol, Thomas W and Sagel, Scott D and Dell, Sharon D and Milla, Carlos and Pittman, Jessica E and Shapiro, Adam J and Sullivan, Kelli M and Nykamp, Keith R and Krischer, Jeffrey P and Zariwala, Maimoona A and Knowles, Michael R and Leigh, Margaret W} } @article {363, title = {International Cooperation to Enable the Diagnosis of All Rare Genetic Diseases.}, journal = {Am J Hum Genet}, volume = {100}, year = {2017}, month = {2017 May 04}, pages = {695-705}, abstract = {

Provision of a molecularly confirmed diagnosis in a timely manner for children and adults with rare genetic diseases shortens their "diagnostic odyssey," improves disease management, and fosters genetic counseling with respect to recurrence risks while assuring reproductive choices. In a general clinical genetics setting, the current diagnostic rate is approximately 50\%, but for those who do not receive a molecular diagnosis after the initial genetics evaluation, that rate is much lower. Diagnostic success for these more challenging affected individuals depends to a large extent on progress in the discovery of genes associated with, and mechanisms underlying, rare diseases. Thus, continued research is required for moving toward a more complete catalog of disease-related genes and variants. The International Rare Diseases Research Consortium (IRDiRC) was established in 2011 to bring together researchers and organizations invested in rare disease research to develop a means of achieving molecular diagnosis for all rare diseases. Here, we review the current and future bottlenecks to gene discovery and suggest strategies for enabling progress in this regard. Each successful discovery will define potential diagnostic, preventive, and therapeutic opportunities for the corresponding rare disease, enabling precision medicine for this patient population.

}, keywords = {Databases, Factual, Exome, Genome, Human, Humans, International Cooperation, Rare Diseases}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.04.003}, author = {Boycott, Kym M and Rath, Ana and Chong, Jessica X and Hartley, Taila and Alkuraya, Fowzan S and Baynam, Gareth and Brookes, Anthony J and Brudno, Michael and Carracedo, Angel and den Dunnen, Johan T and Dyke, Stephanie O M and Estivill, Xavier and Goldblatt, Jack and Gonthier, Catherine and Groft, Stephen C and Gut, Ivo and Hamosh, Ada and Hieter, Philip and H{\"o}hn, Sophie and Hurles, Matthew E and Kaufmann, Petra and Knoppers, Bartha M and Krischer, Jeffrey P and Macek, Milan and Matthijs, Gert and Olry, Annie and Parker, Samantha and Paschall, Justin and Philippakis, Anthony A and Rehm, Heidi L and Robinson, Peter N and Sham, Pak-Chung and Stefanov, Rumen and Taruscio, Domenica and Unni, Divya and Vanstone, Megan R and Zhang, Feng and Brunner, Han and Bamshad, Michael J and Lochm{\"u}ller, Hanns} }