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ObjectiveCblC deficiency, the most common cobalamin metabolic abnormality, is caused by pathogenic variants in the MMACHC gene. The renal complications of this disease have been described only in a small number of cases. This study aimed to better delineate renal phenotype and genetic characteristics in Chinese children with cblC defect.MethodsChildren with cblC deficiency who manifested as kidney damage were enrolled. Clinical, renal pathological, and genetic data were reviewed in detail.ResultsSeven cases were enrolled. Ages at disease onset ranged from 9 months to 5 years. All patients presented with hematuria and proteinuria, and 2/7 cases presented with nephrotic syndrome. Renal dysfunction was observed in 4/7 cases. Renal biopsy was performed in 5/7 cases, and all of them had renal thrombotic microangiopathy. Macrocytic anemia was detected in all seven patients. Six out of seven cases had hypertension, and 2/7 cases presented with pulmonary hypertension. Two of them had a mild intellectual disability, and one suffered from epilepsy. Increased urine methylmalonic acid and plasma homocysteine were detected in seven cases, while two patients had normal levels of urine methylmalonic acid at the initial evaluation. After diagnosis, all seven cases were treated with hydroxocobalamin IM. Six cases were followed-up for 3–8 years. After treatments, anemia was the first to be recovered, followed by proteinuria. Renal function recovered after 1 year in two cases, whereas patient 2 progressed to stage 2 chronic kidney disease 13 years after onset. While a case presented with end-stage kidney disease because of late diagnosis, one case died 3 months after disease onset due to giving up treatment. Three MMACHC pathogenic variants c.80A > G (8/14), c.609G > A (4/14), and c.658_660delAAG (2/14) were detected in all seven children.ConclusionMMACHC variant c.80A > G may be associated with prominent renal complications in Chinese cblC patients. Macrocytic anemia and hyperhomocysteinemia are useful clues for patients with hematuria and proteinuria caused by cblC defect. The most frequent renal pathological manifestation is thrombotic microangiopathy. Early diagnosis and treatment resulted in improving renal and hematological signs.

Background: A false interpretation of homozygosity for pathogenic variants causing autosomal recessive disorders can lead to improper genetic counseling. The aim of this study was to demonstrate the underlying etiologies of presumed homozygous disease-causing variants harbored in six unrelated children with five different genetic renal diseases when the same variant was identified in a heterozygous state in only one of the two parents from each family using direct sequencing.Methods: Peripheral blood genomic DNA samples were extracted. Six short tandem repeats were used to verify the biological relationships between the probands and their parents. Quantitative PCR was performed to detect mutant exons with deletions. Single nucleotide polymorphism analysis and genotyping with polymorphic microsatellite markers were performed to identify uniparental disomy (UPD).Results: Each proband and his/her parents had biological relationships. Patients 2, 4, and 6 were characterized by large deletions encompassing a missense/small deletion in DGKE, NPHP1, and NPHS1, respectively. Patients 1 and 5 were caused by segmental UPD in NPHS2 and SMARCAL1, respectively. In patient 6, maternal UPD, mosaicism in paternal sperm or de novo variant in NPHP1 could not be ruled out.Conclusions: When a variant analysis report shows that a patient of non-consanguineous parents has a pathogenic presumed homozygous variant, we should remember the need to assess real homozygosity for the variant, and a segregation analysis of the variants within the parental DNAs and comprehensive molecular tests to evaluate the potential molecular etiologies, such as a point variant and an overlapping exon deletion, UPD, germline mosaicism and de novo variant, are crucial.

From January 1995 to June 2018, 14 patients with congenital nephrotic syndrome (CNS) were diagnosed in the Department of Pediatrics, Peking University First Hospital. The clinical data were retrospectively studied. Eight patients underwent genetic testing; 7 of them had NPHS1 mutations (primary CNS), and 1 did not have a mutation. Of the 7 patients with NPHS1 mutations, 6 died, and 1 had proteinuria. Of the 14 patients, 8 had cytomegalovirus (CMV) infection, and anti-CMV therapy was administered to 7 of them. The other patient was hospitalized in critically ill condition and died before anti-CMV therapy administration. Of the 7 patients who were administered anti-CMV therapy, proteinuria disappeared in 2 patients; 2 patients died; 2 patients were lost to follow up; and 1 patient still had 3+ proteinuria. Three patients had both NPHS1 mutations and CMV infection. After anti-CMV therapy, proteinuria was resolved in 1 patient but relapsed to 3+ proteinuria due to a new infection. The other 2 patients died. Of 14 patients, only 1 patient underwent renal biopsy, with results showing mesangial proliferative glomerulonephritis pathology, negative CMV inclusion body, and CMV-DNA. In this study, genetic defect could play a primary role in CNS, and CMV could play a secondary role. Primary CNS with NPHS1 mutations has a poor prognosis. Primary CNS might be accompanied by CMV infection that responds poorly to antiviral treatment. Secondary CNS caused by CMV infection may be cured with antiviral therapy. However, genetic analysis is necessary to exclude genetic defects.