VHL mosaicism can be detected by clinical next-generation sequencing and is not restricted to patients with a mild phenotype

Abstract

The identification of Von Hippel-Lindau (VHL) mosaic mutations by conventional Sanger sequencing requires a labour-intensive enrichment step, thus explaining that mosaicism occurrence is underestimated in patients. Nowadays, it is possible to detect mutation in cell sub-populations by next-generation sequencing (NGS). Here, we described a diagnosis strategy using NGS with high coverage in a series of eight patients who were negative for a VHL abnormality by Sanger sequencing and deletion search. In two patients, a mosaic mutation in VHL was detected by NGS. One patient with a 5.7% mutated allele frequency had a severe phenotype and an early disease onset. In conclusion, clinical NGS in an hospital molecular oncogenetics laboratory is an efficient tool to identify VHL mosaic mutation. Its use may improve patient monitoring and genetic counseling.

Von Hippel-Lindau Disease: Genetics and Role of Genetic Counseling in a Multiple Neoplasia Syndrome

“…83,86 Detection of mosaicism is critical in terms of confirming a diagnosis and estimating the risk to siblings and offspring. 84,85 As next-generation sequencing replaces Sanger sequencing, mosaic cases may be more easily detected, which could provide the data needed to elucidate the true frequency of mosaicism in VHL.…”

“…Generally, patients with mosaicism tend to be more mildly affected or asymptomatic, 83 although this is not always the case, and mosaicism has been confirmed in individuals with classic VHL disease as well. 84,85 It is now recommended that additional testing methods be used to rule out mosaicism in the parents of a patient with proband with a seemingly de novo mutation and in cases moderately or highly suspicious of VHL in whom standard testing methods have failed to detect a disease-causing mutation.…”

Somatic mosaicism of a heterogeneous mutation of ACTA1 in nemaline myopathy

“…Although the clinical information for that previous case was unknown, it was described as severe NM . Generally, the phenotype of mosaicism is milder than that of full mutations . The present patient was not thought to have severe NM.…”

“…That might be because the present patient had a mosaicism. NGS should be the first method of choice to detect low‐grade mosaicism and determine its correct ratio . The ratio of mosaicism may predict outcome in patients with NM.…”

Inherited Kidney Disorders in the Age of Genomics

“…A mosaic event refers to a situation wherein tissues or cell populations in a single individual have different genotypes; this can occur when a mutation arises during (fetal) development [76]. For example, Beicht et al [78] recently revealed a mosaic mutation in COLA5 in an individual with Alport syndrome, Tan et al [79] identified a mosaic PKD1 mutation in a patient with ADPKD, and Coppin et al [77] reported a mosaic VHL mutation in a patient with an early manifestation of von Hippel-Lindau disease. In addition, if the mutation is not present in the tissue from which DNA was extracted, the causative mutation may not be identified at all.…”