D4F104S1 deletion in facioscapulohumeral muscular dystrophy: phenotype, size, and detection.
BACKGROUND
The facioscapulohumeral muscular dystrophy (FSHD) locus maps to 4q35 where it is closely linked to D4F104S1 (p13E-11), a probe that recognizes the pathognomonic FSHD deletion involving the subtelomeric D4Z4 tandem repeat array. Extended deletions that include both the more proximal D4F104S1 region and the D4Z4 repeat array proper do, however, occur, albeit rarely, and such deletions can lead to difficulties of interpretation in the diagnostic setting.


OBJECTIVE
To devise a means to determine the true frequency of proximally extended deletions in individuals with FSHD.


METHODS
Three families selected for this study were originally identified during routine FSHD analysis on the basis that the affected individuals in each family had failed to exhibit a small (<38-kb) EcoRI fragment. High molecular weight DNA from these families was analyzed with both conventional and pulsed-field gel electrophoresis using DNA markers p13E-11, 9B6A, B31, 4qA, and 4qB.


RESULTS
Large genomic deletions were identified involving both D4Z4 and D4F104S1. The precise number of D4Z4 repeat units borne by the p13E11 deletion allele was established by the use of an additional restriction enzyme (MseI) digest. All three cases carry different sizes of deletion proximal to the D4Z4 repeat units. With use of a recently described telomeric probe, 4qA, a method was developed that identifies large genomic deletions involving both D4Z4 and D4F104S1 using conventional gel electrophoresis.


CONCLUSIONS
Proximally extended deletions can be found in patients with a normal spectrum of the disease. This assay promises to allow estimation of the true frequency of proximally extended deletions and should improve the accuracy and reliability of molecular diagnostic testing for FSHD.
Lemmers
R J L F
RJ
Department of Human Genetics, Center for Human and Clinical Genetics, Leiden, The Netherlands.
Osborn
M
M
Haaf
T
T
Rogers
M
M
Frants
R R
RR
Padberg
G W
GW
Cooper
D N
DN
van der Maarel
S M
SM
Upadhyaya
M
M
D000328:Adult; D000483:Alleles; D002648:Child; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D004252:DNA Mutational Analysis; D015342:DNA Probes; D015246:Deoxyribonuclease EcoRI; D016521:Electrophoresis, Gel, Pulsed-Field; D005260:Female; D005799:Genes, Dominant; D005819:Genetic Markers; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008840:Microfilament Proteins; D018598:Minisatellite Repeats; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000175:diagnosis / Q000235:genetics*; D009687:Nuclear Proteins; D010375:Pedigree; D010641:Phenotype; D012150:Polymorphism, Restriction Fragment Length; D011506:Proteins; D016601:RNA-Binding Proteins; D017384:Sequence Deletion
D015342:DNA Probes; C101270:FRG1 protein, human; D005819:Genetic Markers; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D011506:Proteins; D016601:RNA-Binding Proteins; D015246:Deoxyribonuclease EcoRI