Mosaicism for a pathogenic MFN2 mutation causes minimal clinical features of CMT2A in the parent of a severely affected child

Katherine Schon,Soo-Mi Park,Kim Brugger,Olivera Spasic-Boskovic,Tracey D Graves,Gautam Ambegaonkar,Stephen Abbs,Ruth Armstrong

doi:10.1007/s10048-016-0504-2

Katherine Schon, Soo-Mi Park + Show 6 more

Open Access

https://doi.org/10.1007/s10048-016-0504-2

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Abstract

Charcot-Marie-Tooth disease (CMT) refers to a genetically heterogeneous group of disorders which cause a peripheral motor and sensory neuropathy. The overall prevalence is 1 in 2500 individuals. Mutations in the MFN2 gene are the commonest cause for the axonal (CMT2) type. We describe a Caucasian 5-year old girl affected by CMT2A since the age of 2 years. She presented with unsteady gait, in-turning of the feet and progressive foot deformities. Nerve conduction studies suggested an axonal neuropathy and molecular testing identified a previously reported pathogenic variant c.1090C > T, p.(Arg364Trp) in the MFN2 gene. This variant was also detected in a mosaic state in blood and saliva by Sanger sequencing in her subjectively healthy father. Next generation sequencing showed that the level of mosaicism was 21% in blood and 24% in saliva. A high recurrence risk was given because the father had proven somatic mosaicism and an affected child implying gonadal mosaicism. The parents were referred for pre-implantation genetic diagnosis. To the best of our knowledge, this is the first reported case of somatic mosaicism for MFN2. This study has important implications for genetic counselling in families with CMT2A.

Highlights

Charcot-Marie-Tooth (CMT) disease refers to a heterogeneous group of hereditary disorders which cause a peripheral motor and sensory neuropathy
Charcot-Marie-Tooth disease type 2A is caused by mutations in the MFN2 gene (OMIM 608507)
CMT2A caused by heterozygous mutations in MFN2 has a variable phenotype with an early onset form with age at onset = 10 years [3]

Summary

Introduction

Charcot-Marie-Tooth (CMT) disease refers to a heterogeneous group of hereditary disorders which cause a peripheral motor and sensory neuropathy. The overall prevalence is approximately 1 in 2500 [1] They are genetically heterogeneous with over 60 reported genes [2]. Charcot-Marie-Tooth disease type 2A is caused by mutations in the MFN2 (mitofusin 2) gene (OMIM 608507). Mosaicism occurs when an individual who has developed from a single fertilised egg has two or more cell lines which are discordant for a genetic feature [7]. This could be a chromosomal abnormality, for example in mosaic Trisomy 21, or it could be a sequence variant. Somatic mosaicism is being increasingly detected as a result of generation sequencing [8]

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