A recurring NFS1 pathogenic variant causes a mitochondrial disorder with variable intra-familial patient outcomes

Tova Hershkovitz; Alina Kurolap; Galit Tal; Tamar Paperna; Adi Mory; Jeffrey Staples; Karlla W Brigatti; Regeneron Genetics Center; Claudia Gonzaga-Jauregui; Elena Dumin; Ann Saada; Hanna Mandel; Hagit Baris Feldman

doi:10.1016/j.ymgmr.2020.100699

A recurring NFS1 pathogenic variant causes a mitochondrial disorder with variable intra-familial patient outcomes

Mol Genet Metab Rep. 2020 Dec 30:26:100699. doi: 10.1016/j.ymgmr.2020.100699. eCollection 2021 Mar.

Authors

Tova Hershkovitz^{1

2}, Alina Kurolap^{1

2}, Galit Tal³, Tamar Paperna¹, Adi Mory¹, Jeffrey Staples⁴, Karlla W Brigatti⁵; Regeneron Genetics Center; Claudia Gonzaga-Jauregui⁴, Elena Dumin^{2

6}, Ann Saada⁷, Hanna Mandel³, Hagit Baris Feldman^{1

2}

Affiliations

¹ The Genetics Institute, Rambam Health Care Campus, Haifa, Israel.
² The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.
³ Metabolic Unit, Ruth Rappaport Children's Hospital, Rambam Health Care Campus, Haifa, Israel.
⁴ Regeneron Genetics Center, Tarrytown, NY, USA.
⁵ Clinic for Special Children, Strasburg, PA, USA.
⁶ Department of Clinical Biochemistry, Rambam Health Care Campus, Haifa, Israel.
⁷ Department of Genetics, Hadassah Medical Center and The Faculty of Medicine, Hebrew University, Jerusalem, Israel.

Abstract

Iron‑sulfur clusters (FeSCs) are vital components of a variety of essential proteins, most prominently within mitochondrial respiratory chain complexes I-III; Fe-S assembly and distribution is performed via multi-step pathways. Variants affecting several proteins in these pathways have been described in genetic disorders, including severe mitochondrial disease. Here we describe a Christian Arab kindred with two infants that died due to mitochondrial disorder involving Fe-S containing respiratory chain complexes and a third sibling who survived the initial crisis. A homozygous missense variant in NFS1: c.215G>A; p.Arg72Gln was detected by whole exome sequencing. The NFS1 gene encodes a cysteine desulfurase, which, in complex with ISD11 and ACP, initiates the first step of Fe-S formation. Arginine at position 72 plays a role in NFS1-ISD11 complex formation; therefore, its substitution with glutamine is expected to affect complex stability and function. Interestingly, this is the only pathogenic variant ever reported in the NFS1 gene, previously described once in an Old Order Mennonite family presenting a similar phenotype with intra-familial variability in patient outcomes. Analysis of datasets from both populations did not show a common haplotype, suggesting this variant is a recurrent de novo variant. Our report of the second case of NFS1-related mitochondrial disease corroborates the pathogenicity of this recurring variant and implicates it as a hot-spot variant. While the genetic resolution allows for prenatal diagnosis for the family, it also raises critical clinical questions regarding follow-up and possible treatment options of severely affected and healthy homozygous individuals with mitochondrial co-factor therapy or cysteine supplementation.

Keywords: Hot-spot variant; Intra-familial variability; Iron‑sulfur clusters; Mitochondrial disease; NFS1.