Uniparental disomy of chromosome 16 unmasks recessive mutations of FA2H /SPG35 in 4 families

Anne S. Soehn, Tim W. Rattay, Stefanie Beck-Wödl, Karin Schäferhoff, David Monk, Marion Döbler-Neumann, Konstanze Hörtnagel, Agatha Schlüter, Montserrat Ruiz, Aurora Pujol, Stephan L Zuchner, Olaf Riess, Rebecca Schüle, Peter Bauer, Ludger Schöls

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Objective: Identifying an intriguing mechanism for unmasking recessive hereditary spastic paraplegias. Method: Herein, we describe 4 novel homozygous FA2H mutations in 4 nonconsanguineous families detected by whole-exome sequencing or a targeted gene panel analysis providing high coverage of all known hereditary spastic paraplegia genes. Results: Segregation analysis revealed in all cases only one parent as a heterozygous mutation carrier whereas the other parent did not carry FA2H mutations. A macro deletion within FA2H, which could have caused a hemizygous genotype, was excluded by multiplex ligation-dependent probe amplification in all cases. Finally, a microsatellite array revealed uniparental disomy (UPD) in all 4 families leading to homozygous FA2H mutations. UPD was confirmed by microarray analyses and methylation profiling. Conclusion: UPD has rarely been described as causative mechanism in neurodegenerative diseases. Of note, we identified this mode of inheritance in 4 families with the rare diagnosis of spastic paraplegia type 35 (SPG35). Since UPD seems to be a relevant factor in SPG35 and probably additional autosomal recessive diseases, we recommend segregation analysis especially in nonconsanguineous homozygous index cases to unravel UPD as mutational mechanism. This finding may bear major repercussion for genetic counseling, given the markedly reduced risk of recurrence for affected families.

Original languageEnglish (US)
Pages (from-to)186-191
Number of pages6
JournalNeurology
Volume87
Issue number2
DOIs
StatePublished - Jul 12 2016

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Uniparental Disomy
Mutation
Hereditary Spastic Paraplegia
Exome
Multiplex Polymerase Chain Reaction
Genetic Counseling
Microarray Analysis
Neurodegenerative Diseases
Microsatellite Repeats
Methylation
Genes
Genotype
Fatty Acid Hydroxylase-Associated Neurodegeneration
Uniparental disomy Chromosome 16
Recurrence

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Soehn, A. S., Rattay, T. W., Beck-Wödl, S., Schäferhoff, K., Monk, D., Döbler-Neumann, M., ... Schöls, L. (2016). Uniparental disomy of chromosome 16 unmasks recessive mutations of FA2H /SPG35 in 4 families. Neurology, 87(2), 186-191. https://doi.org/10.1212/WNL.0000000000002843

Uniparental disomy of chromosome 16 unmasks recessive mutations of FA2H /SPG35 in 4 families. / Soehn, Anne S.; Rattay, Tim W.; Beck-Wödl, Stefanie; Schäferhoff, Karin; Monk, David; Döbler-Neumann, Marion; Hörtnagel, Konstanze; Schlüter, Agatha; Ruiz, Montserrat; Pujol, Aurora; Zuchner, Stephan L; Riess, Olaf; Schüle, Rebecca; Bauer, Peter; Schöls, Ludger.

In: Neurology, Vol. 87, No. 2, 12.07.2016, p. 186-191.

Research output: Contribution to journalArticle

Soehn, AS, Rattay, TW, Beck-Wödl, S, Schäferhoff, K, Monk, D, Döbler-Neumann, M, Hörtnagel, K, Schlüter, A, Ruiz, M, Pujol, A, Zuchner, SL, Riess, O, Schüle, R, Bauer, P & Schöls, L 2016, 'Uniparental disomy of chromosome 16 unmasks recessive mutations of FA2H /SPG35 in 4 families', Neurology, vol. 87, no. 2, pp. 186-191. https://doi.org/10.1212/WNL.0000000000002843
Soehn AS, Rattay TW, Beck-Wödl S, Schäferhoff K, Monk D, Döbler-Neumann M et al. Uniparental disomy of chromosome 16 unmasks recessive mutations of FA2H /SPG35 in 4 families. Neurology. 2016 Jul 12;87(2):186-191. https://doi.org/10.1212/WNL.0000000000002843
Soehn, Anne S. ; Rattay, Tim W. ; Beck-Wödl, Stefanie ; Schäferhoff, Karin ; Monk, David ; Döbler-Neumann, Marion ; Hörtnagel, Konstanze ; Schlüter, Agatha ; Ruiz, Montserrat ; Pujol, Aurora ; Zuchner, Stephan L ; Riess, Olaf ; Schüle, Rebecca ; Bauer, Peter ; Schöls, Ludger. / Uniparental disomy of chromosome 16 unmasks recessive mutations of FA2H /SPG35 in 4 families. In: Neurology. 2016 ; Vol. 87, No. 2. pp. 186-191.
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