SUPERNUMERARI MARKER 15 CROMOSOME IN A PATIENT WITH PRADER WILLI SINDROME

D. BORELINA, ; S. ESPERANTE, ; V. GUTNITSKY, ; V. FERREIRO,; F. GILIBERTO,; M. FERRER, ; G. FRETCHEL, ; L. FRANCIPANE,; I. SZIJAN.

CLINICAL GENETICS

WILEY-BLACKWELL PUBLISHING, INC

Año: 2004 vol. 65 p. 242 - 243

0009-9163

The supernumerary marker 15 chromosome (SMC 15) represents 50% of the marker chromosomes. While some include euchromatin (bands q11–q13) and are linked to severe mental retardation, others without euchromatin associate with a normal phenotype in most cases but rarely with Prader–Willi syndrome (PWS) (1). This is a neurobehavioral disorder due to developmental impairment. PWS results from the loss of expression of imprinted genes in the paternal chromosome 15q11-q13, through several mechanisms such as deletions or uniparental disomy (UPD) (2). Herein, we studied a 13-year-old girl with a characteristic PWS phenotype and a small SMC(15). She was one of two dizygotic twins, underwent a severe neonatal hypotonia followed by hyperphagia, obesity, hypogonadism, and mental retardation, and hypopigmentation was absent. One distinctive feature was an early-onset type 1 diabetes. Cytogenetic results showed 47,XX,þmar, the karyotypes of her parents and the healthy twin being normal thus indicating a de novo origin of the SMC(15). It was monocentric and monosatellited by GTG (Trypsin-Giemsa staining) and Ag/NOR stainings (Fig. 1a). Fluorescence in situ hybridization (FISH) analysis revealed the 15 alpha satellite (D15Z1) signal; neither the probes for SNRPN or D15S10 nor that for PML polymorphisms (15q22) showed any signal on this SMC(15) (Fig. 1b). Thus, the karyotype was 47,XX,þdel(15)(q11.2).ish del(15)(D15Z1þ, SNRPN–, D15S10–, PML–). The methylation test for PWS showed an abnormal SNRPN pattern with no paternal contribution. A family study using DNA polymorphism find a heterozygosity at the PWS/AS locus (A55AC-1) (3) in the patient with two different maternal and no paternal allele (Fig. 1c). These results are consistent with a maternal heterodisomy. The heterozygosity for maternal alleles at a locus close to the centromere suggests that the non-disjunction is a meiosis I error with a 90% likelihood (4). The de novo SMC(15) carried by this patient should therefore be of paternal origin and could arise through a chromosomal rearrangement (deletion of most of the q arm), secondary to maternal chromosome 15 nondisjunction. The breakpoint location may be similar to the proximal common deletion breakpoints in PWS/AS patients (5). The occurrence of SMC(15) in PWS/AS patients was compiled by Cotter et al. (6). Most of them were de novo, inv dup(15), and lacked the PWS/AS region. Coexistence of UPD with SMC can be explained by the formation of a trisomic zygote and the subsequent loss of the single parental chromosome through a breakage event (7). The rearrangements in chromosome 15 may occur through unequal crossover between inverted repeats within proximal 15q. Deletions may occur when the recombination event is intrachromosomal and inv dup(15) chromosomes may result from interchromosomal recombination (8). The genetic alteration resulting in PWS in our patient is associated with advanced maternal age (39 years) like in other UPD reported cases (9). The presence of SMC(15) can be explained as a rescue event from a trisomic conception. The association of early-onset type 1 diabetes (confirmed by genotyping and immunotyping) and PWS is uncommon because these patients usually develop type 2 diabetes of late onset as a consequence of obesity. Both syndromes are probably due to independent causes. To sum up, FISH and microsatellite analyses of a patient with PWS revealed an SMC(15) and a maternal UPD. Data obtained enabled us to uncover one of the possible mechanisms of PWS origin.