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Preferential Paternal Origin of Microdeletions Caused by Prezygotic Chromosome or Chromatid Rearrangements in Sotos Syndrome

2003; Elsevier BV; Volume: 72; Issue: 5 Linguagem: Inglês

10.1086/375166

1537-6605

Noriko Miyake, Naohiro Kurotaki, Hirobumi Sugawara, Osamu Shimokawa, Naoki Harada, Tatsuro Kondoh, Masato Tsukahara, Satoshi Ishikiriyama, Tohru Sonoda, Yoko Miyoshi, Satoru Sakazume, Yoshimitsu Fukushima, Hirofumi Ohashi, Toshiro Nagai, Hiroshi Kawame, Kenji Kurosawa, Mayumi Touyama, Takashi Shiihara, Nobuhiko Okamoto, Junji Nishimoto, Ko‐ichiro Yoshiura, Tohru Ohta, Tatsuya Kishino, Norio Niikawa, Naomichi Matsumoto,

Wnt/β-catenin signaling in development and cancer

Sotos syndrome (SoS) is characterized by pre- and postnatal overgrowth with advanced bone age; a dysmorphic face with macrocephaly and pointed chin; large hands and feet; mental retardation; and possible susceptibility to tumors. It has been shown that the major cause of SoS is haploinsufficiency of the NSD1 gene at 5q35, because the majority of patients had either a common microdeletion including NSD1 or a truncated type of point mutation in NSD1. In the present study, we traced the parental origin of the microdeletions in 26 patients with SoS by the use of 16 microsatellite markers at or flanking the commonly deleted region. Deletions in 18 of the 20 informative cases occurred in the paternally derived chromosome 5, whereas those in the maternally derived chromosome were found in only two cases. Haplotyping analysis of the marker loci revealed that the paternal deletion in five of seven informative cases and the maternal deletion in one case arose through an intrachromosomal rearrangement, and two other cases of the paternal deletion involved an interchromosomal event, suggesting that the common microdeletion observed in SoS did not occur through a uniform mechanism but preferentially arose prezygotically. Sotos syndrome (SoS) is characterized by pre- and postnatal overgrowth with advanced bone age; a dysmorphic face with macrocephaly and pointed chin; large hands and feet; mental retardation; and possible susceptibility to tumors. It has been shown that the major cause of SoS is haploinsufficiency of the NSD1 gene at 5q35, because the majority of patients had either a common microdeletion including NSD1 or a truncated type of point mutation in NSD1. In the present study, we traced the parental origin of the microdeletions in 26 patients with SoS by the use of 16 microsatellite markers at or flanking the commonly deleted region. Deletions in 18 of the 20 informative cases occurred in the paternally derived chromosome 5, whereas those in the maternally derived chromosome were found in only two cases. Haplotyping analysis of the marker loci revealed that the paternal deletion in five of seven informative cases and the maternal deletion in one case arose through an intrachromosomal rearrangement, and two other cases of the paternal deletion involved an interchromosomal event, suggesting that the common microdeletion observed in SoS did not occur through a uniform mechanism but preferentially arose prezygotically. Sotos syndrome (SoS [MIM 117550]), cerebral gigantism, is an overgrowth syndrome characterized by generalized overgrowth with advanced bone age, macrocephaly, frontal bossing, prominent jaw, high hairline, down-slanting palpebral fissures, mental retardation, and possible susceptibility to tumors. We have shown that haploinsufficiency of the NSD1 gene at 5q35 is the major cause of SoS. Two-thirds of Japanese patients with SoS had a common deletion involving the whole NSD1 gene (Kurotaki et al. Kurotaki et al., 2002Kurotaki N Imaizumi K Harada N Masuno M Kondoh T Nagai T Ohashi H Naritomi K Tsukahara M Makita Y Sugimoto T Sonoda T Hasegawa T Chinen Y Tomita H-A Kinoshita A Mizuguchi T Yoshiura K Ohta T Kishino T Fukushima Y Niikawa N Matsumoto N Haploinsufficiency of NSD1 causes Sotos syndrome.Nat Genet. 