SGPL1 was first reported in relation to autosomal recessive nephrotic syndrome 14 in 2017 (Prasad et al., PMID: 28165343 and Lovric et al., PMID: 28165339). This condition can include steroid-resistant nephrotic syndrome, primary adrenal insufficiency, testicular insufficiency, hypothyroidism, ichthyosis, lymphopenia, immunodeficiency, developmental delay, and peripheral motor and sensory neuropathy. Prenatal features of this condition may include fetal hydrops, increased nuchal translucency, skin edema, polyhydramnios, and adrenal calcifications. Fifteen variants (missense, frameshift, nonsense, canonical splice site) that have been reported in 12 probands in five publications (PMIDs: 28165343, 28165339, 28181337, 29501407, 32855188, 32855188) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by animal models (PMIDs: 19119317, 28165343, 28165339). Null mouse models recapitulate the human renal and adrenal phenotype and knock-in of human S1PL in the heterozygous or homozygous state partially rescued enzyme activity. In summary, there is definitive evidence supporting the relationship between SGPL1 and autosomal recessive nephrotic syndrome 14. 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 Prenatal GCEP on September 18, 2024 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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