title: Transmission of an FMR1 premutation allele in a large family identified through newborn screening: the role of AGG interruptions.
abstract: The CGG repeat within the premutation range in the fragile X mental retardation 1 (FMR1) gene can lead to neurodegenerative disorders and intellectual disabilities. An increase in size upon the transmission from parent to child is more likely to occur for larger alleles and without AGG interruptions. We describe the molecular structure and the transmission of an FMR1 premutation allele in a multigenerational family, identified through newborn screening for fragile X syndrome. Transmission of the premutation allele was traced through five generations in 14 of the 23 individuals who were genotyped through cascade testing. Allele size instability during transmission was observed, but no expansions to a full mutation were detected. Clinical and molecular characterizations of the participants lead to the diagnosis of fragile X-associated tremor ataxia syndrome in one subject identified as a premutation carrier. A gradual small increase in the size of the premutation allele was observed during transmission through five generations. The relative stability is likely due to the presence of two AGGs within the allele. The detection of AGG interruptions within the premutation alleles is important in genetic counseling, to better predict the risk of expansion during transmission from a premutation to a full-mutation allele.
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis, School of Medicine, Davis, CA, USA.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Yrigollen
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Mendoza-Morales
authors.forename: Randi
authors.initials: R
authors.lastname: Hagerman
authors.forename: Flora
authors.initials: F
authors.lastname: Tassone
mesh_terms: D000483:Alleles; D019075:Electrophoresis, Capillary; D005190:Family; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009154:Mutation / Q000235:genetics*; D015997:Neonatal Screening; D010375:Pedigree; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; C497683:FMR1 protein, human