2002; 30: 365-366Crossref PubMed Scopus (420) Google Scholar), and a subset of patients had truncate type of NSD1 point mutations. Such frequent, common deletions are seen in many genomic disorders and may occur by low copy repeat (LCR)–mediated chromosomal rearrangements (Shaffer and Lupski Shaffer and Lupski, 2000Shaffer LG Lupski JR Molecular mechanisms for constitutional chromosomal rearrangements in humans.Annu Rev Genet. 2000; 34: 297-329Crossref PubMed Scopus (277) Google Scholar). Recently, another group reported a high rate of NSD1 point mutations but a low rate of microdeletions in patients with SoS (Douglas et al. Douglas et al., 2003Douglas J Hanks S Temple IK Davies S Murray A Upadhyaya M Tomkins S Hughes HE Cole TRP Rahman N NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of Weaver syndrome but are rare in other overgrowth phenotypes.Am J Hum Genet. 2003; 72: 132-143Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar). This difference in deletion frequency needs further investigation. We observed phenotypic differences between patients with SoS with microdeletions and those with point mutations (Nagai et al. Nagai et al., 2003Nagai T Matsumoto N Kurotaki N Harada N Niikawa N Ogata T Imaizumi K Kurosawa K Kondoh T Ohashi H Tsukahara M Makita Y Sugimoto T Sonoda T Yokoyama T Uetake K Sakazune S Fukushima Y Naritomi K Sotos syndrome and haploinsufficiency of NSD1: clinical features of intragenic mutations and submicroscopic deletions.J Med Genet. 2003; 40: 285-289Crossref PubMed Scopus (77) Google Scholar). Dysmorphic craniofacial abnormalities, overgrowth, and mental retardation were present in both types of patients, whereas major anomalies in the central nervous, cardiovascular, and urinary systems were predominantly exhibited by patients with the deletion. These different phenotypes could mainly be due to deletion of other genes in addition to NSD1. To unravel the underlying mechanisms for the common deletion, such as the parental origin and the type of chromosome/chromatid rearrangements, we performed genotype and haplotype analyses of polymorphic marker loci in 26 families with 26 patients with sporadic SoS, 7 of whom were reported elsewhere (Kurotaki et al. Kurotaki et al., 2002Kurotaki N Imaizumi K Harada N Masuno M Kondoh T Nagai T Ohashi H Naritomi K Tsukahara M Makita Y Sugimoto T Sonoda T Hasegawa T Chinen Y Tomita H-A Kinoshita A Mizuguchi T Yoshiura K Ohta T Kishino T Fukushima Y Niikawa N Matsumoto N Haploinsufficiency of NSD1 causes Sotos syndrome.Nat Genet. 2002; 30: 365-366Crossref PubMed Scopus (420) Google Scholar). All 26 subjects (see fig. 1) in this study were referred to us after a possible diagnosis of SoS was made and written informed consent forms were obtained from their parents. Three main symptoms, such as craniofacial dysmorphology, mental retardation, and a history of overgrowth, were basically observed in all the patients, but the diagnostic criteria might not be consistent. Advanced bone age that could be one diagnostic symptom, as suggested by Cole and Hughes (Cole and Hughes, 1994Cole TRP Hughes HE Sotos syndrome: a study of the diagnostic criteria and natural history.J Med Genet. 