Submission Details

The relationship between the SUMF1 gene and multiple sulfatase deficiency (MSD), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of July 31, 2022. SUMF1 encodes sulfatase-modifying factor 1, an enzyme that activates sulfatases via oxidizing cysteine to C-alpha-formylglycine, an aldehyde which is essential for sulfatase catalytic function (PMID: 12757706). Individuals with multiple sulfatase deficiency show impaired SUMF1-mediated activation of multiple sulfatase enzymes, resulting in accumulation of sulfate-containing substrates in multiple tissues, leading to characteristic disease manifestations including neurologic impairment, organomegaly, and ichthyosis (PMID: 32621519).

The disease mechanism of MSD is loss of function. MSD was first reported in 1961 by Mossakowski et al. (PMID: 14476546) and the first reports of biallelic variants in SUMF1 among MSD cases were in 2003 by Dierks et al. (PMID: 12757705) and Cosma et al. (PMID: 12757706). Both case-level (genetic) and experimental evidence support the relationship between SUMF1 and MSD. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants (PMID: 12757706, PMID: 18157819, PMID: 12757705, PMID: 25885655). In total, ten variants from five probands in four publications were curated. Although there is additional published case-level evidence available, the maximum score for genetic evidence (12 points) has already been reached.

Experimental evidence for the relationship between SUMF1 and MSD includes: the biochemical function of the gene product (sulfatase-modifying factor 1) being consistent with the clinical and biochemical findings identified individuals with MSD (PMID: 12757706, PMID: 32621519); the biochemical and clinical features of SUMF1 knockout mice (PMID: 17360554); and rescue of enzyme function via gene therapy in SUMF1 knockout mice (PMID: 21326216). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached.

In sum, SUMF1 is definitively associated with MSD. The association has been repeatedly demonstrated in both clinical and research settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Lysosomal Diseases GCEP on September 6, 2022 (SOP v9).

The relationship between the SUMF1 gene and multiple sulfatase deficiency (MSD), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of July 31, 2022. SUMF1 encodes sulfatase-modifying factor 1, an enzyme that activates sulfatases via oxidizing cysteine to C-alpha-formylglycine, an aldehyde which is essential for sulfatase catalytic function (PMID: 12757706). Individuals with multiple sulfatase deficiency show impaired SUMF1-mediated activation of multiple sulfatase enzymes, resulting in accumulation of sulfate-containing substrates in multiple tissues, leading to characteristic disease manifestations including neurologic impairment, organomegaly, and ichthyosis (PMID: 32621519).

The disease mechanism of MSD is loss of function. MSD was first reported in 1961 by Mossakowski et al. (PMID: 14476546) and the first reports of biallelic variants in SUMF1 among MSD cases were in 2003 by Dierks et al. (PMID: 12757705) and Cosma et al. (PMID: 12757706). Both case-level (genetic) and experimental evidence support the relationship between SUMF1 and MSD. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants (PMID: 12757706, PMID: 18157819, PMID: 12757705, PMID: 25885655). In total, ten variants from five probands in four publications were curated. Although there is additional published case-level evidence available, the maximum score for genetic evidence (12 points) has already been reached.

Experimental evidence for the relationship between SUMF1 and MSD includes: the biochemical function of the gene product (sulfatase-modifying factor 1) being consistent with the clinical and biochemical findings identified individuals with MSD (PMID: 12757706, PMID: 32621519); the biochemical and clinical features of SUMF1 knockout mice (PMID: 17360554); and rescue of enzyme function via gene therapy in SUMF1 knockout mice (PMID: 21326216). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached.

In sum, SUMF1 is definitively associated with MSD. The association has been repeatedly demonstrated in both clinical and research settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Lysosomal Diseases GCEP on September 6, 2022 (SOP v9).

The ClinGen Prenatal GCEP contributed the following data on the prenatal presentation of the disorder, on October 16, 2024: The prenatal and early neonatal phenotypes reported for SUMF1 associated Multiple sulfatase deficiency (MSD) is variable. Reported prenatal phenotypes include congenital ascites (1/10), hydrops (2/10), hepatosplenomegaly (2/10), and oligohydramnios (3/10). Several reports also include cases with fetal distress, fetal growth restriction (5/10), and respiratory distress shortly after birth (6/10), but the contribution of the SUMF1 variants to these non-specific phenotypes is not certain. Prenatal-onset phenotypes can be present but are not a common feature of SUMF1 associated Multiple sulfatase deficiency (MSD). (PMID: PMID: 19697114, 25818962, 25885655, 31497481, 28566233, 32048457). This data does not alter the original scoring or clinical validity classification from the ClinGen Lysosomal Diseases GCEP.