Combinatorial filtering supplemented by PolyPhen predictions initially identified a second candidate gene, DNAH5, in kindred 1 under a recessive model (Table 1). However, this candidate was excluded in subsequent comparisons to kindreds 2 and 3. DNAH5 encodes a dynein heavy chain found in cilia, and mutations in DNAH5 are a well-known cause of primary ciliary dyskinesia (PCD; OMIM #608644), a disorder characterized by recurrent sinopulmonary infections, bronchiectasis, and chronic lung disease. This was of particular interest because some of the clinical findings in the siblings in kindred 1 are unique among reported cases of Miller syndrome. Specifically, both siblings have recurrent lung infections, bronchiectasis, and chronic obstructive pulmonary disease for which they have received medical management in a specialty clinic for individuals with cystic fibrosis. Accordingly, exome analysis revealed that both siblings in kindred 1 have, in addition to Miller syndrome, PCD due to mutations in DNAH5.