1994; 31: 20-32Crossref PubMed Scopus (200) Google Scholar), was not evaluated, because sufficient data were not available. DNA samples and chromosome preparations from patients and both of their parents were available in 21 families. In the other five families, the samples were available in only patients and their mothers. Experimental protocols were approved by the Committee for the Ethical Issues on Human Genome and Gene Analysis, Nagasaki University. Microdeletions of all 26 patients with SoS were confirmed by FISH analysis (fig. 1). Six BAC/PAC clones (CTC-355H11, RP11-1006E8, RP11-606E24, RP1-118M12, RP11-147K7, and RP11-158F10) were selected for FISH probes, according to the UCSC genome browser. Cloned DNA was labeled with SpectrumGreen-11-dUTP or SpectrumOrange-11-dUTP (Vysis) by nick translation and denatured at 76°C for 10 min. Probe-hybridization mixtures (10 μl) were applied on the chromosomes, were incubated at 37°C for 16 h, and then were washed. Fluorescence photomicroscopy was performed under a Zeiss Axioskop microscope equipped with a quad filter set with single band excitation filters (84000, Chroma Technology). Images were collected and merged using a cooled CCD camera (TEA/CCD-1317-G1, Princeton Instruments) and IPLab/MAC software (Scanalytics). RP11-606E24 and RP1-118M12 involving NSD1 were deleted in all cases. RP11-1006E8 was deleted in all but three cases (SS19, SS44, and SS109). RP11-147K7 is not deleted in SS44 but is deleted in others. Thus, 23 patients had the same deletion spanning a region at least from RP11-1006E8 to RP11-147K7 (fig. 1). The size of the common deletion was originally reported as 2.2 Mb, but it turned out to range from 1.3 Mb to 2.7 Mb, according to the most current UCSC database (November 2002). A de novo microdeletion in 21 individuals and normal karyotypes in both of their respective parents were confirmed by FISH. Mothers of the remaining five patients also showed a normal FISH karyotype. To trace the parental origin of the deletion in the 26 families, we carried out PCR-based microsatellite analysis using four markers (STS02 [GenBank accession number BV005166], STS03 [GenBank accession number BV005165], STS04 [GenBank accession number BV005168], and STS06 [GenBank accession number BV005167]) that were newly generated from BAC clones mapped to the common deletion (figs. 1 and 2) and that showed high heterozygosity among 10 normal Japanese control individuals. Twelve other markers included D5S2111 within the common deleted region, and D5S436, D5S410, D5S422, D5S400, D5S429, D5S677, D5S2008, D5S2073, D5S1354, D5S408, and D5S2006, which flank the deletion, were also used (fig. 2). PCR amplification was performed in a 20−μl PCR mixture containing 50 ng genomic DNA, 10 pM of each fluorescent primer and reverse primer, 250 μM dNTP, 0.5 U Ex Taq polymerase (Takara), and 10× PCR buffer (Takara). PCR was cycled 40 times at 98°C for 10 s, 55–60°C for 30 s, and 72°C for 30 s. PCR products were electrophoresed in ABI PRISM 377 automated sequencer (PE Applied Biosystems) and analyzed with fragment analysis software (PE Applied Biosystems). As a result, 20 of the 26 families were informative for the parent-of-origin (fig. 1). In 18 of the 20 families, microdeletions had occurred in the paternally derived chromosome 5, whereas the occurrence of deletions in the maternally derived chromosome was confirmed in only two informative cases. In addition, all the patients from the other five families in which only the maternal DNA was available retained the maternally derived alleles at the marker loci examined; therefore, the finding supports the paternal origin of their microdeletions. We then genotyped six 3-generation families and two 2-generation families with an unaffected sib. Haplotype analysis disclosed the type of chromosome/chromatid rearrangements in the patients. Five instances of paternal