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

Orna Staretz-Chacham; Lars Schlotawa; Ohad Wormser; Inbal Golan-Tripto; Ohad S Birk; Carlos R Ferreira; Thomas Dierks; Karthikeyan Radhakrishnan

doi:10.1002/mgg3.1167

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

Mol Genet Genomic Med. 2020 Sep;8(9):e1167. doi: 10.1002/mgg3.1167. Epub 2020 Feb 12.

Authors

Orna Staretz-Chacham^{1

2

3}, Lars Schlotawa⁴, Ohad Wormser^{5

6}, Inbal Golan-Tripto³, Ohad S Birk^{5

6

7}, Carlos R Ferreira⁸, Thomas Dierks⁹, Karthikeyan Radhakrishnan⁹

Affiliations

¹ Metabolic Clinic, Soroka University Medical Center, Ben Gurion University, Beer Sheva, Israel.
² Neonatlogy Unit, Soroka University Medical Center, Ben Gurion University, Beer Sheva, Israel.
³ Division of Pediatrics, Soroka University Medical Center, Ben Gurion University, Beer Sheva, Israel.
⁴ Department of Paediatrics and Adolescent Medicine, University Medical Center, Goettingen, Germany.
⁵ The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev and Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel.
⁶ Shraga Segal Department of Microbiology, Immunology and Genetics, Ben Gurion University of the Negev, Beer-Sheva, Israel.
⁷ Genetic Institute, Soroka University Medical Center, Ben Gurion University, Beer Sheva, Israel.
⁸ Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
⁹ Biochemistry I, Faculty of Chemistry, Bielefeld University, Bielefeld, Germany.

Abstract

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.

Keywords: Multiple sulfatase deficiency; SUMF1; deafness; developmental delay; dysmorphism; formylglycine-generating enzyme; hypotonia; lysosomal storage disorders; persistent pulmonary hypertension of the newborn; sulfatases.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Child, Preschool
Enzyme Stability
Homozygote
Humans
Infant
Male
Multiple Sulfatase Deficiency Disease / genetics*
Multiple Sulfatase Deficiency Disease / pathology
Mutation, Missense*
Oxidoreductases Acting on Sulfur Group Donors / genetics*
Oxidoreductases Acting on Sulfur Group Donors / metabolism
Phenotype*

Substances

Oxidoreductases Acting on Sulfur Group Donors
SUMF1 protein, human