A homozygous missense variant of SUMF1 in the Bedouin population extends the clinical spectrum in ultrarare neonatal multiple sulfatase deficiency

Background Multiple sulfatase deficiency (MSD, MIM #272200) is an ultrarare congenital disorder caused by SUMF1 mutation and often misdiagnosed due to its complex clinical presentation. Impeded by a lack of natural history, knowledge gained from individual case studies forms the source for a reliable diagnosis and consultation of patients and parents. Methods We collected clinical records as well as genetic and metabolic test results from two MSD patients. The functional properties of a novel SUMF1 variant were analyzed after expression in a cell culture model. Results We report on two MSD patients—the first neonatal type reported in Israel—both presenting with this most severe manifestation of MSD. Our patients showed uniform clinical symptoms with persistent pulmonary hypertension, hypotonia, and dysmorphism at birth. Both patients were homozygous for the same novel SUMF1 mutation (c.1043C>T, p.A348V). Functional analysis revealed that the SUMF1‐encoded variant of formylglycine‐generating enzyme is highly instable and lacks catalytic function. Conclusion The obtained results confirm genotype‒phenotype correlation in MSD, expand the spectrum of clinical presentation and are relevant for diagnosis including the extremely rare neonatal severe type of MSD. Multiple sulfatase deficiency (MSD) is an ultra‐rare congenital disorder caused by SUMF1 dysfunction and often misdiagnosed due to its complex clinical presentation. Here we report two Israeli patients with a neonatal MSD caused by a likely‐founder mutation SUMF1‐A348V, in the Bedouin population. We show that A348V mutation leads to loss of stability of SUMF1 resulting in loss of function. The presented clinical and biochemical findings expand the spectrum of MSD, adding data on the rare neonatal severe type of MSD.