deletion and an instance of maternal deletion had intrachromosomal type of rearrangements, whereas rearrangements in the other two instances of paternal deletion were interchromosomal type (fig. 2). Occurrence of double recombination between the two closest markers flanking the microdeletion is very unlikely, because the genetic distance between them is only 7.8 (D5S677–D5S2008) to 15.8 cM (D5S429–D5S2073). Therefore, it is reasonable that the rearrangements in the former six subjects are interpreted to be intrachromosomal (fig. 2). The absence of somatic mosaicism was confirmed in 100 mitotic cells by FISH in each of these eight subjects. Parental origin of microdeletions and/or duplications have been investigated in several genomic disorders. Deletions in Williams syndrome (WS) at 7q11.23 and velocardiofacial syndrome (VCFS) at 22q11.2 were of equally paternal and maternal origin (Nickerson et al. Nickerson et al., 1995Nickerson E Greenberg F Keating MT McCaskill C Shaffer LG Deletions of the elastin gene at 7q11.23 occur in ∼90% of patients with Williams syndrome.Am J Hum Genet. 1995; 56: 1156-1161PubMed Google Scholar; Dutly and Schinzel Dutly and Schinzel, 1996Dutly F Schinzel A Unequal interchromosomal rearrangements may result in elastin gene deletions causing the Williams-Beuren syndrome.Hum Mol Genet. 1996; 5: 1893-1898Crossref PubMed Scopus (85) Google Scholar; Urban et al. Urban et al., 1996Urban Z Helms C Fekete G Csiszar K Bonnet D Munnich A Donis-Keller H Boyd CD 7q11.23 deletions in Williams syndrome arise as a consequence of unequal meiotic crossover.Am J Hum Genet. 1996; 59: 958-962PubMed Google Scholar; Baumer et al. Baumer et al., 1998Baumer A Dutly F Balmer D Riegel M Tukel T Krajewska-Walasek M Schinzel AA High level of unequal meiotic crossovers at the origin of the 22q11.2 and 7q11.23 deletions.Hum Mol Genet. 1998; 7: 887-894Crossref PubMed Scopus (101) Google Scholar). Deletions at 17p11.2 in Smith-Magenis syndrome (SMS) and their reciprocal chromosomal events, duplications of 17p11.2, tended to occur more frequently in the paternally derived chromosomes than the maternally derived chromosomes, but a significant parent-of-origin bias was not observed (Shaw et al. Shaw et al., 2002Shaw CJ Bi W Lupski JR Genetic proof of unequal meiotic crossovers in reciprocal deletion and duplication of 17p11.2.Am J Hum Genet. 2002; 71: 1072-1081Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar). Instead, duplications in Charcot-Marie-Tooth disease type 1A (CMT1A) at 17p11.2–p12 (Palau et al. Palau et al., 1993Palau F Lofgren A De Jonghe P Bort S Nelis E Sevilla T Martin JJ Vilchez J Prieto F Van Broeckhoven C Origin of the de novo duplication in Charcot-Marie-Tooth disease type 1A: unequal nonsister chromatid exchange during spermatogenesis.Hum Mol Genet. 1993; 2: 2031-2035Crossref PubMed Scopus (108) Google Scholar; Bort et al. Bort et al., 1997Bort S Martinez F Palau F Prevalence and parental origin of de novo 1.5-Mb duplication in Charcot-Marie-Tooth disease type 1A.Am J Hum Genet. 1997; 60: 230-233PubMed Google Scholar; Lopes et al. Lopes et al., 1997Lopes J Vandenberghe A Tardieu S Ionasescu V Levy N Wood N Tachi N Bouche P Latour P Brice A LeGuern E Sex-dependent rearrangements resulting in CMT1A and HNPP.Nat Genet. 1997; 17: 136-137Crossref PubMed Scopus (49) Google Scholar) were of preferential paternal origin. In contrast, microdeletions in neurofibromatosis type 1 (NF1) at 17q11.2 were of predominantly maternal origin (Lazaro et al. Lazaro et al., 1996Lazaro C Gaona A Ainsworth P Tenconi R Vidaud D Kruyer H Ars E Volpini V Estivill X Sex differences in mutational rate and mutational mechanism in the NF1 gene in neurofibromatosis type 1 patients.Hum Genet. 