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Genes 2019, 10(4), 279; https://doi.org/10.3390/genes10040279

Clinical and Molecular Differences between 4-Year-Old Monozygous Male Twins Mosaic for Normal, Premutation and Fragile X Full Mutation Alleles

1
Victorian Clinical Genetics Services and Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, VIC 3052, Australia
2
Diagnosis and Development, Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, VIC 3052, Australia
3
Faculty of Medicine, Dentistry and Health Sciences, Department of Paediatrics, University of Melbourne, Parkville, VIC 3052, Australia
4
Brain and Mind, Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, VIC 3052, Australia
*
Author to whom correspondence should be addressed.
Received: 6 February 2019 / Revised: 1 April 2019 / Accepted: 1 April 2019 / Published: 5 April 2019
(This article belongs to the Section Human Genomics and Genetic Diseases)
PDF [682 KB, uploaded 5 April 2019]

Abstract

This study describes monozygotic (MZ) male twins with fragile X syndrome (FXS), mosaic for normal size (NS: <44 CGGs), premutation (PM: 55–199 CGG) and full mutation (FM alleles ≥ 200) alleles, with autism. At 4 years of age chromosomal microarray confirmed monozygosity with both twins showing an XY sex complement. Normal size (30 CGG), PM (99 CGG) and FM (388–1632 CGGs) alleles were detected in Twin 1 (T1) by standard polymerase chain reaction (PCR) and Southern blot testing, while only PM (99 CGG) and FM (672–1025) alleles were identified in Twin 2 (T2). At ~5 years, T2 had greater intellectual impairments with a full scale IQ (FSIQ) of 55 and verbal IQ (VIQ) of 59, compared to FSIQ of 62 and VIQ of 78 for T1. This was consistent with the quantitative FMR1 methylation testing, revealing 10% higher methylation at 80% for T2; suggesting that less active unmethylated alleles were present in T2 as compared to T1. AmplideX methylation PCR also identified partial methylation, including an unmethylated NS allele in T2, undetected by standard testing. In conclusion, this report demonstrates significant differences in intellectual functioning between the MZ twins mosaic for NS, PM and FM alleles with partial FMR1 promoter methylation.
Keywords: Fragile-X syndrome; FMR1 gene; methylation; mosaicism; expansion; retraction; monozygous twins Fragile-X syndrome; FMR1 gene; methylation; mosaicism; expansion; retraction; monozygous twins
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Pandelache, A.; Baker, E.K.; Aliaga, S.M.; Arpone, M.; Forbes, R.; Stark, Z.; Francis, D.; Godler, D.E. Clinical and Molecular Differences between 4-Year-Old Monozygous Male Twins Mosaic for Normal, Premutation and Fragile X Full Mutation Alleles. Genes 2019, 10, 279.

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