Developmental delay referrals and the roles of Fragile X testing and molecular karyotyping: A New Zealand perspective

Doherty,Elaine; O'Connor,Rachel; Zhang,Anna; Lim,Christina; Love,Jennifer  M.; Ashton,Fern; Claxton,Karen; Gregersen,Nerine; George,Alice  M.; Love,Donald  R.

doi:10.3892/mmr.2013.1386

Developmental delay referrals and the roles of Fragile X testing and molecular karyotyping: A New Zealand perspective

Authors:
- Elaine Doherty
- Rachel O'Connor
- Anna Zhang
- Christina Lim
- Jennifer M. Love
- Fern Ashton
- Karen Claxton
- Nerine Gregersen
- Alice M. George
- Donald R. Love
View Affiliations

Affiliations: Diagnostic Genetics, LabPlus, Auckland City Hospital, Auckland 1148, New Zealand, Genetic Health Service New Zealand-Northern Hub, Auckland City Hospital, Auckland 1142, New Zealand
Published online on: March 20, 2013 https://doi.org/10.3892/mmr.2013.1386
Pages: 1710-1714

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Global developmental delay (GDD) affects ~1-3% of children, many of whom will also have intellectual disability (ID). Fragile X is the major genetic cause of GDD with mental retardation (MR) in males, accounting for ~20% of all X-linked MR. As Fragile X has serious genetic implications, the overwhelming majority of developmental delay (DD) cases referred to our laboratory are concerned with the exclusion of a diagnosis of Fragile X, along with simultaneous karyotype analysis to confirm chromosome aberrations. Critically, molecular laboratories have generally experienced a falling positive detection frequency of Fragile X. In this context, the recent implementation of array‑based technology has significantly increased the likelihood of detecting chromosome aberrations that underpin DD. In the current study, we report a Fragile X mutation detection frequency for DD referrals that is comparable with the falling UK detection frequencies. In addition, we find that there is a 9‑fold greater likelihood of detecting clinically significant chromosomal aberrations than of detecting a full Fragile X mental retardation 1 (FMR1) gene CGG repeat expansion in cases referred on the basis of DD. We propose a more efficent sequential testing algorithm that involves an initial molecular karyotype, cascading to FMR1 gene analysis in the event of a negative result.

View Figures

View References

1	Michelson DJ, Shevell MI, Sherr EH, et al: Evidence report: genetic and metabolic testing on children with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 77:1629–1635. 2011. View Article : Google Scholar
2	Miller DT, Shen Y, Harris DJ, et al: Genetic testing for developmental delay: keep searching for an answer. Clin Chem. 55:827–832. 2009. View Article : Google Scholar : PubMed/NCBI
3	Raymond FL: X linked mental retardation: a clinical guide. J Med Genet. 43:193–200. 2006. View Article : Google Scholar : PubMed/NCBI
4	Fishburn J, Turner G, Daniel A, et al: The diagnosis and frequency of X-linked conditions in a cohort of moderately retarded males with affected brothers. Am J Med Genet. 14:713–724. 1983. View Article : Google Scholar : PubMed/NCBI
5	Coffee B, Keith K, Albizua I, et al: Incidence of fragile X syndrome by newborn screening for methylated FMR1 DNA. Am J Hum Genet. 85:503–514. 2009. View Article : Google Scholar : PubMed/NCBI
6	Loesch DZ, Huggins RM and Hagerman RJ: Phenotypic variation and FMRP levels in fragile X. Ment Retard Dev Disabil Res Rev. 10:31–41. 2004. View Article : Google Scholar : PubMed/NCBI
7	Rousseau F, Heitz D, Tarleton J, et al: A multicenter study on genotype-phenotype correlations in the fragile X syndrome, using direct diagnosis with probe StB12.3: the first 2,253 cases. Am J Hum Genet. 55:225–237. 1994.PubMed/NCBI
8	Chudley AE and Hagerman RJ: Fragile X syndrome. J Pediatr. 110:821–831. 1987. View Article : Google Scholar
9	Lachiewicz AM and Dawson DV: Do young boys with Fragile X syndrome have macroorchidism? Pediatrics. 93:992–995. 1994.PubMed/NCBI
10	Kunkel TA: Nucleotide repeats. Slippery DNA and diseases. Nature. 365:207–208. 1993. View Article : Google Scholar : PubMed/NCBI
11	Deng H, Le W and Jankovic J: Premutation alleles associated with Parkinson disease and essential tremor. JAMA. 292:1685–1686. 2004.PubMed/NCBI
12	Loesch DZ, Khaniani MS, Slater HR, et al: Small CGG repeat expansion alleles of FMR1 gene are associated with parkinsonism. Clin Genet. 76:471–476. 2009. View Article : Google Scholar : PubMed/NCBI
13	Cilia R, Kraff J, Canesi M, et al: Screening for the presence of FMR1 premutation alleles in women with parkinsonism. Arch Neurol. 66:244–249. 2009. View Article : Google Scholar : PubMed/NCBI
14	Kraff J, Tang HT, Cilia R, et al: Screen for excess FMR1 premutation alleles among males with parkinsonism. Arch Neurol. 64:1002–1006. 2007. View Article : Google Scholar : PubMed/NCBI
15	Nolin SL, Brown WT, Glicksman A, et al: Expansion of the fragile X CGG repeat in females with premutation or intermediate alleles. Am J Hum Genet. 72:454–464. 2003. View Article : Google Scholar : PubMed/NCBI
16	Rousseau F, Labelle Y, Bussieres J, et al: The fragile x mental retardation syndrome 20 years after the FMR1 gene discovery: an expanding universe of knowledge. Clin Biochem Rev. 32:135–162. 2011.PubMed/NCBI
17	Schwartz CE, Dean J, Howard-Peebles PN, et al: Obstetrical and gynecological complications in fragile X carriers: a multicenter study. Am J Med Genet. 51:400–402. 1994. View Article : Google Scholar : PubMed/NCBI
18	Lu R, Wang H, Liang Z, et al: The fragile X protein controls microtubule-associated protein 1B translation and microtubule stability in brain neuron development. Proc Natl Acad Sci USA. 101:15201–15206. 2004. View Article : Google Scholar
19	Lunt P: Testing criteria for fragile X syndrome: report of the outcome from the UKGTN Fragile X Workshop. http://www.ukgtn.nhs.uk/gtn/digitalAssets/0/971_UKGTNFraXworkshopFINAL2010.pdf. Accessed November, 2012
20	Gallo JH, Ordonez JV, Brown GE and Testa JR: Synchronization of human leukemic cells: relevance for high-resolution chromosome banding. Hum Genet. 66:220–224. 1984. View Article : Google Scholar : PubMed/NCBI
21	Moorhead PS, Nowell PC, Mellman WJ, et al: Chromosome preparations of leukocytes cultured from human peripheral blood. Exp Cell Res. 20:613–616. 1960. View Article : Google Scholar : PubMed/NCBI