Submission Details

The LMX1B gene is located on chromosome 9 at 9q33.3 and encodes the LIM homeodomain transcription factor 1 beta, a transcription factor that plays a central role in cell differentiation during development. Mutations in LMX1B were first reported in relation to autosomal dominant nail-patella syndrome (NPS) in 1998 (Dreyer at al., 1998 PMID 9590287), although the first clinical description of the disorder was reported in 1933 (Turner JW, 1933 JAMA). The syndrome is characterised by a classic tetrad of congenital changes in the nails (absent, hypoplastic, or dystrophic), patellae (absent, small, or irregularly shaped), and elbows (limited range of motion), and the presence of iliac horns. Although not part of the classic tetrad, kidney disease and glaucoma also occur. While this disorder is highly penetrant, the expressivity of the clinical features is extremely variable both within and between families. More than 170 variants in LMX1B have been reported in NPS. onsense, frameshift, and splice site variants are observed throughout the entire gene, missense variants cluster predominantly in the LIM domains, and the the rest occur in the homeodomain. Partial and complete gene deletions have also been reported. 11 probands from 5 publications have been included in this curation (Dreyer at al., 1998 PMID 9590287; McIntosh et al., 1998 PMID 9837817; Sato et al., 2005 PMID 15774843; Bongers et al., 2008 PMID 18414507; Harita et al., 2020 PMID 32457516) to give a maximum score or 12 points for genetic evidence. . Additional evidence is available in the literature. This gene-disease association is also supported by experimental evidence, including animal models, expression studies, and in vitro functional assays. LMX1B was originally identified as a candidate gene for NPS due to the high degree of phenotypic similarity between lmx1b-knockout mice and humans with the disorder. Homozygous mice have absent patellae, absent nails, and renal abnormalities (Chen et al., 1998 PMID 9590288). Multiple studies examining the spatial and temporal expression pattern of LMX1B, using in situ hybridisation, have demonstrated its expression in the tissue types affected by NPS (Chen et al., 1998 PMID 9590288; Dreyer et al., 2000 PMID 10767331; Pressman et al., 2000 PMID 10660670). The mechanism of pathogenicity in NPS has been demonstrated to be loss of function, with mutated protein showing decreased or absent DNA binding ability and negligible transcriptional activity. No evidence has been observed to support a dominant-negative effect (Dreyer at al., 1998 PMID 9590287; Sato et al., 2005 PMID 15774843; Harita et al., 2020 PMID 32457516). Of note, variants in LMX1B have also been implicated in a renal-restricted nail-patella-like nephropathy. As per the criteria outlined by the ClinGen Lumping and Splitting Working Group, there was sufficient phenotypic variability and differences in the molecular mechanisms to support splitting these disorders into two distinct disease entities; nail-patella syndrome (OMIM: 161200) and focal segmental glomerulosclerosis 10 (OMIM:256020). Autosomal dominant focal segmental glomerulosclerosis 10 has therefore been curated separately. In summary, LMX1B is definitively associated with autosomal dominant nail-patella syndrome. 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 Syndromic Disorders Gene Curation Expert Panel on the meeting date February 3rd, 2021 (SOP Version 8).