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

• Published in: European journal of medical genetics Vol. 60; no. 10; pp. 548 - 552
• Main Authors: Matthews, A.M., Tarailo-Graovac, M., Price, E.M., Blydt-Hansen, I., Ghani, A., Drögemöller, B.I., Robinson, W.P., Ross, C.J., Wasserman, W.W., Siden, H., van Karnebeek, C.D.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Masson SAS 01.10.2017
• Subjects: Autism Spectrum Disorder - diagnosis; Autism Spectrum Disorder - genetics; Autistic Disorder - diagnosis; Autistic Disorder - genetics; Autosomal dominant (SPG4); Child; Chromosome Deletion; Chromosome Duplication; Chromosomes, Human, Pair 1 - genetics; Heart Defects, Congenital - diagnosis; Heart Defects, Congenital - genetics; Hereditary (HPS); Humans; Intellectual Disability - diagnosis; Intellectual Disability - genetics; Male; Mosaic; Mosaicism; Mutation, Missense; Paraplegia - diagnosis; Paraplegia - genetics; Paternal Inheritance; Phenotype; SPAST; Spastic paraplegia; Spastic paraplegia 4; Spastin - genetics; Whole exome sequencing (WES); SPAST; Hereditary (HPS); Whole exome sequencing (WES); Spastic paraplegia 4; Autosomal dominant (SPG4); Spastic paraplegia; Mosaic
• ISSN: 1769-7212; 1878-0849
• DOI: 10.1016/j.ejmg.2017.07.015

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.