Premature chromatid separation is not a useful diagnostic marker for Cornelia de Lange syndrome.
Cornelia de Lange syndrome (CdLS) is a rare, multiple congenital anomaly/mental retardation syndrome characterized by clinical variability and caused by mutations in the NIPBL (50-60%), SMC1L1 and SMC3 genes (5%), which encode for proteins involved in sister chromatid cohesion. Almost all of the studies of premature chromatid separation (PCS) in CdLS patients have failed to demonstrate that it is specific to CdLS, thus making its diagnostic use controversial. In order to verify the diagnostic usefulness of PCS screening in CdLS, we analysed metaphase spreads from 29 CdLS patients and 24 controls using a rigorous protocol to induce PCS, and precise criteria to score the affected chromosomes. Following exclusion of significant intra-sample variation we scored under blind conditions 150 spreads from a single preparation of each case and computed the ratio between the number of prematurely separated chromatids and the total number of chromatids. The results indicate the extreme variability of PCS in both cohorts (CdLS: mean 2.8 +/- 2.8%; controls: mean 4.0 +/- 5.4%) and highlight the difficulty of PCS monitoring, especially when selecting the control population. The absence of any difference in the frequency of PCS between the patients and controls, or between patients with different clinical or genetic backgrounds, precludes its potential use as an additional diagnostic tool.
Castronovo
Paola
P
Division of Medical Genetics, San Paolo School of Medicine, University of Milan, via A. di Rudinì 8, 20142 Milan, Italy.
Gervasini
Cristina
C
Cereda
Anna
A
Masciadri
Maura
M
Milani
Donatella
D
Russo
Silvia
S
Selicorni
Angelo
A
Larizza
Lidia
L
D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002842:Chromatids / Q000235:genetics* / Q000473:pathology; D020090:Chromosome Segregation / Q000235:genetics*; D002877:Chromosomes, Human / Q000235:genetics; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D003635:De Lange Syndrome / Q000175:diagnosis / Q000235:genetics*; D005189:False Positive Reactions; D005260:Female; D005819:Genetic Markers; D006801:Humans; D008297:Male; D008677:Metaphase; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D012854:Sister Chromatid Exchange / Q000235:genetics*; D055815:Young Adult
D005819:Genetic Markers
Clin Genet. 1979 Dec;16(6):441-7
527250
Am J Med Genet. 1995 Mar 13;56(1):76-9
7747791
Exp Gerontol. 2004 May;39(5):849-54
15130680
Cell. 1997 Oct 3;91(1):47-57
9335334
Am J Med Genet A. 2003 Feb 15;117A(1):85-6
12548747
Ann N Y Acad Sci. 2009 Jan;1151:22-37
19154515
Am J Med Genet. 1993 Nov 15;47(7):947-58
8291538
Am J Med Genet A. 2004 May 1;126A(4):432
15098245
Am J Med Genet A. 2005 Sep 15;138(1):27-31
16100726
Hum Mol Genet. 2007 Jun 15;16(12):1478-87
17468178
Nat Genet. 2004 Nov;36(11):1159-61
15475955
Mol Cell Biol. 2004 Apr;24(8):3100-11
15060134
Eur J Cancer Prev. 1996 Oct;5(5):343-50
8972253
J Neurochem. 2008 Sep;106(5):2218-23
18624923
Hum Genet. 1988 Jun;79(2):151-6
3164705
Hum Mol Genet. 2009 Feb 1;18(3):418-27
18996922
Am J Hum Genet. 2007 Mar;80(3):485-94
17273969
Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3443-8
18299561
Curr Opin Genet Dev. 2005 Jun;15(3):258-64
15917200
Nat Genet. 2004 Jun;36(6):636-41
15146185
Pediatr Blood Cancer. 2009 Aug;53(2):208-10
19373780
Cell. 1997 Oct 3;91(1):35-45
9335333
Nat Genet. 2006 May;38(5):528-30
16604071
Am J Med Genet. 2002 Oct 1;112(2):215-6
12244559
Genetics. 1999 Jun;152(2):577-93
10353901
Hum Mol Genet. 2005 Mar 15;14(6):813-25
15703196
Am J Med Genet. 1998 Jul 7;78(3):245-9
9677059
Clin Genet. 2007 Aug;72(2):98-108
17661813
Chromosoma. 2008 Feb;117(1):51-66
17909832
Nat Genet. 2004 Jun;36(6):631-5
15146186
Ann Genet. 1992;35(3):183-5
1466571
Am J Med Genet A. 2004 Jun 1;127A(2):128-32
15108198
AIDS. 2005 Sep 2;19(13):1434-8
16103780
Am J Med Genet A. 2007 Jun 15;143A(12):1287-96
17508425
Clin Genet. 2008 Dec;74(6):531-8
18798846
Am J Med Genet. 1983 Mar;14(3):545-56
6859105