% of the marker chromosomes. While some include euchromatin (bands q11–q13) and are linked to severe mental retardation, others without euchromatin associate with a normal phenotype in most cases but rarely with Prader–Willi syndrome (PWS) (1). This is a neurobehavioral disorder due to developmental impairment. PWS results from the loss of expression of imprinted genes in the paternal chromosome 15q11-q13, through several mechanisms such as deletions or uniparental disomy (UPD) (2). Herein, we studied a 13-year-old girl with a characteristic PWS phenotype and a small SMC(15). She was one of two dizygotic twins, underwent a severe neonatal hypotonia followed by hyperphagia, obesity, hypogonadism, and mental retardation, and hypopigmentation was absent. One distinctive feature was an early-onset type 1 diabetes. Cytogenetic results showed 47,XX,þmar, the karyotypes of her parents and the healthy twin being normal thus indicating a de novo origin of the SMC(15). It was monocentric and monosatellited by GTG (Trypsin-Giemsa staining) and Ag/NOR stainings (Fig. 1a). Fluorescence in situ hybridization (FISH) analysis revealed the 15 alpha satellite (D15Z1) signal; neither the probes for SNRPN or D15S10 nor that for PML polymorphisms (15q22) showed any signal on this SMC(15) (Fig. 1b). Thus, the karyotype was 47,XX,þdel(15)(q11.2).ish del(15)(D15Z1þ, SNRPN–, D15S10–, PML–). The methylation test for PWS showed an abnormal SNRPN pattern with no paternal contribution. A family study using DNA polymorphism find a heterozygosity at the PWS/AS locus (A55AC-1) (3) in the patient with two different maternal and no paternal allele (Fig. 1c). These results are consistent with a maternal heterodisomy. The heterozygosity for maternal alleles at a locus close to the centromere suggests that the non-disjunction is a meiosis I error with a 90% likelihood (4). The de novo SMC(15) carried by this patient should therefore be of paternal origin and could arise through a chromosomal rearrangement (deletion of most of the q arm), secondary to maternal chromosome 15 nondisjunction. The breakpoint location may be similar to the proximal common deletion breakpoints in PWS/AS patients (5). The occurrence of SMC(15) in PWS/AS patients was compiled by Cotter et al. (6). Most of them were de novo, inv dup(15), and lacked the PWS/AS region. Coexistence of UPD with SMC can be explained by the formation of a trisomic zygote and the subsequent loss of the single parental chromosome through a breakage event (7). The rearrangements in chromosome 15 may occur through unequal crossover between inverted repeats within proximal 15q. Deletions may occur when the recombination event is intrachromosomal and inv dup(15) chromosomes may result from interchromosomal recombination (8). The genetic alteration resulting in PWS in our patient is associated with advanced maternal age (39 years) like in other UPD reported cases (9). The presence of SMC(15) can be explained as a rescue event from a trisomic conception. The association of early-onset type 1 diabetes (confirmed by genotyping and immunotyping) and PWS is uncommon because these patients usually develop type 2 diabetes of late onset as a consequence of obesity. Both syndromes are probably due to independent causes. To sum up, FISH and microsatellite analyses of a patient with PWS revealed an SMC(15) and a maternal UPD. Data obtained enabled us to uncover one of the possible mechanisms of PWS origin.þmar, the karyotypes of her parents and the healthy twin being normal thus indicating a de novo origin of the SMC(15). It was monocentric and monosatellited by GTG (Trypsin-Giemsa staining) and Ag/NOR stainings (Fig. 1a). Fluorescence in situ hybridization (FISH) analysis revealed the 15 alpha satellite (D15Z1) signal; neither the probes for SNRPN or D15S10 nor that for PML polymorphisms (15q22) showed any signal on this SMC(15) (Fig. 1b). Thus, the karyotype was 47,XX,þdel(15)(q11.2).ish del(15)(D15Z1þ, SNRPN–, D15S10–, PML–). The methylation test for PWS showed an abnormal SNRPN pattern with no paternal contribution. A family study using DNA polymorphism find a heterozygosity at the PWS/AS locus (A55AC-1) (3) in the patient with two different maternal and no paternal allele (Fig. 1c). These results are consistent with a maternal heterodisomy. The heterozygosity for maternal alleles at a locus close to the centromere suggests that the non-disjunction is a meiosis I error with a 90% likelihood (4). The de novo SMC(15) carried by this patient should therefore be of paternal origin and could arise through a chromosomal rearrangement (deletion of most of the q arm), secondary to maternal chromosome 15 nondisjunction. The breakpoint location may be similar to the proximal common deletion breakpoints in PWS/AS patients (5). The occurrence of SMC(15) in PWS/AS patients was compiled by Cotter et al. (6). Most of them were