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PRRT2-related phenotypes in patients with a 16p11.2 deletion

Danique R M Vlaskamp1, Petra M C Callenbach2, Patrick Rump3

  • 1University of Groningen, University Medical Center Groningen, Department of Neurology, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.

European Journal of Medical Genetics
|August 21, 2018
PubMed

Insights

Genetic variants in PRRT2 are linked to benign infantile epilepsy (BIE) and paroxysmal kinesigenic dyskinesia (PKD). However, the study found these conditions are less common with 16p11.2 deletions than PRRT2 variants, impacting genetic counseling.

Area of Science:

  • Genetics
  • Neurology
  • Pediatrics

Background:

  • Benign infantile epilepsy (BIE), paroxysmal kinesigenic dyskinesia (PKD), and PKD with infantile convulsions (PKD/IC) are associated with PRRT2 gene variants.
  • The 16p11.2 deletion, which can include PRRT2, and PRRT2 sequence variants are both loss-of-function mechanisms.
  • Understanding the penetrance of these phenotypes in relation to genetic alterations is crucial for accurate diagnosis and counseling.

Purpose of the Study:

  • To investigate the prevalence of BIE, PKD, and PKD/IC in patients with a 16p11.2 deletion encompassing PRRT2 or with a PRRT2 loss-of-function sequence variant.
  • To compare the clinical presentation and ascertainment bias between these two genetic groups.
  • To clarify the implications for genetic counseling when PRRT2-related phenotypes are not evident despite variant detection.

Main Methods:

  • Retrospective evaluation of BIE, PKD, and PKD/IC using questionnaires and medical records in index patients from seven Dutch university hospitals.
  • Inclusion of 33 patients with a 16p11.2 deletion and 12 patients with a PRRT2 sequence variant.
  • Analysis of genetic testing indications and phenotype prevalence within each group.

Main Results:

  • Nine percent of patients with a 16p11.2 deletion had BIE; none had PKD or PKD/IC.
  • Patients with a PRRT2 sequence variant showed higher prevalence of BIE (p=0.069), PKD (p<0.001), and PKD/IC (p=0.067).
  • Ascertainment bias was observed, with deletions often identified due to developmental issues and variants due to movement disorders or epilepsy.

Conclusions:

  • BIE, PKD, and PKD/IC exhibit incomplete penetrance in individuals with 16p11.2 deletions.
  • The study suggests ascertainment differences may overestimate the frequency of these phenotypes in PRRT2 variant carriers.
  • Accurate genetic counseling is essential when genome-wide sequencing reveals variants in patients without classic PRRT2-related phenotypes.

Keywords:
Benign infantile epilepsyMicroarrayMovement disorderSeizureSequencing

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