1996; 98: 696-699Crossref PubMed Scopus (78) Google Scholar; López Correa et al. López Correa et al., 2000López Correa C Brems H Lázaro C Marynen P Legius E Unequal meiotic crossover: a frequent cause of NF1 microdeletions.Am J Hum Genet. 2000; 66: 1969-1974Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar). A 15q11–q13 deletion occurring in the paternally and the maternally derived chromosome results in Prader-Willi (PWS) and Angelman (AS) syndromes, respectively, because of the imprinting effect at the chromosomal region. Furthermore, some terminal deletion syndromes also showed biased parental origin. Deletions in Wolf-Hirschhorn syndrome (WHS) at 4p16.3 (Quarrell et al. Quarrell et al., 1991Quarrell OWJ Snell RG Curtis MA Roberts SH Harper PS Shaw DJ Paternal origin of the chromosomal deletion resulting in Wolf-Hirschhorn syndrome.J Med Genet. 1991; 28: 256-259Crossref PubMed Scopus (29) Google Scholar; Tupler et al. Tupler et al., 1992Tupler R Bortotto L Butler EM Alkan M Malik NJ Bosch-Al Jadooa N Memo L Maraschio P Paternal origin of the de novo deleted chromosome 4 in Wolf-Hirschhorn syndrome.J Med Genet. 1992; 29: 53-55Crossref PubMed Scopus (28) Google Scholar; Wieczorek et al. Wieczorek et al., 2000Wieczorek D Krause M Majewski F Albrecht B Horn D Riess O Gillessen-Kaesbach G Effect of the size of the deletion and clinical manifestation in Wolf-Hirschhorn syndrome: analysis of 13 patients with a de novo deletion.Eur J Hum Genet. 2000; 8: 519-526Crossref PubMed Scopus (86) Google Scholar) and cri du chat syndrome (CCS) at 5p15.3 (Mainardi et al. Mainardi et al., 2001Mainardi PC Perfumo C Cali A Coucourde G Pastore G Cavani S Zara F Overhauser J Pierluigi M Bricarelli FD Clinical and molecular characterisation of 80 patients with 5p deletion: genotype-phenotype correlation.J Med Genet. 2001; 38: 151-158Crossref PubMed Scopus (146) Google Scholar) are of preferential paternal origin, and the 1p36 deletion syndrome showed predominant maternal deletions (Wu et al. Wu et al., 1999Wu Y-Q Heilstedt HA Bedell JA May KM Starkey DE McPherson JD Shapira SK Shaffer LG Molecular refinement of the 1p36 deletion syndrome reveals size diversity and a preponderance of maternally derived deletions.Hum Mol Genet. 1999; 8: 313-321Crossref PubMed Scopus (85) Google Scholar). Mechanisms resulting in terminal deletions may be different from those in interstitial deletions in genomic disorders. Preferential paternal origin of microdeletions in our patients with SoS may be explained by either (1) the influence of the parental origin of microdeletions on the SoS phenotype or (2) more susceptibility of a region at or around the microdeletion on the paternally derived chromosomes to abnormal chromosomal rearrangements than that on the maternally derived chromosome. Since the two patients with the maternal deletion had typical clinical manifestations for the syndrome, and no imprinted genes have been identified in the region (Brzustowicz et al. Brzustowicz et al., 1994Brzustowicz LM Allitto BA Matseoane D Theve R Michaud L Chatkupt S Sugarman E Penchaszadeh GK Suslak L Koenigsberger MR Gilliaam TC Handelin BL Paternal isodisomy for chromosome 5 in a child with spinal muscular atrophy.Am J Hum Genet. 1994; 54: 482-488PubMed Google Scholar; Ledbetter and Engel Ledbetter and Engel, 1995Ledbetter DH Engel E Uniparental disomy in humans: development of an imprinting map and its implications for prenatal diagnosis.Hum Mol Genet. 1995; 4: 1757-1764PubMed Google Scholar; Morison and Reeve Morison and Reeve, 1998Morison IM Reeve AE A catalogue of imprinted genes and parent-of-origin effects in humans and animals.Hum Mol Genet. 