de novo, inv dup(15), and lacked the PWS/AS region. Coexistence of UPD with SMC can be explained by the formation of a trisomic zygote and the subsequent loss of the single parental chromosome through a breakage event (7). The rearrangements in chromosome 15 may occur through unequal crossover between inverted repeats within proximal 15q. Deletions may occur when the recombination event is intrachromosomal and inv dup(15) chromosomes may result from interchromosomal recombination (8). The genetic alteration resulting in PWS in our patient is associated with advanced maternal age (39 years) like in other UPD reported cases (9). The presence of SMC(15) can be explained as a rescue event from a trisomic conception. The association of early-onset type 1 diabetes (confirmed by genotyping and immunotyping) and PWS is uncommon because these patients usually develop type 2 diabetes of late onset as a consequence of obesity. Both syndromes are probably due to independent causes. To sum up, FISH and microsatellite analyses of a patient with PWS revealed an SMC(15) and a maternal UPD. Data obtained enabled us to uncover one of the possible mechanisms of PWS origin.de novo origin of the SMC(15). It was monocentric and monosatellited by GTG (Trypsin-Giemsa staining) and Ag/NOR stainings (Fig. 1a). Fluorescence in situ hybridization (FISH) analysis revealed the 15 alpha satellite (D15Z1) signal; neither the probes for SNRPN or D15S10 nor that for PML polymorphisms (15q22) showed any signal on this SMC(15) (Fig. 1b). Thus, the karyotype was 47,XX,þdel(15)(q11.2).ish del(15)(D15Z1þ, SNRPN–, D15S10–, PML–). The methylation test for PWS showed an abnormal SNRPN pattern with no paternal contribution. A family study using DNA polymorphism find a heterozygosity at the PWS/AS locus (A55AC-1) (3) in the patient with two different maternal and no paternal allele (Fig. 1c). These results are consistent with a maternal heterodisomy. The heterozygosity for maternal alleles at a locus close to the centromere suggests that the non-disjunction is a meiosis I error with a 90% likelihood (4). The de novo SMC(15) carried by this patient should therefore be of paternal origin and could arise through a chromosomal rearrangement (deletion of most of the q arm), secondary to maternal chromosome 15 nondisjunction. The breakpoint location may be similar to the proximal common deletion breakpoints in PWS/AS patients (5). The occurrence of SMC(15) in PWS/AS patients was compiled by Cotter et al. (6). Most of them were de novo, inv dup(15), and lacked the PWS/AS region. Coexistence of UPD with SMC can be explained by the formation of a trisomic zygote and the subsequent loss of the single parental chromosome through a breakage event (7). The rearrangements in chromosome 15 may occur through unequal crossover between inverted repeats within proximal 15q. Deletions may occur when the recombination event is intrachromosomal and inv dup(15) chromosomes may result from interchromosomal recombination (8). The genetic alteration resulting in PWS in our patient is associated with advanced maternal age (39 years) like in other UPD reported cases (9). The presence of SMC(15) can be explained as a rescue event from a trisomic conception. The association of early-onset type 1 diabetes (confirmed by genotyping and immunotyping) and PWS is uncommon because these patients usually develop type 2 diabetes of late onset as a consequence of obesity. Both syndromes are probably due to independent causes. To sum up, FISH and microsatellite analyses of a patient with PWS revealed an SMC(15) and a maternal UPD. Data obtained enabled us to uncover one of the possible mechanisms of PWS origin.in situ hybridization (FISH) analysis revealed the 15 alpha satellite (D15Z1) signal; neither the probes for SNRPN or D15S10 nor that for PML polymorphisms (15q22) showed any signal on this SMC(15) (Fig. 1b). Thus, the karyotype was 47,XX,þdel(15)(q11.2).ish del(15)(D15Z1þ, SNRPN–, D15S10–, PML–). The methylation test for PWS showed an abnormal SNRPN pattern with no paternal contribution. A family study using DNA polymorphism find a heterozygosity at the PWS/AS locus (A55AC-1) (3) in the patient with two different maternal and no paternal allele (Fig. 1c). These results are consistent with a maternal heterodisomy. The heterozygosity for maternal alleles at a locus