A discarded synonymous variant in NPHP3 explains nephronophthisis and congenital hepatic fibrosis in several families.

Half of patients with a ciliopathy syndrome remain unsolved after initial analysis of whole exome sequencing (WES) data, highlighting the need for improved variant filtering and annotation. By candidate gene curation of WES data, combined with homozygosity mapping, we detected a homozygous predicted synonymous allele in NPHP3 in two children with hepatorenal fibrocystic disease from a consanguineous family. Analyses on patient-derived RNA shows activation of a cryptic mid-exon splice donor leading to frameshift. Remarkably, the same rare variant was detected in four additional families with hepatorenal disease from UK, US, and Saudi patient cohorts and in addition, another synonymous NPHP3 variant was identified in an unsolved case from the Genomics England 100,000 Genomes data set. We conclude that synonymous NPHP3 variants, not reported before and discarded by pathogenicity pipelines, solved several families with a ciliopathy syndrome. These findings prompt careful reassessment of synonymous variants, especially if they are rare and located in candidate genes.

Is low birth weight an antecedent of CKD in later life? A systematic review of observational studies.

BACKGROUND: There has been considerable interest in the hypothesis that low birth weight may be a marker of impaired nephrogenesis and that this is causally related to chronic kidney disease (CKD). STUDY DESIGN: Systematic review and meta-analysis of observational studies. SETTING & POPULATION: Studies of the relationship between birth weight and CKD published before February 1, 2008, were identified by using electronic searches. SELECTION CRITERIA: All studies that had collected data for birth weight and kidney function at greater than 12 months of age were eligible for inclusion, except for studies of extremely low-birth-weight infants, very premature infants, or toxic exposure in utero. STUDY FACTOR: Birth weight. OUTCOMES: CKD defined as albuminuria, low estimated glomerular filtration rate (<60 mL/min/1.73 m(2) or < 10th centile for age/sex), or end-stage renal disease. RESULTS: We analyzed 31 relevant cohort or case-control studies with data for 49,376 individuals and data for 2,183,317 individuals from a single record-linkage study. Overall, 16 studies reported a significant association between low birth weight and risk of CKD and 16 observed a null result. The combination of weighted estimates from the 18 studies for which risk estimates were available (n = 46,249 plus 2,183,317 from the record linkage study) gave an overall odds ratio (OR) of 1.73 (95% confidence interval [CI], 1.44 to 2.08). Combined ORs were consistent in magnitude and direction for risks of albuminuria (OR, 1.81; 95% CI, 1.19 to 2.77), end-stage renal disease (OR, 1.58; 95% CI, 1.33 to 1.88), or low estimated glomerular filtration rate (OR, 1.79; 95% CI, 1.31 to 2.45). LIMITATIONS: A reliance on published estimates and estimates provided on request rather than individual patient data and the possibility of reporting bias. CONCLUSIONS: Existing data indicate that low birth weight is associated with subsequent risk of CKD, although there is scope for additional well-designed population-based studies with accurate assessment of birth weight and kidney function and consideration of important confounders, including maternal and socioeconomic factors.