Submission Details

NPHP4 was first reported in relation to autosomal recessive nephronopthisis (NPHP4)-NPHP4 in 2002 (Mollet et al., PMID: 12244321). At least 81 unique likely pathogenic or pathogenic variants (missense, nonsense, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. NPHP4 has been noted to be associated with nephronophthisis and Senior-Løken syndrome. Per criteria outlined by the ClinGen Lumping and Splitting Working Group we found no significant differences in molecular mechanisms and inheritance patterns, therefore, the disease entities have been lumped into the term NPHP-NPHP4. Variants in this gene have been reported in at least 7 probands in 5 publications (PMIDs: 12244321, 23354436, 1577426, 23188109, 23559409). Variants in this gene segregated with disease in 2 additional family members. The mechanism for disease is biallelic loss of function. This gene-disease association is supported by animal models, expression studies, rescued cell culture assays, and protein interactions (PMIDs: 15661758, 19755384, 16339905, 21078623, 15817158). In summary, there is definitive evidence to support the relationship between NPHP4 and autosomal recessive NPHP-NPHP4. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Cystic and Ciliopathy Expert Panel on the meeting date 2/10/21 (SOP Version 8).