close to the centromere suggests that the non-disjunction is a meiosis I error with a 90% likelihood (4). The de novo SMC(15) carried by this patient should therefore be of paternal origin and could arise through a chromosomal rearrangement (deletion of most of the q arm), secondary to maternal chromosome 15 nondisjunction. The breakpoint location may be similar to the proximal common deletion breakpoints in PWS/AS patients (5). The occurrence of SMC(15) in PWS/AS patients was compiled by Cotter et al. (6). Most of them were de novo, inv dup(15), and lacked the PWS/AS region. Coexistence of UPD with SMC can be explained by the formation of a trisomic zygote and the subsequent loss of the single parental chromosome through a breakage event (7). The rearrangements in chromosome 15 may occur through unequal crossover between inverted repeats within proximal 15q. Deletions may occur when the recombination event is intrachromosomal and inv dup(15) chromosomes may result from interchromosomal recombination (8). The genetic alteration resulting in PWS in our patient is associated with advanced maternal age (39 years) like in other UPD reported cases (9). The presence of SMC(15) can be explained as a rescue event from a trisomic conception. The association of early-onset type 1 diabetes (confirmed by genotyping and immunotyping) and PWS is uncommon because these patients usually develop type 2 diabetes of late onset as a consequence of obesity. Both syndromes are probably due to independent causes. To sum up, FISH and microsatellite analyses of a patient with PWS revealed an SMC(15) and a maternal UPD. Data obtained enabled us to uncover one of the possible mechanisms of PWS origin.þdel(15)(q11.2).ish del(15)(D15Z1þ, SNRPN–, D15S10–, PML–). The methylation test for PWS showed an abnormal SNRPN pattern with no paternal contribution. A family study using DNA polymorphism find a heterozygosity at the PWS/AS locus (A55AC-1) (3) in the patient with two different maternal and no paternal allele (Fig. 1c). These results are consistent with a maternal heterodisomy. The heterozygosity for maternal alleles at a locus close to the centromere suggests that the non-disjunction is a meiosis I error with a 90% likelihood (4). The de novo SMC(15) carried by this patient should therefore be of paternal origin and could arise through a chromosomal rearrangement (deletion of most of the q arm), secondary to maternal chromosome 15 nondisjunction. The breakpoint location may be similar to the proximal common deletion breakpoints in PWS/AS patients (5). The occurrence of SMC(15) in PWS/AS patients was compiled by Cotter et al. (6). Most of them were de novo, inv dup(15), and lacked the PWS/AS region. Coexistence of UPD with SMC can be explained by the formation of a trisomic zygote and the subsequent loss of the single parental chromosome through a breakage event (7). The rearrangements in chromosome 15 may occur through unequal crossover between inverted repeats within proximal 15q. Deletions may occur when the recombination event is intrachromosomal and inv dup(15) chromosomes may result from interchromosomal recombination (8). The genetic alteration resulting in PWS in our patient is associated with advanced maternal age (39 years) like in other UPD reported cases (9). The presence of SMC(15) can be explained as a rescue event from a trisomic conception. The association of early-onset type 1 diabetes (confirmed by genotyping and immunotyping) and PWS is uncommon because these patients usually develop type 2 diabetes of late onset as a consequence of obesity. Both syndromes are probably due to independent causes. To sum up, FISH and microsatellite analyses of a patient with PWS revealed an SMC(15) and a maternal UPD. Data obtained enabled us to uncover one of the possible mechanisms of PWS origin.