UFM1 founder mutation in the Roma population causes recessive variant of H-ABC

Eline M.C. Hamilton, Enrico Bertini, Luba Kalaydjieva, Bharti Morar, Dana Dojčáková, Judy Liu, Adeline Vanderver, Julian Curiel, Claudia M. Persoon, Daria Diodato, Lorenzo Pinelli, Nathalie L. Van Der Meij, Barbara Plecko, Susan Blaser, Nicole I. Wolf, Quinten Waisfisz, Truus E.M. Abbink, Marjo S. Van Der Knaap*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review


Objective: To identify the gene defect in patients with hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) who are negative for TUBB4A mutations. Methods: We performed homozygosity mapping and whole exome sequencing (WES) to detect the disease-causing variant. We used a Taqman assay for population screening.We developed a luciferase reporter construct to investigate the effect of the promoter mutation on expression. Results: Sixteen patients from 14 families from different countries fulfilling the MRI criteria for H-ABC exhibited a similar, severe clinical phenotype, including lack of development and a severe epileptic encephalopathy. The majority of patients had a known Roma ethnic background. Single nucleotide polymorphism array analysis in 5 patients identified one large overlapping homozygous region on chromosome 13. WES in 2 patients revealed a homozygous deletion in the promoter region of UFM1. Sanger sequencing confirmed homozygosity for this variant in all 16 patients. All patients shared a common haplotype, indicative of a founder effect. Screening of 1,000 controls from different European Roma panels demonstrated an overall carrier rate of the mutation of 3%-25%. Transfection assays showed that the deletion significantly reduced expression in specific CNS cell lines.

Original languageEnglish
Pages (from-to)1821-1828
Number of pages8
Issue number17
Publication statusPublished - 24 Oct 2017


From the Department of Child Neurology (E.M.C.H., N.I.W., T.E.M.A., M.S.v.d.K.), Amsterdam Neuroscience (E.M.C.H., N.I.W., T.E.M.A., M.S.v.d.K.), Department of Clinical Genetics (C.M.P., Q.W.), Department of Functional Genomics, Center for Neurogenomics and Cognitive Research (M.S.v.d.K.), VU University and VU University Medical Center, Amsterdam, the Netherlands; Unit of Neuromuscular and Neurodegenerative Disorders (E.B., D. Diodato), Laboratory of Molecular Medicine, “Bambino Gesù” Children’s Hospital, IRCCS, Rome, Italy; Harry Perkins Institute of Medical Research and Centre for Medical Research (L.K., B.M.), University of Western Australia, Perth; Department of Biology (D. Doj≤cáková), Faculty of Humanities and Natural Sciences, University of Presov, Slovakia; Center for Neuroscience Research (J.L., J.C.), Children’s Research Institute; Department of Neurology, Center for Genetic Medicine Research (A.V.), Children’s National Medical Center, Washington, DC; Department of Neuroradiology (L.P.), Section of Pediatric Neuroradiology, Spedali Civili, Brescia, Italy; MRC Holland (N.L.v.d.M.), Amsterdam, the Netherlands; Division of Neurology (B.P.), Children’s Hospital, University of Zurich, Switzerland; and Division of Pediatric Neuroradiology (S.B.), Hospital for Sick Children, Toronto, Canada. Coinvestigators are listed at Neurology.org. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. The Article Processing Charge was funded by VU University Medical Center. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. This study received financial support from the ZonMw TOP grant 91211005 (M.S.v.d.K.), the Optimix Foundation for Scientific Research (E.M.C.H., M.S.v.d.K.), and the Italian Ministry of Health (E.B.). E. Hamilton, E. Bertini, L. Kalaydjieva, B. Morar, D. Doj≤cáková, J. Liu, A. Vanderver, J. Curiel, C. Persoon, D. Diodato, and L. Pinelli report no disclosures relevant to the manuscript. N. van der Meij is an employee of MRC-Holland, provider of commercially available MLPA assays. B. Plecko, S. Blaser, N. Wolf, Q. Waisfisz, T. Abbink, and M. van der Knaap report no disclosures relevant to the manuscript. Go to Neurology. org for full disclosures.

FundersFunder number
Italian Ministry of Health
Optimix Foundation for Scientific Research
VU University Medical Center


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