June 2021 – Laboratory Genetics and Genomics

The correct answer is: Fragile X syndrome; Risk for primary ovarian insufficiency.

Fragile X syndrome is a repeat expansion disorder. The 5’UTR and promoter region of the FMR1 gene become methylated once the number of CGG repeats in the 5’UTR reaches a threshold of around 200 repeats. This shuts down FMR1 gene expression and a subsequent absence of the FMR1 protein, which plays a central role in neuronal development and synaptic plasticity.

The patient is mosaic for a normal allele and a methylated, full mutation allele. Fragile X syndrome is X-linked, meaning that he has a diagnosis for fragile X syndrome. The severity of mosaic fragile X syndrome can range from mild to severe, depending on the proportion of normal to full mutation alleles in tissues important for fragile X pathogenesis like the brain (1). 

The patient’s mother is at risk of for primary ovarian insufficiency as well as fragile X-associated tremor and ataxia syndrome because she has a premutation allele. She also has a risk of passing on a full mutation allele to her children because of the relative instability of the premutation allele. 

The combination of the normal and full mutation alleles seen in the patient is quite rare (2). Males with mosaic fragile X syndrome typically have a combination of the premutation allele and the full mutation allele. This is because of the premutation allele’s propensity to expand to the full mutation during embryogenesis. The mechanism behind a mosaic of normal and full mutation alleles is thought to be both the contraction and expansion of the unstable premutation allele (3). Therefore, the most likely explanation for the patient’s mosaicism is that he inherited the premutation allele from his mother, which then expanded to the full mutation in a subset of cells and contracted to the normal allele in others.

References

• Pretto et al. Clinical and molecular implications of mosaicism in FMR1 full mutations. Front. Genet. 2014; 5:318. PMID: 25278957
• Bonarrigo et al. J Child Neurol. Think about it: FMR1 gene mosaicism. 2014;29(9):NP74-7. PMID: 24065579
• Schmucker and Seidel. Mosaicism for a full mutation and a normal size allele in two fragile X males. Am J Med Genet. 1999;84(3):221-5. PMID: 10331596