Two rare copy number variants involving loss of NPHP1 , MALL , and MTLN genes contribute to nephronophthisis-induced nephropathy progression in a family: A case report.

Nephronophthisis (NPHP) is a common pediatric cystic kidney disease, accounting for approximately 10% of end-stage renal failure cases in children. NPHP is primarily diagnosed through the identification of indel mutations and copy number variants (CNVs), and patients carrying NPHP1 mutations usually progress to renal failure at a mean age of 13 years old. However, the association between CNVs containing NPHP1 variations and the progression of NPHP-induced disease remains unclear. Here, we report three NPHP patients in a family. The proband had developed stage 4 chronic kidney disease (CKD) at 9 years old, and her younger brother and older sister had developed renal failure at 8 and 10 years old, respectively. A genetic diagnosis showed that they carried two rare CNVs, including homozygous loss of NPHP1, MALL, ACTR1AP1, MTLN, and LOC100507334. Heterozygous deletions mainly consisted of non-coding RNA genes on both sides of the CNVs. The proband was in stage 4 of CKD while her brother had progressed to renal failure, probably due to more extensive heterozygous deletion of a 67.115 kbp fragment, which included LIMS3-LOC440895, LOC440895, GPAA1P1, ZBTB45P1, and LINC0112 genes. This report demonstrates that larger CNV deletions, including homozygous NPHP1, MALL, and MTLN mutations and heterozygous deletions, presumably accelerate disease progression. Therefore, early genetic diagnosis plays a crucial role in the intervention and prognosis of these patients.