Genetic modifiers in rare disorders: the case of fragile X syndrome

Abstract

Methods employed in genome-wide association studies are not feasible ways to explore genotype-phenotype associations in rare disorders due to limited statistical power. An alternative approach is to examine relationships among specific single nucleotide polymorphisms (SNPs), selected a priori, and behavioural characteristics. Here, we adopt this strategy to examine relationships between three SNPs (5-HTTLPR, MAOA, COMT) and specific clinically-relevant behaviours that are phenotypic of fragile X syndrome (FXS) but vary in severity and frequency across individuals. Sixty-four males with FXS participated in the current study. Data from standardised informant measures of challenging behaviour (defined as physical aggression, property destruction, stereotyped behaviour, and self-injury), autism symptomatology, attention-deficithyperactivity-disorder characteristics, repetitive behaviour and mood/interest and pleasure were compared between each SNP genotype. No association was observed between behavioural characteristics and either 5-HTTLPR (serotonin) or MAOA (monoamine oxidase) genotypes. However, compared to the COMT (dopamine) AG and GG genotypes, the AA genotype was associated with greater interest and pleasure in the environment, and with reduced risk for property destruction, stereotyped behaviour and compulsive behaviour. The results suggest that common genetic variation in the COMT genotype affecting dopamine levels in the brain may contribute to the variability of challenging and repetitive behaviours and interest and pleasure in this population. This study identifies a role for additional genetic risk in understanding the neural and genetic mechanisms contributing to phenotypic variability in neurodevelopmental disorders, and highlights the merit of investigating SNPs that are selected a priori on a theoretical basis in rare populations.

Variable Expressivity in Fragile X Syndrome: Towards the Identification of Molecular Characteristics That Modify the Phenotype

“…Nevertheless, the A/A genotype in COMT that modifies dopamine levels was associated with greater interest and pleasure in the environment, and with less risk of property destruction, stereotyped behavior and compulsive behavior. 54 The authors of the study suggest that the non-reproducibility of the results regarding MAOA-VNTR can be explained by differences in the prevalence of aggressive and stereotyped behavior among the studied populations or by differences in the measurements used to characterize each behavior.…”

“…53 During the identification of modifier genes in the FXS phenotype, a large proportion of the research has aimed towards the susceptibility to developing certain clinical behavioral characteristics, such as aggression, ASD and seizures. 34,[54][55][56][57][58][59] All of the studies use a similar methodological design: they arrange groups of people with or without a specific phenotypic trait and establish the frequency of specific variants in modifier gene candidates.…”

“…appearance of seizures (BNDF) 56,[60][61][62] and associated with mood and aggression (5-HTTLPR, MAOA-VNTR y -COMT). 54,55 Recent research has been done with small groups of patients and there are no conclusive results about the importance of these variants in modifier genes.…”

“…Because high impact clinical manifestations in FXS are related with neurologic phenotypes, the studied candidate genes are involved in CNS development and the appearance of seizures (BNDF) 56 , 60–62 and associated with mood and aggression (5-HTTLPR, MAOA-VNTR y COMT). 54 , 55 Recent research has been done with small groups of patients and there are no conclusive results about the importance of these variants in modifier genes.…”

Modifier Genes in Microcephaly: A Report on WDR62, CEP63, RAD50 and PCNT Variants Exacerbating Disease Caused by Biallelic Mutations of ASPM and CENPJ

“…Genetic modifiers contribute towards phenotypic variability and penetrance and are thus important in precise diagnostic, prognostic, therapeutic and overall patient management strategies [ 12 ]. Such variants or genetic modifiers are being increasingly observed in neurodevelopmental disorders [ 13 , 14 , 15 , 16 ] but they have been rarely reported for microcephaly and associated syndromes [ 17 ]. Interestingly, they have a pronounced appreciation in mouse models of microcephaly [ 18 , 19 ].…”