Minimal phenotype in a girl with trisomy 15q due to t(X;15)(q22.3;q11.2) translocation.
Few cases of de novo unbalanced X;autosome translocations associated with a normal or mild dysmorphic phenotype have been described. We report a 3-year-old dizygotic female twin with prenatally ascertained increased nuchal translucency. Prenatal chromosome studies revealed nearly complete trisomy 15 due to a de novo unbalanced translocation t(X;15)(q22;q11.2) confirmed postnatally. A mild phenotype was observed with normal birth measurements, minor facial dysmorphic features (hypertelorism, short broad nose, and a relatively long philtrum), and moderate developmental delay at the age of 3 years in comparison to her male fraternal twin. Replication timing utilizing BrdU and acridine-orange staining showed that the der(X) chromosome was late-replicating with variable spreading of inactivation into the translocated 15q segment. The der(X) was determined to be of paternal origin by analyses of polymorphic markers and CGG-repeat at FMR1. Methylation analysis at the SNRPN locus and analysis of microsatellites on 15q revealed paternal isodisomy with double dosage for all markers and the unmethylated SNRPN gene. The Xq breakpoint was mapped within two overlapping BAC clones RP11-575K24 and RP13-483F6 at Xq22.3 and the 15q breakpoint to 15q11.2, within overlapping clones RP11-509A17 and RP11-382A4 that are all significantly enriched for LINE-1 elements (36.6%, 43.0%, 26.6%, 22.0%, respectively). We speculate that the attenuated phenotype may be due to inactivation spreading into 15q, potentially facilitated by the enrichment of LINE-1 elements at the breakpoints. In silico analysis of breakpoint regions revealed the presence of highly identical low-copy repeats (LCRs) at both breakpoints, potentially involved in generating the translocation.
Stankiewicz
Paweł
P
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA. pawels@bcm.tmc.edu
Kuechler
Alma
A
Eller
C Daniel
CD
Sahoo
Trilochan
T
Baldermann
Christiane
C
Lieser
Ulla
U
Hesse
Martin
M
Gläser
Christiane
C
Hagemann
Monika
M
Yatsenko
Svetlana A
SA
Liehr
Thomas
T
Horsthemke
Bernhard
B
Claussen
Uwe
U
Marahrens
York
Y
Lupski
James R
JR
Hansmann
Ingo
I
D000483:Alleles; D001324:Autoantigens / Q000235:genetics; D002675:Child, Preschool; D002871:Chromosome Banding; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D041321:Chromosomes, Human, X / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D005838:Genotype; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D017411:Ribonucleoproteins, Small Nuclear / Q000235:genetics; D014178:Translocation, Genetic; D014314:Trisomy; D055517:snRNP Core Proteins
D001324:Autoantigens; D017411:Ribonucleoproteins, Small Nuclear; C526417:SNRPN protein, human; D055517:snRNP Core Proteins