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Eur J Med Genet. 2017 Oct;60(10):548-552. doi: 10.1016/j.ejmg.2017.07.015. Epub 2017 Aug 1.

A de novo mosaic mutation in SPAST with two novel alternative alleles and chromosomal copy number variant in a boy with spastic paraplegia and autism spectrum disorder.

Author information

1
Centre for Molecular Medicine and Therapeutics, Vancouver, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; BC Children's Hospital Research Institute, Vancouver, BC, Canada.
2
Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; BC Children's Hospital Research Institute, Vancouver, BC, Canada.
3
BC Children's Hospital Research Institute, Vancouver, BC, Canada; Department of Pediatrics, BC Children's Hospital, Vancouver, BC, Canada.
4
Department of Pediatrics, BC Children's Hospital, Vancouver, BC, Canada.
5
Centre for Molecular Medicine and Therapeutics, Vancouver, BC, Canada; BC Children's Hospital Research Institute, Vancouver, BC, Canada; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
6
Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; BC Children's Hospital Research Institute, Vancouver, BC, Canada; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
7
BC Children's Hospital Research Institute, Vancouver, BC, Canada; Department of Pediatrics, BC Children's Hospital, Vancouver, BC, Canada; Canuck Place Children's Hospice, Vancouver, BC, Canada.
8
Centre for Molecular Medicine and Therapeutics, Vancouver, BC, Canada; BC Children's Hospital Research Institute, Vancouver, BC, Canada; Department of Pediatrics, BC Children's Hospital, Vancouver, BC, Canada; Departments of Pediatrics and Clinical Genetics, Academic Medical Centre, University of Amsterdam, The Netherlands. Electronic address: cvankarnebeek@cw.bc.ca.

Abstract

Here we report a 12 year old male with an extreme presentation of spastic paraplegia along with autism and dysmorphisms. Whole exome sequencing identified a predicted pathogenic pair of missense variants in SPAST at the same chromosomal location, each with a different alternative allele, while a chromosome microarray identified a 1.73 Mb paternally inherited copy gain of 1q21.1q21.2 resulting in a blended phenotype of both Spastic paraplegia 4 and 1q21.1 microduplication syndrome. We believe that the extreme phenotype observed is likely caused by the presence of cells which contain only mutant SPAST, but that the viability of the patient is possible due mosaicism of mutant alleles observed in different proportions across tissues.

KEYWORDS:

Autosomal dominant (SPG4); Hereditary (HPS); Mosaic; SPAST; Spastic paraplegia; Spastic paraplegia 4; Whole exome sequencing (WES)

PMID:
28778789
DOI:
10.1016/j.ejmg.2017.07.015
[Indexed for MEDLINE]

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