1998; 7: 1599-1609Crossref PubMed Scopus (208) Google Scholar), the first possibility is unlikely. We favor the second hypothesis. Predominant paternal origin of de novo point mutations as well as of de novo structural chromosome abnormalities has repeatedly been reported (Chandley Chandley, 1991Chandley AC On the parental origin of de novo mutation in man.J Med Genet. 1991; 28: 217-223Crossref PubMed Scopus (103) Google Scholar; Moloney et al. Moloney et al., 1996Moloney DM Slaney SF Oldridge M Wall SA Sahlin P Stenman G Wilkie AO Exclusive paternal origin of new mutations in Apert syndrome.Nat Genet. 1996; 13: 48-53Crossref PubMed Scopus (240) Google Scholar; Wirth et al. Wirth et al., 1997Wirth B Schmidt T Hahnen E Rudnik-Schöneborn S Krawczak M Müller-Myhsok B Schönling J Zerres K De novo rearrangements found in 2% of index patients with spinal muscular atrophy: mutational mechanisms, parental origin, mutation rate, and implications for genetic counseling.Am J Hum Genet. 1997; 61: 1102-1111Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar). Most of such de novo mutations may arise at spermatogenesis, and paternal age effect has been documented in many diseases (Wirth et al. Wirth et al., 1997Wirth B Schmidt T Hahnen E Rudnik-Schöneborn S Krawczak M Müller-Myhsok B Schönling J Zerres K De novo rearrangements found in 2% of index patients with spinal muscular atrophy: mutational mechanisms, parental origin, mutation rate, and implications for genetic counseling.Am J Hum Genet. 1997; 61: 1102-1111Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar). The average paternal age in our patients with paternal deletions is 32.3 years (range 27–43 years), not significantly deviating from 31.8 years for the general Japanese population (Web site of Ministry of Health, Labor and Welfare of Japan). Chromosomal rearrangements mediated by possible LCR may not be affected by paternal age. There have been several studies on the type of chromosomal rearrangements. In WS, VCFS, CMT1A, and NF1, most deletions/duplications were associated with interchromosomal rearrangements (Urban et al. Urban et al., 1996Urban Z Helms C Fekete G Csiszar K Bonnet D Munnich A Donis-Keller H Boyd CD 7q11.23 deletions in Williams syndrome arise as a consequence of unequal meiotic crossover.Am J Hum Genet. 1996; 59: 958-962PubMed Google Scholar; Lopes et al. Lopes et al., 1997Lopes J Vandenberghe A Tardieu S Ionasescu V Levy N Wood N Tachi N Bouche P Latour P Brice A LeGuern E Sex-dependent rearrangements resulting in CMT1A and HNPP.Nat Genet. 1997; 17: 136-137Crossref PubMed Scopus (49) Google Scholar; Baumer et al. Baumer et al., 1998Baumer A Dutly F Balmer D Riegel M Tukel T Krajewska-Walasek M Schinzel AA High level of unequal meiotic crossovers at the origin of the 22q11.2 and 7q11.23 deletions.Hum Mol Genet. 1998; 7: 887-894Crossref PubMed Scopus (101) Google Scholar; López Correa et al. López Correa et al., 2000López Correa C Brems H Lázaro C Marynen P Legius E Unequal meiotic crossover: a frequent cause of NF1 microdeletions.Am J Hum Genet. 2000; 66: 1969-1974Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar). Deletions and duplications of 17p11.2 in SMS were caused by either intra- or interchromosomal events (Potocki et al. Potocki et al., 2000Potocki L Chen KS Park SS Osterholm DE Withers MA Kimonis V Summers AM Meschino WS Anyane-Yeboa K Kashork CD Shaffer LG Lupski JR Molecular mechanism for duplication 17p11.2- the homologous recombination reciprocal of the Smith-Magenis microdeletion.Nat Genet. 2000; 24: 84-87Crossref PubMed Scopus (249) Google Scholar; Shaw et al. Shaw et al., 2002Shaw CJ Bi W Lupski JR Genetic proof of unequal meiotic crossovers in reciprocal deletion and duplication of 17p11.2.Am J Hum Genet. 