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Genet Med. 2016 Jun;18(6):600-7. doi: 10.1038/gim.2015.139. Epub 2015 Oct 22.

Novel mutations in genes causing hereditary spastic paraplegia and Charcot-Marie-Tooth neuropathy identified by an optimized protocol for homozygosity mapping based on whole-exome sequencing.

Author information

1
Molecular Neurogenomics Group, Department of Molecular Genetics, VIB, University of Antwerp, Antwerp, Belgium.
2
Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
3
Department of Medical Chemistry and Biochemistry, Molecular Medicine Center, Medical University-Sofia, Sofia, Bulgaria.
4
Department of Molecular Genetics, VIB, University of Antwerp, Antwerp, Belgium.
5
Current address: Cell Biology and Biophysics Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
6
Department of Neurology, Medical University-Sofia, Sofia, Bulgaria.
7
Department of Pediatrics, Dicle University School of Medicine, Diyarbakir, Turkey.
8
Department of Neurological, Neuropsychological, Morphological and Motor Sciences, University of Verona, Verona, Italy.
9
Division of Pediatric Neurology, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey.
10
Department of Cognitive Science and Psychology, New Bulgarian University, Sofia, Bulgaria.
11
Department of Neurology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
12
Department of Molecular Biology and Genetics, Bogazici University, Istanbul, Turkey.

Erratum in

  • Genet Med. 2016 Jan;18(1):108. Parma, Yesim [corrected to Parman, Yesim].

Abstract

PURPOSE:

Homozygosity mapping is an effective approach for detecting molecular defects in consanguineous families by delineating stretches of genomic DNA that are identical by descent. Constant developments in next-generation sequencing created possibilities to combine whole-exome sequencing (WES) and homozygosity mapping in a single step.

METHODS:

Basic optimization of homozygosity mapping parameters was performed in a group of families with autosomal-recessive (AR) mutations for which both single-nucleotide polymorphism (SNP) array and WES data were available. We varied the criteria for SNP extraction and PLINK thresholds to estimate their effect on the accuracy of homozygosity mapping based on WES.

RESULTS:

Our protocol showed high specificity and sensitivity for homozygosity detection and facilitated the identification of novel mutations in GAN, GBA2, and ZFYVE26 in four families affected by hereditary spastic paraplegia or Charcot-Marie-Tooth disease. Filtering and mapping with optimized parameters was integrated into the HOMWES (homozygosity mapping based on WES analysis) tool in the GenomeComb package for genomic data analysis.

CONCLUSION:

We present recommendations for detection of homozygous regions based on WES data and a bioinformatics tool for their identification, which can be widely applied for studying AR disorders.Genet Med 18 6, 600-607.

PMID:
26492578
DOI:
10.1038/gim.2015.139
[Indexed for MEDLINE]

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