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MALL (HGNC:6818) has emerged as a gene of interest in the context of nephronophthisis (MONDO_0019005), a pediatric cystic kidney disease that often progresses to renal failure. Recent case reports have documented copy number variants (CNVs) that include homozygous deletions affecting MALL, in addition to neighboring genes, thereby raising the possibility that loss of MALL may contribute to disease severity (PMID:37203120). The clinical presentations in these patients include renal insufficiency and stage 4 chronic kidney disease, which are common features in nephronophthisis.
In one detailed family case report, three probands were identified with CNVs encompassing not only NPHP1 but also MALL. The affected siblings showed a clear pattern of segregation for the deletion, strengthening the argument for its clinical relevance in the kidney phenotype (PMID:37203120). Such segregation data within a single family underscore the potential contributory role of MALL deletions in the progression of nephronophthisis.
Additional evidence comes from a retrospective case series where five patients with nephronophthisis were found to harbor a deletion of exon 1 of MALL, in concert with the well‐characterized NPHP1 deletions. These patients, diagnosed with stage 5 chronic kidney disease and other renal insufficiency phenotypes, further support the recurring nature of MALL involvement in the disease (PMID:25401970). The recurrence of this CNV in independent cohort studies lends further weight to the genetic association.
The inheritance pattern across these studies is consistent with an autosomal recessive mode, where affected individuals present with severe renal phenotypes such as stage 4 and stage 5 chronic kidney disease. Although no specific single-nucleotide variant meeting HGVS criteria was provided, the CNV data implicate MALL as part of a critical genomic region whose loss may accelerate the progression of nephronophthisis-related nephropathy.
It is important to note that while the genetic evidence linking MALL to nephronophthisis is compelling, the available functional evidence is limited. There are no direct functional assays or animal models reported that isolate the impact of MALL loss on renal pathology. Nevertheless, the concordance between genotype and phenotype across multiple studies implies a plausible pathogenic mechanism, even if the precise functional role of MALL remains to be fully elucidated.
In summary, two independent lines of genetic evidence – a family-based case report and a retrospective patient series – robustly associate deletions including MALL with the nephronophthisis phenotype. Although further functional studies are warranted to clarify the mechanism of pathogenicity, the current evidence supports the clinical utility of screening for MALL deletions in patients with nephronophthisis to aid in early diagnosis and targeted intervention.
Gene–Disease AssociationModerateEvidence from 8 probands (3 from a family report (PMID:37203120) and 5 from a retrospective case series (PMID:25401970)) showing CNVs that include MALL deletions with consistent renal phenotypes and segregation data. Genetic EvidenceModerateIndependent identification of deletions involving MALL in both familial and series settings, with CNVs correlating with disease severity, supports a moderate level of genetic evidence despite the absence of a defined HGVS variant. Functional EvidenceLimitedNo direct functional assays or experimental model studies targeting MALL were provided; thus, functional evidence is currently limited to inferences from genomic and segregation data. |