Recessive SPG35 HSP inherited from just one parent

Posted - September 2016 in Research Highlights

Major implications for genetic counselling

 

Inheritance of autosomal recessive HSP from just one parent* may be more common than currently thought leading to the recommendation for segregation analysis to identify the mutational mechanism in such cases.

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This has major implications for genetic counselling given the markedly reduced risk of recurrence for affected families.

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This study found four families with rare SPG35 HSP, with inheritance coming from just one parent. Four new mutations associated with autosomal recessive SPG35 HSP were discovered in this study.

 

* Uniparental disomy (UPD) is a rare form of inheritance, especially for neurodegenerative diseases, where both copies of a chromosome come from the same parent rather than one from each parent.

 

Abstract

OBJECTIVE:

Identifying an intriguing mechanism for unmasking recessive hereditary spastic paraplegias.

 

METHOD:

Herein, we describe 4 novel homozygous FA2H mutations in 4 non-consanguineous 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 non-consanguineous 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.

 

SOURCE: Neurology. 2016 Jul 12;87(2):186-91. doi: 10.1212/WNL.0000000000002843. Epub 2016 Jun 17. PMID: 27316240 [PubMed – in process] © 2016 American Academy of Neurology.

 

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

 

Soehn AS1, Rattay TW1, Beck-Wödl S1, Schäferhoff K1, Monk D1, Döbler-Neumann M1, Hörtnagel K1, Schlüter A1, Ruiz M1, Pujol A1, Züchner S1, Riess O1, Schüle R1, Bauer P2, Schöls L1.

 

1 From the Institute of Medical Genetics and Applied Genomics (A.S.S., S.B.-W., K.S., O.R., P.B.) and Department of Neurology and Hertie Institute for Clinical Brain Research (T.W.R., R.S., L.S.), University of Tübingen; German Center of Neurodegenerative Diseases (DZNE) (T.W.R., R.S.), Tübingen, Germany; Imprinting and Cancer Group (D.M.), Cancer Epigenetic and Biology Program, Institut d’Investigació Biomedica de Bellvitge, Hospital Duran i Reynals, Barcelona, Spain; Department of Neuropediatrics (M.D.-N.), Tübingen University School of Medicine; CeGaT GmbH (K.H.), Tübingen, Germany; Neurometabolic Diseases Laboratory (A.S., M.R., A.P.), Institut d’Investigació Biomedica de Bellvitge IDIBELL, Hospital Duran i Reynals, Barcelona; Centre for Biomedical Research on Rare Diseases (CIBERER) (A.S., M.R., A.P.), Institute Carlos III, Madrid; Catalan Institution for Research and Advanced Studies (ICREA) (A.P.), Barcelona, Spain; and Hussman Institute for Human Genomics (S.Z., R.S.), University of Miami Miller School of Medicine, FL.

2 From the Institute of Medical Genetics and Applied Genomics (A.S.S., S.B.-W., K.S., O.R., P.B.) and Department of Neurology and Hertie Institute for Clinical Brain Research (T.W.R., R.S., L.S.), University of Tübingen; German Center of Neurodegenerative Diseases (DZNE) (T.W.R., R.S.), Tübingen, Germany; Imprinting and Cancer Group (D.M.), Cancer Epigenetic and Biology Program, Institut d’Investigació Biomedica de Bellvitge, Hospital Duran i Reynals, Barcelona, Spain; Department of Neuropediatrics (M.D.-N.), Tübingen University School of Medicine; CeGaT GmbH (K.H.), Tübingen, Germany; Neurometabolic Diseases Laboratory (A.S., M.R., A.P.), Institut d’Investigació Biomedica de Bellvitge IDIBELL, Hospital Duran i Reynals, Barcelona; Centre for Biomedical Research on Rare Diseases (CIBERER) (A.S., M.R., A.P.), Institute Carlos III, Madrid; Catalan Institution for Research and Advanced Studies (ICREA) (A.P.), Barcelona, Spain; and Hussman Institute for Human Genomics (S.Z., R.S.), University of Miami Miller School of Medicine, FL. [email protected].

 

 

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