Search

The major and most well-studied genetic cause of Fragile-X syndrome (FXS) is expansion of a CGG repeat in the 5'-UTR of the FMR1 gene. Routine testing for this expansion is performed globally. Overall, there is a paucity of intragenic variants explaining FXS, a fact which is being addressed by a more systematic application of whole exome (WES) and whole genome (WGS) sequencing, even in the diagnostic setting. Here we report two families comprising probands with a clinical suspicion of FXS and no CGG repeat expansions. Using WES/WGS we identified deleterious variants within the coding region of FMR1 in both families. In a family from Finland we identified a complex indel c.1021-1028delinsTATTGG in exon 11 of FMR1 which gives rise to a frameshift and a premature termination codon (PTC), p.Asn341Tyrfs*7. Follow-up mRNA and protein studies on a cell line from the proband revealed that although the mRNA levels of FMR1 were not altered, Fragile X Mental Retardation 1 Protein (FMRP) was undetectable. Additionally, we identified a variant, c.881-1G > T, affecting the canonical acceptor splice site of exon 10 of FMR1 in an Australian family. Our findings reinforce the importance of intragenic FMR1 variant testing, particularly in cases with clinical features of FXS and no CGG repeat expansions identified., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

The aim of this study was to investigate the developmental trajectories of verbal aggression, physical aggression, and temper tantrums in four genetic syndrome groups. Participants were part of the Australian Child to Adult Development Study (ACAD), which collected information from a cohort of individuals with an intellectual disability at five time points over 18 years. Data were examined from a total of 248 people with one of the four following syndromes: Down syndrome, Fragile X syndrome, Prader-Willi syndrome, or Williams syndrome. Changes in behaviors were measured using validated items from the Developmental Behavior Checklist (DBC). The results indicate that, while verbal aggression shows no evidence of diminishing with age, physical aggression, and temper tantrums decline with age before 19 years for people with Down syndrome, Fragile X syndrome, and William syndrome; and after 19 years for people with Prader-Willi syndrome. These findings offer a somewhat more optimistic outlook for people with an intellectual disability than has previously been suggested. Research is needed to investigate the mechanisms predisposing people with PWS to persistence of temper tantrums and physical aggression into adulthood., (© 2015 Wiley Periodicals, Inc.)