Clinical and Molecular Investigations Into Ciliopathies

Human diseases caused by defects of the primary cilium (ciliopathies) are a group of distinct disorders with overlapping features. Clinical features of ciliopathies include fibrocystic disease of the kidneys and liver, retinal degeneration, obesity, structural and functional defects of the central nervous system and the eyes, abnormal bone growth, abnormal sidedness of internal organs and polydactyly. Human ciliopathies characterized by variable combinations of these features include autosomal recessive (ARPKD) and dominant (ADPKD) polycystic kidney diseases, nephronophthisis (NPHP), Joubert syndrome and related disorders (JSRD), Bardet-Biedl (BBS), Meckel-Gruber (MKS), Oral-Facial-Digital-type 1 (OFD1), and Alstrom syndromes (AS) and skeletal disorders such as Jeune syndrome (JS) and cleidocranial dysplasia. ARPKD, the most common pediatric ciliopathy, is characterized by cystic degeneration of the kidneys and congenital hepatic fibrosis of the liver. JSRD are a heterogenous group of syndromes characterized by a distinctive cerebellar and brainstem malformation (molar tooth sign), intellectual disability, abnormal eye movements, and abnormal respiratory pattern in infancy. Other common features seen in subsets of JSRD patients include, fibrocystic renal disease, congenital hepatic fibrosis, retinal degeneration, retinal colobomas, occipital encephalocele, and polydactyly. AS and BBS are ciliopathies characterized by obesity and retinal degeneration and hepatorenal disease in most cases. BBS patients also exhibit postaxial polydactyly, cognitive impairment, male hypogonadotrophic hypogonadism and female genitourinary malformations. Additional features in AS include metabolic syndrome associated with insulin resistance and hyperlipidemia, cardiomyopathy and sensorineural deafness. OFD-I is characterized by polycystic kidney disease and oral, digital and brain anomalies including cerebellar hypoplasia with or without Dandy- Walker malformation. JS is a skeletal ciliopathy characterized by small thorax, short- limbed short stature, fibrocystic renal disease and retinal degeneration. The frequency and characteristics and natural history of specific organ/system disease in ciliopathies are either unknown or poorly defined, mostly because of the limited data available from retrospective reports of small numbers of patients.

In this protocol, we will evaluate up to 500 children and adults with various ciliopathies with special emphasis on delineating the characteristics of individual organ system involvement including kidney, liver, eye, central nervous system and bone disease and metabolic derangements associated with obesity/insulin resistance/metabolic syndrome. We will perform mutation analysis of the related ciliopathy genes as needed. Routine outpatient evaluations will last 4-5 days and follow up visits will occur approximately every 1-2 years. This protocol will provide longitudinal information regarding progression of individual organ system disease in a large cohort of ciliopathy patients, and will elucidate genotype-phenotype correlations. The protocol will also allow the investigators to acquire sufficient expertise in relatively common ciliopathies such as ARPKD, JSRD and AS to design therapeutic interventions for specific organ diseases in the future.