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

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

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).

Publication types

  • Case Reports

MeSH terms

  • Autism Spectrum Disorder / diagnosis
  • Autism Spectrum Disorder / genetics*
  • Autistic Disorder / diagnosis
  • Autistic Disorder / genetics
  • Child
  • Chromosome Deletion
  • Chromosome Duplication
  • Chromosomes, Human, Pair 1 / genetics
  • Heart Defects, Congenital / diagnosis
  • Heart Defects, Congenital / genetics*
  • Humans
  • Intellectual Disability / diagnosis
  • Intellectual Disability / genetics*
  • Male
  • Mosaicism*
  • Mutation, Missense
  • Paraplegia / diagnosis
  • Paraplegia / genetics*
  • Paternal Inheritance
  • Phenotype*
  • Spastin / genetics

Substances

  • Spastin
  • SPAST protein, human

Supplementary concepts

  • Chromosome 1q21.1 Duplication Syndrome