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

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