SYNGAP1 Prevalence: Why We Are Sure That SYNGAP1-Related Intellectual Disability is Under-Diagnosed?

Executive Summary

Introduction

EARLY STUDIES LOOKED AT COHORTS OF PEOPLE WITH INTELLECTUAL DISABILITIES AND FOUND SIMILAR PERCENTAGES WITH SYNGAP MUTATIONS.

  • Hamdan in 2009 noted that 3% of patients in his study with “non-syndromic mental retardation” had SYNGAP mutations.
  • Berryer in 2013 found that 9 of 186 [~5%] NSID (non-syndromic intellectual disability) patients had SYNGAP mutations.
  • Samocha in 2014 found that 3 of 151 [~2%] patients had SYNGAP mutations.

THE DDD STUDY IN THE UK REINFORCED BOTH THE IMPORTANCE & RELATIVELY HIGH INCIDENCE OF SYNGAP.

  • 2015 study of 1,133 patients found 7 with SynGAP mutations [0.6%]; this was the fifth most identified gene in the study.
  • 2017 study called SynGAP one of the “six most significantly associated genes”
  • Noting here that this was a much larger cohort and the incidence came down from 2–5% to 0.6%. Read on.

MORE RECENT STUDIES VALIDATE SYNGAP1 AS A TOP DIAGNOSTIC GENE.

  • Wright in 2018 also found SYNGAP1 to be the 6th most diagnostic gene after RID1B, SATB2, SCN2A, ANKRD11, MED13L.
  • Truty, reviewing 9,413 patients tested with the Invitae panel found that SYNGAP1 was the 10th highest incidence gene, accounting for 2.5% of positive diagnoses; notably, however in addition to the 39 hits, there were another 79 VUSs (“variants of unknown significance”).
  • Brimble, in a case report, pointed to an example of a VUS that was found to be pathogenic with RNA testing. How many other VUSs were actually pathogenic but not identified as such?

A RECENT STUDY SUPPORTS THE 0.5% — 1% RANGE

  • Johannesen et al in 2020, sequenced 200 patients with Epilepsy and ID in Denmark. 46 patients [23%] had a genetic cause discovered; one 26 year-old had a SYNGAP1 mutation. 1 in 200 is 0.5%.

Are all our missing patients just mild phenotypes?

Someone boiled a data ocean

But wait… the kinds of mutations matter

Where are all the missense patients?

Where are the Syngapians?

Conclusion — We need more research

BIBLIOGRAPHY

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