2002; 71: 1072-1081Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar) and by deletions in PWS, as well (Carrozzo et al. Carrozzo et al., 1997Carrozzo R Rossi E Christian SL Kittikamron K Livieri C Corrias A Pucci L Fois A Simi P Bosio L Beccaria L Zuffardi O Ledbetter DH Inter- and intrachromosomal rearrangements are both involved in the origin of 15q11-q13 deletions in Prader-Willi syndrome.Am J Hum Genet. 1997; 61: 228-231Abstract Full Text PDF PubMed Scopus (53) Google Scholar; Robinson et al. Robinson et al., 1998Robinson WP Dutly F Nicholls RD Bernasconi F Penaherrera M Michaelis RC Abeliovich D Schinzel AA The mechanisms involved in formation of deletions and duplications of 15q11–q13.J Med Genet. 1998; 35: 130-136Crossref PubMed Google Scholar). It is most likely that interchromosomal rearrangements arise by an unequal crossing-over at the meiosis I through paralogous LCRs between homologous chromosomes. However, intrachromosomal type of rearrangements may occur by an LCR mispairing–mediated unequal sister-chromatid exchange. Alternatively, the rearrangements arise through the formation of an intrachromosomal loop that is also mediated by LCRs within a chromatid. Although both events may occur in a somatic cell, and possibly in a spermatogonial cell (Lopes et al. Lopes et al., 1997Lopes J Vandenberghe A Tardieu S Ionasescu V Levy N Wood N Tachi N Bouche P Latour P Brice A LeGuern E Sex-dependent rearrangements resulting in CMT1A and HNPP.Nat Genet. 1997; 17: 136-137Crossref PubMed Scopus (49) Google Scholar), its occurrence during meiosis remains unknown. Since somatic mosaicism for deletion was never observed in our patients with SoS, the postzygotic occurrence of the intrachromosomal rearrangements is unlikely, and thus all these abnormalities in our series of patients may have arisen at a prezygotic period. An interesting correlation between the parental origin and the type of deletion/duplication has been recognized (Lopes et al. Lopes et al., 1997Lopes J Vandenberghe A Tardieu S Ionasescu V Levy N Wood N Tachi N Bouche P Latour P Brice A LeGuern E Sex-dependent rearrangements resulting in CMT1A and HNPP.Nat Genet. 1997; 17: 136-137Crossref PubMed Scopus (49) Google Scholar). Paternal duplications in CMT1A are always associated with interchromosomal rearrangements, whereas maternal duplications/deletions, both in CMT1A and in hereditary neuropathy with liability to pressure palsies, are associated with intrachromosomal rearrangements. Thus, the mechanism for such rearrangements occurring in females and males may be different in these diseases. However, this is not the case for SoS, since both events were observed in our series of patients. In conclusion, we observed that microdeletions in SoS are mostly of paternal origin, and intra- or interchromosomal rearrangements are both involved in the microdeletion. A physical map construction that covers the common deleted region and its flanking regions is now in progress. It remains to be seen whether LCRs or other repetitive sequences present in the 5q35 region mediate the deletion. The authors are greatly indebted to the patients and their parents. We also thank Keiichi Ozono and Kouji Inui at Department of Developmental Medicine (Pediatrics), Osaka University Graduate School of Medicine, Suita, Japan, for recruiting their patients; and Ms. Yasuko Noguchi, Kazumi Miyazaki, Naoko Takaki, and Naoko Yanai, for their technical assistance. This work was supported by a grant from the Core Research for Evolutional Science and Technology unit of the Japan Science and Technology Corporation.