þ, SNRPN–, D15S10–, PML–). The methylation test for PWS showed an abnormal SNRPN pattern with no paternal contribution. A family study using DNA polymorphism find a heterozygosity at the PWS/AS locus (A55AC-1) (3) in the patient with two different maternal and no paternal allele (Fig. 1c). These results are consistent with a maternal heterodisomy. The heterozygosity for maternal alleles at a locus close to the centromere suggests that the non-disjunction is a meiosis I error with a 90% likelihood (4). The de novo SMC(15) carried by this patient should therefore be of paternal origin and could arise through a chromosomal rearrangement (deletion of most of the q arm), secondary to maternal chromosome 15 nondisjunction. The breakpoint location may be similar to the proximal common deletion breakpoints in PWS/AS patients (5). The occurrence of SMC(15) in PWS/AS patients was compiled by Cotter et al. (6). Most of them were de novo, inv dup(15), and lacked the PWS/AS region. Coexistence of UPD with SMC can be explained by the formation of a trisomic zygote and the subsequent loss of the single parental chromosome through a breakage event (7). The rearrangements in chromosome 15 may occur through unequal crossover between inverted repeats within proximal 15q. Deletions may occur when the recombination event is intrachromosomal and inv dup(15) chromosomes may result from interchromosomal recombination (8). The genetic alteration resulting in PWS in our patient is associated with advanced maternal age (39 years) like in other UPD reported cases (9). The presence of SMC(15) can be explained as a rescue event from a trisomic conception. The association of early-onset type 1 diabetes (confirmed by genotyping and immunotyping) and PWS is uncommon because these patients usually develop type 2 diabetes of late onset as a consequence of obesity. Both syndromes are probably due to independent causes. To sum up, FISH and microsatellite analyses of a patient with PWS revealed an SMC(15) and a maternal UPD. Data obtained enabled us to uncover one of the possible mechanisms of PWS origin.% likelihood (4). The de novo SMC(15) carried by this patient should therefore be of paternal origin and could arise through a chromosomal rearrangement (deletion of most of the q arm), secondary to maternal chromosome 15 nondisjunction. The breakpoint location may be similar to the proximal common deletion breakpoints in PWS/AS patients (5). The occurrence of SMC(15) in PWS/AS patients was compiled by Cotter et al. (6). Most of them were de novo, inv dup(15), and lacked the PWS/AS region. Coexistence of UPD with SMC can be explained by the formation of a trisomic zygote and the subsequent loss of the single parental chromosome through a breakage event (7). The rearrangements in chromosome 15 may occur through unequal crossover between inverted repeats within proximal 15q. Deletions may occur when the recombination event is intrachromosomal and inv dup(15) chromosomes may result from interchromosomal recombination (8). The genetic alteration resulting in PWS in our patient is associated with advanced maternal age (39 years) like in other UPD reported cases (9). The presence of SMC(15) can be explained as a rescue event from a trisomic conception. The association of early-onset type 1 diabetes (confirmed by genotyping and immunotyping) and PWS is uncommon because these patients usually develop type 2 diabetes of late onset as a consequence of obesity. Both syndromes are probably due to independent causes. To sum up, FISH and microsatellite analyses of a patient with PWS revealed an SMC(15) and a maternal UPD. Data obtained enabled us to uncover one of the possible mechanisms of PWS origin.de novo, inv dup(15), and lacked the PWS/AS region. Coexistence of UPD with SMC can be explained by the formation of a trisomic zygote and the subsequent loss of the single parental chromosome through a breakage event (7). The rearrangements in chromosome 15 may occur through unequal crossover between inverted repeats within proximal 15q. Deletions may occur when the recombination event is intrachromosomal and inv dup(15) chromosomes may result from interchromosomal recombination (8). The genetic alteration resulting in PWS in our patient is associated with advanced maternal age (39 years) like in other UPD reported cases (9). The presence of SMC(15) can be explained as a rescue event from a trisomic conception. The association of early-onset type 1 diabetes (confirmed by genotyping and immunotyping) and PWS is uncommon because these patients usually develop type 2 diabetes of late onset as a consequence of obesity. Both syndromes are probably due to independent causes. To sum up, FISH and microsatellite analyses of a patient with PWS revealed an SMC(15) and a maternal UPD. Data obtained enabled us to uncover one of the possible mechanisms of PWS origin.