Study Reveals Genetic Factors Influencing Syngap1 Encephalopathy Disease Severity

SYNGAP1 encephalopathy is simply a uncommon familial upset for which location is nary treatment, causing epilepsy, intelligence disability, psychomotor hold and, frequently, autism. It is caused by mutations successful nan SYNGAP1 gene, which produces a macromolecule basal for encephalon and cognitive development. Now, a multicentre study describes nan wide variability successful objective symptoms among patients and reveals that nan severity of nan illness does not dangle exclusively connected nan SYNGAP1 gene, but connected different familial factors that whitethorn modulate its objective expression. 

The study, published successful nan diary Neurobiology of Disease, opens up caller avenues for amended knowing really variants successful nan SYNGAP1 cistron power nan severity of nan disease, which has highly analyzable and adaptable objective manifestations. Furthermore, nan study has identified 4 caller variants of nan SYNGAP1 gene, which grow our knowing of nan familial ground of nan condition. The findings could thief expect imaginable objective trajectories and amended guideline therapeutic decisions successful nan guidance of this familial condition, affecting 1 successful each 16,000 people.

The lead authors of nan study are nan experts Marina Mitjans, Bru Cormand and Ferran Casals, from nan Faculty of Biology and nan Institute of Biomedicine astatine nan University of Barcelona (IBUB), nan Sant Joan de Déu Research Institute (IRSJD) and nan CIBER Area for Mental Health (CIBERSAM) and nan Area for Rare Diseases (CIBERER); Àlex Bayés, from nan Sant Pau Research Institute (IR Sant Pau) and nan Universitat Autònoma de Barcelona (UAB), and Àngels García-Cazorla, from IRSJD.

The study besides highlights nan publication of researchers Selena Aranda (UB's Faculty of Biology and IBUB), Juliana Ribeiro (UB's Faculty of Medicine and Health Sciences and IRSJD) and Alba Tristán (UB's Faculty of Biology and IR Sant Pau).

Clinical symptoms and mutations: What is nan link?

To date, various mutations successful nan SYNGAP1 cistron associated pinch encephalopathy person been identified, but nan catalogue of variants continues to turn arsenic much patients are studied.

The caller study examines nan genotype-phenotype relationship successful nan condition, that is, really alterations successful nan SYNGAP1 cistron manifest arsenic objective symptoms. For this purpose, nan squad analysed a cohort of 44 patients - each of whom were good characterized clinically - from 16 hospitals crossed Spain, each carrying a ascendant mutation successful nan SYNGAP1 gene.

The first cardinal uncovering of nan study is that location is sizeable objective variability among patients, moreover erstwhile they stock mutations successful nan aforesaid gene."

Professor Bru Cormand, caput of nan UB's Neurogenetics Research Group and an ICREA Academia 2021 researcher

"Secondly - he continues - a nexus has been discovered betwixt familial characteristics and symptoms, though it is neither nonstop nor straightforward."

Another important uncovering suggests that nan severity of nan illness does not dangle solely connected mutations successful nan SYNGAP1 gene, "but besides connected different familial factors that whitethorn power its objective presentation," notes Marina Mitjans, a interrogator pinch nan Ramón y Cajal programme astatine nan UB's Department of Genetics, Microbiology and Statistics.

The study has besides identified 4 caller variants of nan SYNGAP1 gene, "which are apt to beryllium pathogenic and had not been described previously; specifically, nan variants p.Ala591Pro, p.Val447Leufs*5, p.Thr674Profs*36 and p.Arg143Glnfs*9", notes Professor Ferran Casals, from nan aforesaid section astatine nan UB. He besides adds that "in cases wherever we could analyse nan parents' DNA, we could corroborate that these variants person arisen de novo; successful different words, they are caller mutations that person not been inherited from nan parents."

Can mutations successful nan cistron foretell illness severity?

One of nan cardinal questions raised by nan study was whether nan type of familial version tin foretell nan severity of nan disease.

Although this relation is only partial, immoderate important patterns person been identified. "For example, we cognize that nan location of nan version wrong nan cistron is an important factor. More specifically, variants located successful nan PH domain of nan cistron are associated pinch a milder phenotype, pinch little impairment of language, less cases of epilepsy and little wide severity," says Bru Cormand.

"For this reason, we propose that a relationship betwixt genotype and phenotype does beryllium successful this encephalopathy, but it is complex. It is not conscionable a mobility of which version is present, but besides wherever it is located and nan patient's wide familial context," adds Cormand.

Another important uncovering is that patients pinch nan aforesaid SYNGAP1 mutation tin show markedly different objective manifestations. "This uncovering suggests that nan severity of nan illness does not dangle solely connected nan circumstantial SYNGAP1 mutation, but astir apt besides connected different familial modifier factors," opportunity Mitjans and Casals.

It is besides worthy noting that two-thirds of patients affected by this encephalopathy person besides been diagnosed pinch autism. "For this reason, we are talking astir 1 of nan monogenic forms of autism spectrum disorder, which is usually of polygenic origin," nan squad points out.

To get these results, nan squad analysed whole-genome sequencing information covering each nan exons successful galore of nan patients - that is, astir 200,000 segments comprising immoderate 40 cardinal nucleotides.

"These sequences person enabled nan detection, successful summation to nan alteration successful nan SYNGAP1 gene, of different mutations successful genes whose products interact pinch nan SYNGAP1 protein, specified arsenic SHANK1, SHANK3 and NLGN2, among others. In general, patients pinch uncommon mutations successful these genes look to person a much terrible shape of nan disease", nan researchers conclude.